NO138210B - PROCEDURE FOR MAKING TRICYCLIC COMPOUNDS - Google Patents

Description

The present invention relates to a method for producing

position of tricyclic compounds with then general formula I

in which means hydrogen, alkoxyalkyl with a total of no more than 6

carbon atoms, alkyl or hydroxyalkyl with up to 4 carbon atoms,

since the hydroxyalkyl group can optionally be further acylated,

R 4 stands for hydrogen, alkyl, alkoxy or alkylthio, in which

the alkyl groups have 1-4 carbon atoms, or stand for halogen or trifluoromethyl and A stands for the structures

whereas,

a) when A stands for Zl, x means a -CH2~, -0-, -S-, -NH- or an -N-alkyl group in which alkyl has 1-3 carbon atoms, R2 stands for

hydrogen, alkyl dialkylaminosulfonyl, alkylsulfonyl, wherein the alkyl groups have 1-4 carbon atoms, alkoxy or alkylthio with 1-4 carbon atoms, halogen, nitro, trifluoromethylsulfonyl, trifluoromethoxy, trifluoromethylthio, acetyl, cyano or trifluoromethyl and Rj stands for hydrogen, halogen or alkyl with 1-4 carbon atoms, respectively

b) when A stands for Z2, X means a -CH2~ or an -S group, and the peculiarity of the method according to the invention is that a

compound of formula II

wherein X, A and have the above meaning, are reacted with a metal amine complex consisting of titanium or zirconium and a compound of the general formula III

wherein R^ has the above meaning,

and obtained compounds of formula I, in which R 1 stands for an acylated hydroxyalkyl group, are optionally saponified, respectively obtained compounds of formula I, in which R 1 stands for a hydroxyalkyl group, are optionally esterified.

In the substituents R2, R3 and R4, halogen preferably means chlorine or bromine, especially chlorine. If the hydroxyalkyl group in the substituent R1 is acylated, the acyl group preferably has no more than 18 carbon atoms. in particular no more than 10 carbon atoms. The alkyl group is preferably aliphatic and can be saturated or unsaturated.

A preferred embodiment of the method consists in the compounds of formula II being reacted with the metal amine complex in the presence of an acid-binding agent. A tertiary amine can be used as an acid-binding agent, such as e.g. triethylamine, pyridine, dimentylaniline or also an excess of a compound of formula III. The proportion of the acid-binding amino compound in relation to (1 mol) of the metal amine complex must amount to at least one mol (equivalent amount) and preferably 2 mol (double equivalent amount).

The reaction is best carried out in an organic solvent, e.g. in

an aromatic solvent such as toluene, a halogenated aromatic solvent such as chlorobenzene, a halogenated aliphatic solvent such as dichloroethane, or an ether such as anisole. The reaction temperature must be between room temperature and 150°C, preferably between 50 and 120°C.

The metalamine complex used is obtained by reacting a halide, preferably the tetrachloride or tetrabromide of titanium or zirconium with a compound of the general formula III, preferably in a molar ratio of 1:4. The reaction is best carried out in the solvent that will later be used for the main reaction. Hereby, the metal halide is introduced in the form of its soluble (mono- or di-) etherate, preferably the anisole dietherate.

Of the metals, titanium is preferably used for carrying out

the present method.

After completion of the reaction, the almost insoluble metal compounds found in the reaction mixture are transferred to a soluble form by the addition of an alcohol, e.g. isopropanol, .

and then they are precipitated by the addition of aqueous ammonia. From the reaction mixture, which is thus freed from metal compounds, the compounds of formula I are obtained according to a known method by evaporation of the reaction mixture and crystallization and are then purified in a known manner, e.g. by recrystallization from

isopropanol, of the compound obtained.

