DE1180751B - Process for the preparation of 5, 10, 11, 12-tetra-hydrodibenz- [b, g] azocine derivatives - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Boarding school Class: C07d

Number:
File number:
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German class: 12p-5

S 74667 IVd / 12 ρ

5th July 1961

5th November 1964

The invention relates to a process for the preparation of 5,10,11,12-tetrahydrodibenz [b, g] azocine derivatives the general formula

(CH ₂ ) ₃

A-Z

in Z an amino, monoalkylamino, dialkylamino, pyrrolidino, piperidino, morpholino, thiomorpholino, Piperazino, N-alkylpiperazino, N-alkylpiperidyl or N-alkylpyrrolidyl radical or radicals the general formulas

- N

C _n H _2n OR - N

C _n H _2n OR

- N

N — CmHamOR

in which R is a hydrogen atom or a lower hydroxyalkyl radical, «0, 1, 2 or 3 and m is 2 or 3, and the piperazino, N-alkylpiperazino, N-hydroxyalkylpiperazino and N-hydroxyalkoxyalkylpiperazino radicals on their ring carbon atoms optionally have one or carry several lower alkyl groups and in which A is a trivalent saturated hydrocarbon radical with 1 to 6 carbon atoms and B is a hydrogen atom or the radical Z 'or CH2Z', in which Z 'has the same meaning as Z, and their salts.

A lower alkyl radical should be understood to mean an alkyl radical with a maximum of 4 carbon atoms.

The compounds of the general formula I are prepared according to the following procedures which are known per se obtain:

a) 5,10,11,12 - tetrahydrodibenz [b, g] azocine becomes with reactive esters of the general formula

Υ —Α —Ζ

B II

in which A, B and Z have the meaning given and Y is the radical of a reactive ester, for example a halogen atom or the remainder of a process for the preparation of 5,10,11,12-tetrahydrodibenz- [b, g] azocine derivatives

Applicant:

Rhone-Poulenc SA, Paris
Representative:

Dr. F. Zumstein,

Dipl.-Chem. Dr. rer. nat. E. Assmann and Dipl.-Chem. Dr. R. Koenigsberger, Patent Attorneys, Munich 2, Bräuhausstr. 4th

Named as inventor:
Robert Michel Jacob,
Ablon, Seine, Seine-et-Oise,
Jean-Clement Louis Fouche,
Paris, France)

Claimed priority:

France of July 5, 1960 (832 058), of June 1, 1961 (863 626), dated June 2, 1961 (863 760)

Sulfuric acid or sulfonic acid esters, such as an alkyloxysulfonyloxy radical, alkanesulfonyloxy, benzenesulfonyloxy or means p-toluenesulfonyloxy radical, implemented.

The reaction can be carried out with or without a solvent and in the presence or absence of a condensing agent. It is beneficial in a solvent, e.g. B. an aromatic hydrocarbon such as toluene or xylene, a Ether, such as ethyl ether or a tertiary amide, such as dimethylformamide, and in the presence of Condensing agents, preferably alkali metals and their derivatives, such as hydrides, amides, hydroxides, Alcoholates, metal alkyls or aryls, and especially in the presence of metallic sodium or potassium, sodium amide, powdered sodium or potassium hydroxide, lithium or sodium hydride, Sodium tert-butoxide, butyllithium, phenyllithium or phenylsodium to work. Man preferably works at the boiling point of the solvent. It is particularly beneficial to have the reactive ester of the general formula II in the form of the free base in solution, for example in

409 710/402

3 4

Benzene, toluene or xylene, and to use it. The 5,10,11,12-tetra-

the 5,10,11,12-tetrahydrodibenz [b, g] azocine, the zu- hydrodibenz [b, g] azocine derivatives and their salts

at least partially already in the form of an alkali salt there is an intense antidepressant effect. the

may be present to add. The implementation can psychoses of manic-depressive origin, the endo-

also with a salt of the ester of the general 5 genes of depression and involutional depression,

Formula II can be carried out, yet in this it is the reactive depression or psychasthenic

If necessary, a larger amount of condensation or that caused by exhaustion

to use the acidity of the induced depression to speak to this psychological

applied salt to neutralize. therapeutics. In certain cases these work

b) Amines of the general formula H - Z are also used on other mental disorders, such as hysteria with compounds of the general formula and obsessions. Also stand out

the products of the process are characterized by a very good anti-emetic effectiveness.

Compared to known compounds HI 15 of the same therapeutic indication, they have a much stronger antidepressant effect with slightly improved toxicity, as in pharmacological comparative experiments on rats, e.g. B. with the 5- (3'-dimethylamino-20 2'-methylpropyl) -5,10, ll, 12-tetrahydrodibenz [b, g] -azocine prepared according to the process compared to the known antidepressant in which B 'has a hydrogen atom or the rest Y, acting 5- (3'-DimethyIaminopropyl) -iminodiben-CH ₂ Y, Z 'or CH ₂ Z' is implemented. zyl.

c) Compounds of the general formula rats which were trained to target the indigenous

25 direct stimulation by a bell of length

/ \ / (CHüh \ / \ ^{nacn e} ' ^{n lowered recntes} pipe to go through, received

/ τγ ii ί an electric shock beforehand using eye electrodes

L 1 Jl J ^{Iv of} 150 mA and 0.2 seconds duration. While

\ / ^^ N ^^ \ y a time between 30 minutes and an hour

] 30 after the electric shock they were no longer able to

QQQ a 2 to accomplish this achievement. The conditioned reflex

I does not fully recover before 6 to 12 hours have elapsed. The test consisted of intravenously administering the compound to be subjugated to the rats immediately after the electric shock by heating to a temperature between 100 and 220 ^° C., decarboxylated. This reaction is preferably carried out at a temperature between 150 and 220 ^° C. that is correct for the required temperature described above. To provide reflexes. The amount to be determined was the amount you can do without a solvent or in one of the compounds (DA50) in mg / kg, which enabled 50% of the inert diluents, such as di- 40 rats, the performance in a maximum of 10 sephenyl, diphenyl ether, a chlorinated aroma - announce to accomplish.

table hydrocarbon, or in a common for 5- (3'-dimethylamino-2'-methylpropyl) -

Diluents for decarboxylation such as 5,10,1 l, 12-tetrahydrodibenz [b, g] azocine became a

Quinoline or weak bases with increased antidepressant effectiveness DA50 in mg / kg of

Boiling point, work. 45 0.036 and a toxicity DL50 in mg / kg of 45

The bases of the general formula I are determined. The corresponding values for the 5- (3'-di-

optionally by treatment with acids in methylaminopropyl) -iminodibenzyl were 0.078

Acid addition salts transferred. As a solvent and 42.

you can use organic solvents, such as alcohols, the following examples illustrate the invention

Ethers, ketones and solvents containing chlorine, appropriate procedures,

turn around. It can also be advantageous to use water as B 's η' 1 1

To use reactants. The formed salt P

precipitates out of the solution, if necessary after mixing 6.0g of 5,10,11,12-tetrahydrodibenz [b, g] -Einengen, and is obtained by filtration or decanazocine, 50 ecm anhydrous xylene, 1.03 g sodium animals severed. 55 amide and 19.8 ecm of a xylene solution with a. Examples of addition salts are the salts with a content of 176 g of 1-dimethylamino-3-chloropropane inorganic acids, such as the hydrochloride, SuI per liter of solution.

fate. Nitrates and phosphates, or organic one is stirred and heated under reflux

Acids, such as the acetates, propionates, and succinates, a stream of nitrogen, until the ammonia development

Benzoates, Fumarates, Maleates, Theophylline Acetates, ^& o is finished (7 hours).

Salicylates, phenolphthalinates or methylene-bis- After cooling down, add 100 ecm of distilled

/ i-oxynaphthoate, called. Water too. The decanted xylene solution is used twice

The products of the process can be physically washed with 50 ecm of distilled water and then

lical methods, such as distillation, crystallization, three times with a total of 200 ecm of aqueous 2N salt

Chromatography, or by chemical methods, ⁶ 5 acid extracted. The acidic solutions are

how formation of salts, K istallization of the same, and then with 100 ecm 10 N sodium hydroxide solution

and decomposition of these salts in an alkaline medium, made alkaline. The oil that forms is with

getting cleaned. 50 ecm and then extracted with 30 ecm of ether. the

Essential solutions are collected and dried over anhydrous potassium carbonate. After this Filtering and evaporation of the ether, the oily residue obtained is dissolved in 35 ecm acetone. This solution is poured into a solution of 1.75 g of anhydrous oxalic acid in 35 ecm of acetone. It the reaction product crystallizes out. After suctioning off, washing with acetone and drying 5.8 g of acidic oxalate of 5- (3'-dimethylaminopropyl) -5,10,11,12-tetrahydro- ίο are obtained in vacuo dibenz [b, g] azocins from 146 to 147 ° C.

The 5,10,11,12-tetrahydrodibenz [b, g] azocine with a temperature of 55 to 57 ° C used as the starting substance can be obtained by heating 1,3-di- (o-aminophenyl) propane in the form of a salt (in particular of the diphosphate) to 220 to 300 ⁰ C are produced.

Example 2

Mix 4.0 g of 5,10,11,12-tetrahydrodibenz [b, g] -azocine, 30 ecm of anhydrous xylene, 0.83 g of sodium amide and 27.0 ecm of a xylene solution with a Content of 124 g of 3- (4'-methylpiperazino) -l-chloropropane per liter of solution. It is stirred and heated under reflux under a stream of nitrogen until the evolution of ammonia ceases (3 hours).

After cooling, 100 ecm of distilled water are added. The xylene solution is decanted, then washed twice with 50 ecm of distilled water and extracted three times with a total of 200 ecm of aqueous 2η hydrochloric acid. The acidic solutions are combined and then made alkaline with 100 ecm 10 N sodium hydroxide solution. The oil that forms is extracted three times with 100 ecm of ether each time. The ethereal solutions are collected and dried over anhydrous potassium carbonate. After the ether has been filtered and evaporated, the oily residue obtained is dissolved in 20 ecm of anhydrous ethanol. 8.2 ecm of a solution of dry hydrogen chloride in anhydrous ether which contains 144 g of hydrogen chloride per liter of solution is added dropwise. After cooling, the crystals are filtered off with suction and washed with 5 ecm of ethanol and then twice with 20 ecm of ether each time. After drying in vacuo, 5.9 g of 5- [3 '- (4 "-Methylpiperazino) propyl] -5,10,11,12-tetrahydrodibenz [b, g] azocine dihydrochloride with a melting point of 198 to 200 are obtained ⁰ C.

Example 3

Mix 8.36g5.10, ll, 12-tetrahydrodibenz [b, g] -azocine, 27.5 ecm of a toluene solution with a content of 177 g of l-dimethylamino-2-chloropropane each Liter of solution, 1.64 g of sodium amide and 100 ecm of anhydrous toluene.

The mixture is refluxed with stirring under a stream of dry nitrogen for 23 hours.

After cooling, 100 ecm of distilled water and then 100 ecm of ether are added. The organic phase is decanted and then washed twice with 40 ecm of distilled water each time. The aqueous solutions are combined and extracted twice with 100 ecm of ether each time. The organic solutions are collected and extracted three times with 100 ecm aqueous 2η-acetic acid each time. The acidic solutions are combined and made alkaline with 100 ecm 1 of sodium hydroxide solution. The oil formed is extracted three times with a total of 300 ecm of ether. The ethereal solutions are combined, dried over anhydrous potassium carbonate, filtered and evaporated. The oily residue (8 g) is dissolved in 15 ecm boiling ethanol. A boiling solution of 3 g of fumaric acid in 35 ecm of ethanol is then added. After cooling, the crystals are filtered off with suction, washed with 10 ecm of ice-cold ethanol and then three times with 10 ecm of ether each time and dried in vacuo. This gives 7.7 g of 5- (2'-dimethylamino-propyl) -5,10,11,12-tetrahydrodibenz [b, g] azocine fumarate, melting at 176 to 178 ⁰ C.

0.6 g of 5- [r-dimethylarmno-propyl- (2 ')] -5,10,11,12-tetrahydrodibenz [b, g] azocine fumarate with a melting point of 209 to 211 ^{0 is obtained from the crystallization solutions of this fumarate} C.

Example 4

The procedure is as described in Example 2, except that 8.36 g of 5,10,11,12-tetrahydrodibenz [b, g] -azocine are used and 18.0 ecm of a toluene solution with a content of 304 g of 1-chloro ^ -methyl-S-dimethylaminopropane per liter of solution. 11.4 g of 5- (3'-dimethylamino-2'-methyl-propyl) -5,10,11,12-tetrahydrodibenz [b, g] azocine hydrochloride are obtained, which is solvated with ethanol. M.p. 204 to 207 ° C.