In the preparation of the compounds of formula I, in which

for a hydroxyalkyl group, the reaction product may precipitate as a gel, because the hydroxyalkyl group also reacts with the metal halide during ester formation. In order to prevent too strong gel formation, which could disturb the course of the reaction, it is advantageous to carry out the reaction in close proximity to larger quantities of solvent, e.g. chlorobenzene' or anisole, and while adding an excess (10-20 times molar excess) of tertiary amine, e.g. triethylamine.

The compounds of formula I, in which R^ represents a hydroxyalkyl group, can likewise be prepared by the compounds of formula I, in which R^ represents an acylated hydroxyalkyl group, saponified alkaline, e.g. using a dilute sodium hydroxide solution.

The esterification of the compounds of formula I, in which R^ represents

a hydroxyalkyl group, can be carried out in a known manner, e.g. with the help of a reactive acid derivative, e.g. a halide of a corresponding acid, in a solvent such as chloroform, and preferably in the presence of an acid-binding agent such as triethylamine, cg at room temperature.

The compounds of formula I can be transferred and converted into their acid addition salts. Suitable salts are the hydrogen chloride, hydrogen bromide, sulfate, fumarate, maleate, p-toluenesulfonate, etc.

The starting compounds of formula II used are mostly known compounds or can be prepared from known starting compounds. Preparation of hitherto unknown compounds of formula II will be described in the examples, and the preparation can be carried out with reference to these examples. The compounds of formula III are generally also known or can be prepared in a known manner from known starting compounds. The compounds of formula III, in which R 1 stands for an acylated hydroxyalkyl group, can e.g. is prepared by reacting N-benzyl-piperazine with a haloalcohol, the hydroxy group is esterified with the help of a reactive acid derivative, e.g. a halide, especially the chloride of a corresponding acid and then the benzyl group is removed hydrogenolytically.

The prepared compounds of formula I are for the most part already known and, as such compounds, can be used for therapeutic purposes in a known manner. E.g. is the compound 2-chloro-11-(4-methyl-1-piperazinyl)dibenz /b,f/ D- i^ J tiazepine, known under the name "Clothiapine" (entumin), a highly active antipsychotic. The hitherto unknown compounds of formula I, especially the 10H-thieno Z3,2-c_7 1X7 benzazepines, can be used as antipsychotic, sedative, sleeping and muscle relaxant agents.

In the general formula I, if A stands for Zl, the substituent R2 is preferably in the 2-position or 3-position, the substituent Rg is preferably in the 4-position and, if A stands for Zl and Z2,

the substituent R 1 is preferably in the 7- or 8-position.

In the following examples, the temperature is stated in °C and room temperature stands for a temperature between 20 and 30°C when not stated otherwise.

EXAMPLE 1: 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo- /b,e/ /1,47diazepine

In a 2.5 L sulphiding flask equipped with a dropping funnel, reflux condenser and thermometer, 840 ml of toluene, 90 ml of anisole and 79.2 g of titanium tetrachloride are added at room temperature, whereby a dark-brown clear solution is formed. To this is added, under external cooling with water, a mixture of 167 g of N-methylpiperazine and 100 ml of toluene, whereupon the temperature rises to 50 - 55°C and the amine complex forms in finely divided form a beige to dark brown colored substance. Then 102 g of 8-chloro-10.11-dihydro-11-oxo-5H-dibenzo £b,& 7 £X,47-diazepine and 83 g of N-methylpiperazine are added and the reaction mixture is heated for 3 hours by boiling (110-112 °C) and with stirring. The solution is then cooled to 60-70°C and 125 ml of isopropanol is added, whereby the insoluble titanium compound formed during the reaction goes into solution again. After adding 8 g of silica 1 and finally 115 ml of concentrated ammonia (approx. 27%), the solution is cooled while stirring to approx. 30°C and the precipitate formed is filtered off. The filter residue is washed with 2-3 portions of 330 ml toluene each. Finally, the filtrate is divided against water and the organic phase is extracted with diluted, approx. 10% hydrochloric acid. The base is precipitated by dropwise addition of the hydrochloric acid extract i

an excess of dilute ammonia. Dissolution is then carried out in ether and the ether solution is washed with water and dried over sodium sulphate. After evaporation of the ether and recrystallization from igspropano1, 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo-Zb,e/ /1,47diazepine is obtained with m.p. 184°C in a yield of 90% of the theoretical with respect to the starting lactam compound.