Example 5

30 g of crude 5- (3'-chloro-2'-methyl-propyl) -5,10, ll, 12-tetrahydrodibenz [b, g] azocine, which is produced in a manner known per se by reacting 3-p-toluenesulfonyloxy 2-methyl-1-chloropropane with the lithium derivative of 5,10,11,12-tetrahydrodibenz [b, g] azocine is dissolved in 100 ecm of anhydrous ethanol. 73 g of diethylamine are added. The mixture is heated ^{to 100 °} C. in a pressure-tight bottle for 21 hours. The solvent is then evaporated under a weak vacuum and the oily residue is taken up in 300 ecm of distilled water and 400 ecm of ether. The ethereal phase is extracted with aqueous 2η-acetic acid (three times 200 ecm) and the entire acetic acid solution is washed with 150 ecm of ether and made alkaline with sodium hydroxide solution. The oil that forms is extracted twice with 150 ecm of ether each time. The ethereal solutions are washed with water until neutral and then dried over anhydrous potassium carbonate. After evaporation of the ether, 11.8 g of an oily reaction product are obtained, which is dissolved in 25 ecm of isopropanol. 10 ecm of a solution of anhydrous hydrogen chloride in anhydrous ether with a content of 3.6 mol of hydrogen chloride per liter of solution is added. After 4 hours of cooling at 0 ⁰ C, the crystals are filtered off with suction and then washed with 10 cc of isopropanol and 30 cc of anhydrous ether. After drying in vacuo, 10.5 g of 5- (3'-diethylamino-2'-methyl-propyl) -5,10,11,12-tetrahydrodibenz [b, g] -azocine hydrochloride with a melting point of 180 bis are obtained 183 ⁰ C.

B e i s ρ i e 1 6

15 g of crude 5- (3'-chloro-2'-methyl-propyl) -5, 10, ll, 12-tetrahydrodibenz [b, g] azocine are dissolved in 110 ecm anhydrous ethanol. The solution obtained 20.2 g of 4-hydroxypiperidine are added. The mixture is in a pressure-tight bottle for 21 hours heated at 100 ° C. After cooling down, this will be Ethanol removed under low vacuum. The oily residue is taken in distilled 300 ecm

Water and 300 ecm of ether. The ethereal phase is decanted, washed with 300 ecm of distilled water and then extracted twice with 250 ecm of aqueous 2η acetic acid each time. The acetic acid solutions are combined, washed with 150 ecm of ether and then made alkaline with sodium hydroxide solution. The oil that forms is extracted twice with 300 ecm of ether each time. The ethereal solution is dried over anhydrous potassium carbonate, filtered and evaporated. The residue amounting to 12.2 g is dissolved in 80 ecm of heptane while hot. The reaction product crystallizes out on cooling. After 15 hours of standing at 0 ⁰ C, the crystals are filtered off with suction, washed with 70 cc of heptane and then with 50 cc of petroleum ether and dried in vacuo. This gives 11.2 g of 5- [3 '- (4 "-Hydroxypiperidino) -2'-methyl-propyl] -5,10,11,12-tetrahydrodibenz [b, g] azocine, mp 78 to 80.5 ⁰ C.

Example 7

20th

21 g of crude 5- (3'-chloro-2'-methyl-propyl) -5,10,11,12-tetrahydrodibenz [b, g] azocine are in 100 ecm Dissolved ethanol. A solution of 36.4 g of 1-hydroxyethyl piperazine in 100 ecm of ethanol is then used to.

The mixture is heated in a pressure-tight bottle at 100 ^° C. for 23 hours. After cooling, the ethanol is removed under a weak vacuum. The residue is taken up in 400 ecm distilled water and 400 ecm ether. The ether phase is washed with 350 ecm of distilled water and then extracted twice with 250 ecm of aqueous 2η-acetic acid each time.

The acetic acid solutions are combined, washed with 200 ecm of ether and then made alkaline with sodium hydroxide solution. The oil formed is extracted twice with 300 ecm of ether each time. The ether solution is dried over anhydrous potassium carbonate, filtered and evaporated. The residue, amounting to 16.7 g, is dissolved in 50 ecm of isopropyl ether while hot. The reaction product crystallizes out on cooling. After 15 hours of standing at 0 ⁰ C, the crystals are filtered off with suction, washed with 25 cc of ice cold isopropyl ether and then dried in vacuo. 13.0 g of 5 - [3 '- (4 "- hydroxyethyl - piperazino) - 2' - methylpropyl] -5,10,11,12-tetrahydrodibenz [b, g] azocine with a melting point of 78.5 to 81 are obtained , 5 ° C.

Example 8

18 g of 5- (3'-chloro-2'-methyl-propyl) -5,10,11,12-tetrahydrodibenz [b, g] azocine are dissolved in 100 ecm of ethanol. A solution of 24.0 g of 1-methylpiperazine in 100 ecm of ethanol is then added. The mixture is heated in a pressure-tight bottle at 100 ^° C. for 44 hours. After cooling, the ethanol is evaporated off under a weak vacuum. The residue is taken up in 400 ecm distilled water and 350 ecm ether. The ether solution is washed with 250 ecm of water and then extracted twice with 200 ecm of aqueous 2N acetic acid each time. The acetic acid solution is washed with 200 ecm of ether and then made alkaline with sodium hydroxide solution. The oil formed is extracted twice with 200 ecm of ether each time. The ether solution obtained is washed twice with 400 ecm of distilled water each time, dried over anhydrous potassium carbonate, filtered and evaporated. The oily residue amounting to 11.7 g is dissolved in 25 ecm anhydrous ethanol. The solution is treated with 8.4 ecm of a solution of anhydrous hydrogen chloride in anhydrous ethanol containing 8 mol of hydrogen chloride per liter of solution; Then 7 ecm of anhydrous ether is added. The reaction product crystallizes out on cooling. After 15 hours of standing at 0 ⁰ C, the crystals are filtered off with suction and then washed with 15 cc of ice-cold anhydrous ethanol and 60 cc of anhydrous ether. The precipitate is dried for 32 hours at 60 ^° C. in a vacuum at 0.2 mm. The crystals are hygroscopic when dry. It is allowed to hydrate in air for 48 hours and 13.2 g of 5- [3 '- (4 "-methylpiperazino) -2'-methyl-propyl] -5,10,11,12-tetrahydrodibenz [b, g] are obtained azocine dihydrochloride, solvated with 2 moles of water from 198 to 201 ° C.

Example 9

21 g of crude 5- (3 '-chloro-2'-methyl-propyI) -5,10,11, 12-tetrahydrodibenz [b, g] azocine are dissolved in 320 ecm of a solution of 31 g of methylamine in anhydrous Dissolved ethanol. The mixture is heated to 100 ° C. in a pressure-tight bottle for 22 hours. To After cooling, the ethanol is evaporated under a weak vacuum. The residue is in 400 ecm Absorbed water and 400 ecm of ether. The ether solution is mixed with 150 ecm of distilled water washed and then extracted twice with 250 ecm of aqueous 2η-acetic acid each time. All of the acetic acid solution is washed with 100 ecm of ether and then made alkaline with sodium hydroxide solution. The educated oil is extracted twice with 150 ecm of ether each time. The ether solution is washed twice with 300 ecm of distilled water each time, over anhydrous Dried potassium carbonate, filtered and evaporated.

The 7.0 g oily residue is dissolved in 13 ecm of ethanol and treated with 7.8 ecm of an ethereal solution of anhydrous hydrogen chloride containing 3.3 mol of hydrogen chloride per liter of solution. The reaction product crystallizes out on cooling. After 15 hours of standing at 0 ⁰ C, the crystals are filtered off with suction, then washed with 10 cc of ethanol and 30 cc of ether and dried in vacuo. 7.2 g of 5- (3'-methylamino-2'-methyl-propyl) -5,10,1!, N-tetrahydrodibenzfb ^ jazocin hydrochloride with a melting point of 201 ° to 203 ° C. are obtained.

Example 10

18 g of crude 5- (3'-chloro-2'-methyl-propyl) -5,10,11,12-tetrahydrodibenz [b, g] azocine are in 100 ecm dissolved in anhydrous ethanol. A solution of 49 g of 1-hydroxyethoxyethyl piperazine is then used in 100 ecm anhydrous ethanol. The mixture is kept in a pressure-tight bottle for 23 hours 100 ° C heated. After cooling, the ethanol is evaporated off under a weak vacuum. The residue is taken up in 300 ecm distilled water and 300 ecm ether. The ethereal solution becomes Washed with 250 ecm of distilled water and then twice with 200 ecm of aqueous 2η-acetic acid extracted. The entire acetic acid solution is washed with 100 ecm of ether and then with sodium hydroxide solution made alkaline. The occurring oil will

extracted twice with 150 ecm ether each time. The ether solution is washed twice with 300 ecm of water each time, dried over anhydrous potassium carbonate, filtered and evaporated. The residue obtained of 14.4 g is dissolved in 25 ecm of isopropyl ether in the heat. The reaction product crystallizes out on cooling. After standing for 15 hours at 0 ° C., the crystals are filtered off with suction, washed with 30 ecm of ice-cold isopropyl ether and then dried in vacuo. 12.4 g of 5- [3 '- (4 "-Hydroxyethoxyethyl-piperazino) -2 ^/ -methylpropyl] -5,10,11,12-tetrahydrodibenz [b, g] azocine with a melting point of 78.5 to 80 are obtained , 5 ⁰ C.

Example 11 ^J 5

To a mixture obtained from 0.80 g of 97% sodium amide and 30 ecm of anhydrous toluene a solution of 4.18 g of 5,10,11,12-tetrahydrodibenz [b, g] azocine in 80 ecm is added with stirring anhydrous toluene and then a solution of 3.0 g of l-diethylamino-2-chloroethane in 15 ecm of anhydrous Toluene too. The mixture is stirred under a nitrogen flow for 24 hours with mechanical stirring heated to reflux. After cooling, add 150 ecm of distilled water and 200 ecm of ether to. The organic solution is decanted, washed with 150 ecm of distilled water and then extracted twice with 200 ecm of aqueous 2η-acetic acid each time.

The entire acetic acid solution is washed with 150 ecm of ether and then made alkaline with sodium hydroxide solution. The oil formed is extracted twice with 150 ecm of ether each time. The ethereal solution is washed with water until neutral, dried over anhydrous potassium carbonate and evaporated. The 3.1 g oily residue is dissolved in 10 ecm isopropanol and acidified with 3.8 ecm of an ethereal solution of anhydrous hydrogen chloride containing 3.3 mol of hydrogen chloride per liter of solution. The reaction product crystallizes out. After standing for ^{15 hours at 0} ° C., the crystals are filtered off with suction and washed with 4 ecm isopropanol and then with 15 ecm anhydrous ether. After drying in vacuo, 2.6 g of 5- (2'-diethylaminoethyl) -5,10,11,12-tetrahydrodibenz [b, g] azocine hydrochloride, melting at 176 to 178 ⁰ C.

Example 12

5.7 g of crude 5- (3'-chloropropyl) -5,10,11,12-tetrahydrodibenz [b, g] azocine, which is obtained in a manner known per se by reacting 1-p-toluenesulfonyloxy-3-chloropropane with the Lithium derivative of 5,10,11,12-tetrahydrodibenz [b, g] azocine has been obtained, and 10.4 g of 1-hydroxyethylpiperazine are dissolved in 65 ecm of anhydrous ethanol. The mixture is heated in a pressure-tight bottle at 100 ^° C. for 29 hours. After cooling, the ethanol is removed under a weak vacuum. The residue is taken up in 250 ecm distilled water and 250 ecm ether. The organic solution is washed with 250 ml of distilled water and then extracted twice with 200 ml of aqueous 2N acetic acid each time. The entire acetic acid solution is washed with 150 ecm of ether and then made alkaline with sodium hydroxide solution. The oil formed is extracted twice with 150 ecm of ether each time. The ethereal solution is washed with water until neutral, dried over anhydrous potassium carbonate and evaporated. The 4.9 g of oily residue is dissolved in 10 ecm of ethanol and treated with 3.9 ecm of an ethanolic solution of anhydrous hydrogen chloride with a content of 7.3 mol of hydrogen chloride per liter of solution. The reaction product crystallizes out. After standing at ⁰ ° C. for 15 hours, the crystals are filtered off with suction, washed with 10 ecm of ice-cold ethanol and then with 20 ecm of anhydrous ether and dried in vacuo. This gives 5.3 g of 5- [3 '- (4 "-Hydroxyäthylpiperazino) -propyl] -5,10,11, 21 -tetrahydrodibenzfb ^ azocine dihydrochloride, melting at 200-202 ⁰ C.

Example 13

11.4 g of crude 5- (3'-chloropropyl) -5,10, ll, 12-tetrahydrodibenz [b, g] azocine and 30 g of 1-hydroxyethoxyethyl piperazine are dissolved in 150 ecm of anhydrous ethanol and placed in a pressure-tight bottle 24 Heated to 100 ⁰ C hours. After cooling, the ethanol is evaporated off under a weak vacuum. The residue is taken up in 300 ecm distilled water and 450 ecm ether. The organic phase is washed with 150 ecm of distilled water and then extracted twice with 250 ecm of aqueous 2η-acetic acid each time. The entire acetic acid solution is washed with 150 ecm of ether and then made alkaline with sodium hydroxide solution. The oil that appears is extracted twice with 200 ecm of ether each time. The ethereal solution is washed with water until neutral, dried over anhydrous potassium carbonate and evaporated. The oily residue amounting to 12 g is dissolved in 40 ecm of ethanol and treated with 8.3 ecm of an ethanolic solution of anhydrous hydrogen chloride with a content of 7.3 mol of hydrogen chloride per liter of solution. The reaction product crystallizes out. After 15 hours of standing at 0 ⁰ C, the crystals are filtered off with suction, washed with 30 cc of ethanol and 60 cc of ether and dried in vacuo. 13.7 g of 5- [3 '- (4 "-Hydroxyäthoxyäthylpiperazino) -propyl] -5,10,11,12-tetrahydrodibenz [b, g] azocine dihydrochloride with a melting point of 164 ° to 166 ° C. are obtained.

Example 14

To a mixture obtained from 2.05 g of 95% sodium amide and 40 ecm of anhydrous toluene a solution of 10.45 g of 5,10,11,12-tetrahydrodibenz [b, g] azocine is added with stirring under a slow stream of nitrogen in 100 ecm of anhydrous toluene and then a solution of 5.9 g of 1-dimethylamino-2-chloroethane in 40 ecm anhydrous toluene and heated under reflux for 24 hours. After cooling, add 250 ecm of distilled water to. The organic solution is decanted. The aqueous solution is washed with 250 ecm of ether and the ether phase added to the toluene solution. The organic solution obtained is used twice extracted with 200 ecm of aqueous 2η-acetic acid. The entire acetic acid solution is with 150 ecm Washed with ether and then made alkaline with sodium hydroxide solution. The formed oil is used twice each 125 ecm of ether extracted. The ethereal solution is washed over with water until neutral

409 710/402

dried anhydrous potassium carbonate and evaporated. The 6.9 g amount oily residue is dissolved in 15 cc of ethanol and 9.0 cc of an ether solution of anhydrous hydrogen chloride "with a content of 3 mole of hydrogen chloride per liter of solution treated. The reaction product crystallizes out. After 15 hours of standing at 0 ⁰ C the crystals are suctioned off, washed with 15 ecm ethanol and 20 ecm anhydrous ether

Potassium carbonate dried and evaporated. 0.44 g of 5- (2'-dimethylaminoethyl) -5,10,11,12-tetrahydrodibenz [b, g] azocine are obtained, its hydrochloride melts at 236 to 239 ° C.

Benz [b, g] azocine hydrochloride with a temperature of 242 to 244 ° C. Example 15

To a mixture obtained from 2.05 g of 95% sodium amide and 40 ecm of anhydrous toluene a solution of 10.45 g of 5,10,11,12-tetrahydrodi-

Example 17

To a mixture obtained from 2.4 g of 97% sodium amide and 80 ecm of anhydrous toluene is set with stirring under a slow and then dried in vacuo. 6.5 g of nitrogen stream 12.6 g of 5,10,11,12-tetrahydrodibenz-5- (2'-dimethy] aminoethyl) -5,10,11,12-tetrahydrodi- [b, g] azocine are obtained, dissolved in 100 ecm anhydrous toluene,

and then 10.85 g of 1,3-bis (dimethylamino) -2-chloropropane, dissolved in 80 ecm anhydrous toluene, too. The reaction mixture is under re-15 for 24 hours river heated. After cooling, 450 ecm of distilled water and 350 ecm of ether are added. the decanted organic layer is washed with 350 ecm of distilled water and then twice extracted with 250 ecm of aqueous 2η-acetic acid.

benz [b, g] azocine in 100 ecm anhydrous toluene 20 The entire acetic acid solution is washed with 100 ecm and then a solution of 8.1 g of 1-piperidino ether and then made alkaline 2-chloroethane in 30 ecm anhydrous toluene with sodium hydroxide solution. The oil that appears is refluxed twice and heated for 24 hours. Extracted after the 150 ecm ether. The ether solution is cooled down, 200 ecm of distilled water with distilled water is added until neutral and 150 ecm of ether are added. The organic solution is washed, washed over anhydrous potassium carbonate with 150 ml of distilled water and dried and then evaporated. The 14 g total then twice with 200 ecm aqueous 2 η-vinegar-oily residue is extracted dissolved in 65 ecm isopropanol acid. The acetic acid solution is washed with and then with 27 ecm of an ethereal solution of 200 ecm of ether and then made alkaline with anhydrous hydrogen chloride containing sodium hydroxide. The U1 formed is extracted twice from 3.3 mol of hydrogen chloride per liter of solution with 200 ecm of ether each time. The ether act. The reaction product crystallizes out. solution will be with water up to neutrality overall After 15 hours of standing at 0 ⁰ C

wash, suck off the crystals over anhydrous potassium carbonate and dry with 45 ecm ice-cold and evaporate. The residue obtained isopropanol and then anhydrous with 50 ecm is distilled in vacuo. 5.5 g of a washed ether are obtained. After drying in vacuo the oil with a boiling point of 0.1 158 to 188 ° C., which is dissolved in 13 ecm of water, 16.7 g of 5- [2 ', 3'-bis- (dimethylamino) -profree acetone and with 5.7 ecm of an ethereal solution of anhydrous hydrogen chloride
containing 3.2 moles of hydrogen chloride each
Liters of solution are treated. The reaction 40
product crystallizes out. After cooling for ² hours at 0 ° C., the crystals are filtered off with suction,
with 10 ecm anhydrous acetone and 30 ecm water- To a solution of 16 g 5- (3'-chloro-2'-methyl-

washed with free ether and then dried in vacuo (propyl) -5,10,11,12-tetrahydrodibcnz [b, g] azocine. 5.6 g of 5- (2'-piperidinoethyl) - 45,200 ecm of ethanol are obtained, and 23.3 g of morpholine are added. 5.10,11,12-tetrahydrodibenz [b, g] azocine hydrochloride The mixture is heated to 100 ³ C 19 hours.

After cooling, the ethanol is removed in vacuo and the residue is mixed with 300 ecm of ether, 300 ecm of water and 10 ecm of sodium hydroxide solution (J --- 1.33) 50. The ether phase is decanted, washed with 100 ecm of distilled water and then twice

pyl] -5,10,11,12-tetrahydrodibenz [b, g] azocine dihydrochloride from 195 to 198 ° C. (A rearrangement takes place in the course of the reaction.)

Example 18

from 208 to 212 ° C.

Example 16

3,6g5- (2'-dimethylamino-ethoxycarbonyl) -5.10.11, 12-tetrahydrodibenz [b, g] azocine, which is produced in a manner known per se by reacting 5-chlorocarbonyl-5,10,1 l, 12-tetrahydrodibenzfb, g] azocine with

extracted with 250 ecm of aqueous 2η-acetic acid. The combined acidic extracts are washed with 100 ecm of ether and then with sodium hydroxide solution (d = 1.33)

Dimethylaminoalhanol made alkaline in the presence of excess sodium. The occurring

amide has been obtained, are extracted on a Teinpe oil is extracted twice with 150 ecm of ether each time,

ratiir between 230 and 250 ⁰ C 45 minutes in The ether solutions are combined, over water

Heated nitrogen stream. It finds a carbon dioxide-free potassium carbonate dried and evaporated,

Development takes place, and a volatile product is distilled. The oily residue amounting to 10.7 g is in

away. The residue is dissolved in vacuo (0.4 mm) 60 23 ecm of ethanol. Then you put 8.0 ecm

distilled. The fraction between 135 of a solution of hydrogen chloride in anhydrous is recovered

and] 45 ° C. 2.2 g of an oil are obtained, which is dissolved in ether with a content of 4 moles of chlorinated water

50 ecm of ether dissolves. It is extracted three times with each substance per liter of solution. The reaction product

20 ecm of aqueous 2η-acetic acid. The entire vinegar crystallizes out. After cooling down for 2 hours

acid solution is washed with 30 ecm ether and 65 0 ⁰ C, the crystals are suctioned off, with 30 ecm

then made alkaline with caustic soda. The on ice-cold ethanol and then with 30 ecm of ether

emerging oil is washed twice with 30 ecm of ether each time and dried in vacuo. You get

extracted. The ether solution is over anhydrous 10.7 g of 5- (3'-morpholino-2'-methyl-propyl) -5,10,11,

12-tetrahydrodibenz [b, g] azocine hydrochloride, melting at 200-205 ⁰ C.

Example 19

To a mixture obtained from 2.46 g of 95% strength sodium amide and 30 ecm of anhydrous toluene, a solution of 12.54 g of 5,10,11,12-tetrahydrodibenz [b, g] azocine in 70 ecm of anhydrous toluene is added with stirring . 112 ecm of a solution of 10.66 g of 1-methyl-2- (chloroethyl) piperidine in anhydrous toluene are then added. The reaction mixture is refluxed for 20 hours.
After cooling, the reaction products are treated with 100 ecm of ether and then with 150 ecm of water. The organic solution is decanted, washed with 200 ecm of water and then extracted twice with 200 ecm of aqueous 2η-acetic acid each time. The combined acidic extracts are washed with 100 ecm of ether and then made alkaline with excess sodium hydroxide solution (d = 1.33). The oil that appears is extracted twice with 150 ecm of ether each time. The combined ether solutions are washed with distilled water and then dried over anhydrous potassium carbonate. After the ether has evaporated, the residue is distilled in vacuo (0.1 mm). 8.6 g of an oily fraction with a boiling point of 0.1 182 to 195 ° C. are obtained. 7.8 g of it are dissolved in 25 ecm isopropanol and treated with 18 ecm of a solution of anhydrous hydrogen chloride in ether with a content of 4.1 mol of hydrogen chloride per liter of solution. After cooling to ⁰ ° C. for 15 hours, the crystals are filtered off with suction and washed with 25 ecm of ice-cold isopropanol and then with 60 ecm of anhydrous ether. After drying in vacuo, 8.4 g of 5- [l'-methyl-piperidyl- (2 ') -ethyl] -5, 10, 11, 12-tetrahydrodibenz [b, g] azocine dihydrochloride with a melting point of 140 are obtained up to 145 ° C.

Example 21 Example 20

40

23.1 g of piperidine are added to a solution of 16.3 g of 5- (3'-chloro-2'-methylpropyl) -5,10,11,12-tetrahydrodibenz [b, g] azocine in 200 ecm of ethanol. The mixture is ^{heated at 100 °} C. for 20 hours. After cooling, the ethanol is evaporated in vacuo. The residue is treated with 450 ecm of ether, 350 ecm of distilled water and 10 ecm of sodium hydroxide solution (d = 1.33). The ether phase is decanted, washed with 200 ecm of distilled water and then extracted twice with 250 ecm of aqueous 2η acetic acid each time. The combined acidic extracts are washed with 100 ecm of ether and then made alkaline with excess sodium hydroxide solution (d = 1.33). The oil that appears is extracted twice with 150 ecm of ether each time. The ether solutions are combined, washed with distilled water, dried over anhydrous potassium carbonate and then evaporated. The 11.3g oily residue is dissolved in 20 ecm ethanol and poured into a warm solution of 3.5 g fumaric acid in 42 ecm ethanol. Crystals are formed. After cooling for 5 hours at ⁰ ° C., the reaction product is filtered off with suction, washed with 30 ecm of ethanol and then with 60 ecm of ether and dried in vacuo. 10.2 g of 5- (3'-piperidino-2'-methyl-propyl) -5,10,11,12-tetrahydrodibenz [b, g] azocine fumarate with a melting point of 147 ° C. are obtained

18.4 g of pyrrolidine are added to a solution of 15.5 g of 5- (3'-chloro-2'-methylpropyl) -5,10,11,12-tetrahydrodibenz [b, g] azocine in 200 ecm of ethanol. The mixture is ^{heated at 100 °} C. for 22 hours. After cooling, the ethanol is removed in vacuo. The residue is treated with 300 ecm of ether, 250 ecm of distilled water and 10 ecm of 5N sodium hydroxide solution. The ether phase is decanted, washed with 250 ecm of distilled water and then extracted twice with 250 ecm of aqueous 2N acetic acid each time. The combined acidic extracts are washed with 150 ecm of ether and then made alkaline with excess sodium hydroxide solution (d = 1.33). The oil that appears is extracted twice with 150 ecm of ether each time. The ether solutions are combined, washed with distilled water, dried over anhydrous potassium carbonate and evaporated. The 9.6 g oily residue is dissolved in 22 ecm of ethanol and treated with 7.5 ecm of a solution of anhydrous hydrogen chloride in ether with a content of 4 moles of hydrogen chloride per liter of solution. After 19stündigem cooling to 0 ⁰ C, the crystals are filtered off with suction and then washed with 20 cc of ice-cold ethanol and with 30 cc of anhydrous ether. After drying in vacuo, 10.3 g of 5- (3'-pyrrolidino - 2 '- methyl - propyl) - 5,10,11,12 - tetrahydrodibenz [b, g] azocine hydrochloride, solvated with ethanol, from F. 140 and then 210 ⁰ C.

Example 22

26.6 g of 4-hydroxypiperidine are added to a solution of 15 g of 5- (3'-chloro-propyl) -5,10,11,12-tetrahydrodibenz [b, g] azocine in 200 ecm of ethanol. The mixture is ^{heated to 100 °} C. for 20 hours. After cooling, the ethanol is evaporated in vacuo. The residue is treated with 300 ecm ether, 250 ecm distilled water and 10 ecm sodium hydroxide solution (d = 1.33). The ether phase is decanted, washed with 250 ecm of distilled water and then extracted twice with 250 ecm of aqueous 2η-acetic acid each time. The combined acidic extracts are washed with 150 ecm of ether and then made alkaline with excess sodium hydroxide solution (J = 1.33). The oil that appears is extracted twice with 150 ecm of ether each time. The ether solutions are combined, washed with distilled water, dried over anhydrous potassium carbonate and then evaporated. The oily residue of 12.9 g is dissolved in 30 ecm of acetone and poured into a warm solution of 3.45 g of 90% strength oxalic acid in 30 ecm of acetone. It is allowed to cool slowly, crystals forming. After 15 hours at ⁰ ° C., the crystals are filtered off with suction and washed with 30 ecm acetone and then with 50 ecm anhydrous ether. After drying in vacuo, 12.6 g of 5- [3 '- (4 "-hydroxypiperidino) propyl] -5,10,11,12-tetrahydrodibenz [b, g] azocine oxalate with a melting point of 115 ° C. are obtained

Example 23

22.8 g of morpholine are added to a solution of 15 g of 5- (3'-chloro-propyl) -5,10,11,12-tetrahydrodibenz [b, g] azocine in 200 ecm of ethanol. The mixture is ^{heated to 100 °} C. for 22 hours. After cooling, the ethanol is treated in vacuo

steams. The residue is treated with 300 ecm ether, 250 ecm distilled water and 10 ecm sodium hydroxide solution (d = 1.33). The ethereal phase is decanted, washed with 250 ecm of distilled water and then extracted twice with 250 ecm of aqueous 2η-acetic acid each time. The combined acidic extracts are washed with 150 ecm of ether and then made alkaline with excess sodium hydroxide solution (d = 1.33). The oil formed is extracted twice with 150 ecm of ether each time. The ether solutions are combined, washed with distilled water, dried over anhydrous potassium carbonate and then evaporated. The oily residue amounting to 10.7 g is dissolved in 18 ecm of ethanol and poured into a boiling solution of 3.2 g of 90% oxalic acid in 18 ecm of ethanol. After cooling for 5 hours at ⁰ ° C., the crystals formed are filtered off with suction and washed with 40 ecm of ice-cold ethanol and then with 50 ecm of anhydrous ether. After drying in vacuo, 11.5 g of 5- (3'-morpholinopropyl) -5,10,11,12-tetrahydrodibenz [b, g] azocine oxalate with a melting point of 173 ° to 175 ° C. are obtained.

Example 24

22.2 g of piperidine are added to a solution of 15 g of 5- (3'-chloropropyl) -5,10,11,12-tetrahydrodibenz [b, g] azocine in 200 ecm of ethanol. The mixture is ^{heated at 100 °} C. for 26 hours. After cooling, the ethanol is evaporated in vacuo. The V lagging behind is treated with 300 cc of ether, 250 cc of distilled water and 10 cc of sodium hydroxide solution (d = 1.33). The ether phase is decanted, washed with 250 ecm of distilled water and then extracted twice with 250 ecm of aqueous 2N acetic acid each time. The combined acidic extracts are washed with 150 ecm of ether and then made alkaline with excess sodium hydroxide solution (d = 1.33). The oil that appears is extracted twice with 150 ecm of ether each time. The ether solutions are combined, washed with distilled water, dried over anhydrous potassium carbonate and evaporated. The 11.4 g oily residue is dissolved in 25 ecm of acetone and treated with 30 ecm of a solution of anhydrous hydrogen chloride in ether with a content of 4 moles of hydrogen chloride per liter of solution. After 5 hours of cooling at 0 ⁰ C, the crystals formed are drained, ECM 25 with ice-cold acetone and then washed with 60 cc of anhydrous ether and dried in vacuo. This gives 9.9 g of 5- (3'-Piperidonopropyl) -5,10,11,12-tetrahydrodibenz [b, g] azocindihydrochlorid, mp 106 to 110 ⁰ C.

If the dihydrochloride is dissolved in water, made alkaline with sodium hydroxide solution, extracted with ether, dried over anhydrous potassium carbonate, the solution evaporated and the residue treated with tartaric acid in acetone, 5- (3'-piperidino-propyI) -5.10 is obtained , 11,12-tetrahydrodibenz [b, g] azocintartrat, mp 140 to 142 ⁰ C.

Example 25

16 coarse 5- (3 '-chloropropyl) -5,10.11,12-tetrahydrodibenz [b, g] azocine and 19.9 g pyrrolidine are dissolved in 200 ecm anhydrous ethanol and heated to 100 ° C in a pressure-tight bottle for 42 hours. After cooling, the ethanol is evaporated off under a weak vacuum. The residue is taken up in 300 ecm of distilled water and treated with 300 ecm of ether and 10 ecm of sodium hydroxide solution (d = 1.33). The organic phase is washed with 250 ml of distilled water and then extracted twice with 250 ml of aqueous 2N acetic acid each time. The acetic acid extracts are washed with 100 ecm of ether and then made alkaline with sodium hydroxide solution (d = 1.33). The oil that appears is extracted twice with 150 ecm of ether. The ethereal solution is mixed with water until neutral

ίο washed, dried over anhydrous potassium carbonate and evaporated. An oily residue of 12 g is obtained. 9.6 g of this oil are dissolved in 50 ecm acetone. This solution is poured onto 2.25 g of tartaric acid while hot. Heating under reflux gives a clear solution which crystallizes on cooling. After 15 hours of standing at 0 ⁰ C, the crystals are filtered off with suction, washed with 20 cc of ice-cold acetone and then washed with 40 cc of anhydrous ether and dried in vacuo. This gives 8.3 g of neutral tartrate of 5- (3'-PyrrolidinopropyI) -5,10, ll, 12-tetrahydrodibenz [b, g] azocine, mp 128 to 130 ⁰ C.

Example 26

30grohes5- (3'-ChIorpropyI) -5,10, l 1,12-tetrahydrodibenz [b, g] azocine and 73 g of diethylamine are dissolved in 150 cc of anhydrous ethanol and heated 42 hours at 100 ⁰ C in a pressure-resistant bottle. After cooling, the ethanol is evaporated off under a weak vacuum. The residue is taken up in 250 ecm distilled water, 300 ecm ether and 10 ecm sodium hydroxide solution (d 1.33). The organic phase is washed with 300 ecm of distilled water and then extracted twice with 250 ecm of aqueous 2η-acetic acid. The acetic acid extracts are washed with 100 ecm of ether and then made alkaline with sodium hydroxide solution (d - 1.33). The oil that appears is extracted twice with 200 ecm of ether each time. The ethereal solution is washed with water until neutral, dried over anhydrous potassium carbonate and evaporated. The oily residue amounting to 20.5 g is dissolved in 50 ecm of acetone in the heat. This solution is poured into a solution of 6.6 g of 90 ° / üiger oxalic acid in 80 ecm of acetone while warm. After 4 hours cooling at 0 ⁰ C, the crystals are filtered off with suction, then washed with 50 cc of acetone and 60 cc of ether and dried in vacuo. 24.9 g of 5- (3'-diethylaminopropyl) -5,10,11,12-tetrahydrodibenz [b, g] azocine oxalate with a melting point of 130 to 133 ° C. are obtained.

Example 27

A solution of 5-methanesulfonylethyl-5,10,11,12-tetrahydrodibenz [b, g] azocine, obtained by reacting 5 g of crude 5-hydroxyethyl-5,10,11,12-tetrahydrodibenz [b, g] azocine with 4.53 g of methanesulfonyl chloride has been obtained in 80 ecm of benzene is treated with 40 ecm of a benzene dimethylamine solution containing 5.7 mol of dimethylamine per liter of solution. The mixture is ^{heated at 100 °} C. for 17 hours. After cooling, the benzene is evaporated. The residue is taken up in 80 ecm water, 150 ecm ether and 10 ecm sodium hydroxide solution (i / = 1.33). The ether solution is washed with 50 ecm of water and then extracted twice with 60 ecm of aqueous 2N acetic acid each time.

The combined acetic acid extracts are washed with 1cm ether and then made alkaline with sodium hydroxide solution (d- 1.33). The oil that appears is extracted twice with 50 ecm of ether each time. The ethereal solution is washed with water until neutral, dried over anhydrous potassium carbonate and evaporated. The oily residue amounting to 3.3 g is dissolved in 6 ecm of ethanol and treated with 4.3 ecm of an ethereal solution of dry hydrogen chloride with a content of moles of hydrogen chloride per liter of solution. After 4 hours cooling at 0 ⁰ C, the crystals are filtered off with suction, washed with ice-cold 5 cc of ethanol and then with 10 cc of anhydrous ether and dried in vacuo. 3.25 g of - dimethylaminoethyl - 5, 10, 11, 12 - tetrahydrodibenz [b, g] azocine hydrochloride with a melting point of 242 to 244 ° C. are obtained.

Claims (1)

Claim: Process for the preparation of 5,10,11,12-tetrahydrodibenz [b, g] azocine derivatives the general formula 20th in Z an amino, monoalkylamino, dialkylamino, pyrrolidino, piperidino, morpholino, Thiomorpholine, piperazino, N-alkylpiperazino, N-alkylpiperidyl or N-alkylpyrrolidyl radical or remnants of the general formulas - N -C _n H _8n OR - N '—Y .CnH _2n OR or NG _n IW) R in which R represents a hydrogen atom or a lower hydroxyalkyl radical, «0, 1, 2 or 3 and m represents 2 or 3, and the piperazino, N-alkylpiperazino, N-hydroxyalkylpiperazino and N-hydroxyalkoxyalkylpiperazino radicals on their ring carbon atoms optionally have one or carry more lower alkyl groups and in which A is a trivalent saturated hydrocarbon radical having 1 to 6 carbon atoms and B is a hydrogen atom or the radical Z 'or CH ₂ Z', in which Z 'has the same meaning as Z, and salts thereof , characterized in that either in the manner known per se a) 5,10,11,12-tetrahydrodibenz [b, g] azocine with reactive esters of the general formula X r \ £ -i in which Y is the radical of a reactive ester, converts or b) amines of the general formula Η —Ζ
with compounds of the general formula AY
B ' in which B 'denotes a hydrogen atom or the radical Y, CH ₂ Y, Z' or CH ₂ Z ', converts or
c) compounds of the general formula A-Z decarboxylated by heating to a temperature between 100 and 220 ⁰ C and optionally treated the bases obtained with acids. Considered publications:
Austrian Patent No. 196 879; German medical weekly, Vol. 84 (1959), pp. 2249 to 2253.