EXAMPLE 2: 6-(4-tert.butyl-1-piperazinyl)-morphanthridine

In a 2.5 L sulphiding flask equipped with a dropping funnel, reflux condenser and thermometer, 840 ml of toluene, 90 ml of anisole and 93.5 g of zirconium tetrachloride are added at room temperature, whereby a dark brown clear solution is formed. To this is added, under external cooling with water, a mixture of 248 g of N-tert.butylpiperazine and 100 ml of toluene, whereby the temperature rises to 50 - 55°C and the amine complex forms in finely divided form a dark brown colored suspension. Then 87 g of morphanthridin-6-one and 123.5 g of N-tert.butylpiperazine are added and the reaction mixture is heated for 3 hours by boiling (110 - 112°C) with stirring. The solution is then cooled to 60 - 70°C and 125 ml of isopropanol is added, whereby the insoluble zirconium compound formed during the reaction again goes into solution. After adding 8 g of silica gel and finally 115 ml of concentrated ammonia (approx. 27%), the mixture is cooled while stirring for approx. 30°C and the formed precipitate is filtered off. •• The filter residue is washed with 2-3 portions of 330 ml toluene each. Finally, the filtrate is divided against water and the organic phase is extracted with diluted (approx. 10%) hydrochloric acid. The base is precipitated by dropwise addition of the hydrochloric acid extract in an excess of dilute ammonia. Dissolution in ether is then carried out, the ether solution is washed with water and dried over sodium sulphate. After evaporation of the ether, the residue is dissolved in acetone and the solution is mixed with 38 g of maleic acid. The solution is then evaporated, ethyl acetate and a little ether are added and the formed precipitate is filtered off. After recrystallization from acetone/ethyl acetate/ether, the obtained 6-(4-tert.butyl-1-piperazinyl)-morphanthridine maleate melts at 138-141°C.

The above-mentioned starting material 1-tert.butyl-piperazine can be prepared in the following way: A solution of bis-(2-chloroethyl)-tert.butylamine in 500 ml of ethanol and a solution of 1095 g of benzylamine in 750 ml of ethanol are added dropwise simultaneously to 1000 ml boiling ethanol. After the addition is complete, the reaction mixture is heated for a further 1 hour at the boiling point temperature. The solution is then evaporated in a vacuum and the residue is dissolved in dilute hydrochloric acid. The acidic solution is washed with ether and then made alkaline with concentrated aqueous sodium hydroxide solution. The base liberated in this way is shaken off with ether and the ether residue is distilled. 1-Benzyl-4-tert.butylpiperazine boils at 160 - 162°C/12 mm Hg.

2) 1-tert-butyl-piperazine

348.5 g of 1-benzyl-4-tert.butylpiperazine are dissolved in 1200 ml of 95% ethanol and the resulting solution is mixed with 10 g of a 5% palladium-carbon catalyst. The solution is then shaken in a hydrogenation apparatus under a hydrogen atmosphere (1 atm.) and at room temperature until hydrogen absorption is complete. Finally, the solution is filtered, the filtrate is evaporated in vacuum and the residue is distilled in vacuum. 1-tert.butyl-piperazine is thereby obtained in the form of a colorless oil which boils at 66 - 70°C/12 mm Hg and which crystallizes on standing. The crystals melt at 35 - 40°C.

Using the method described in examples 1 and 2 as well as corresponding starting compounds, the following compounds are obtained in an analogous manner: 5-methyl-11-(4-methyl-1-piperazinyl)-dibenz/b,ey/1,4/diazepine with m.p. . 122 - 124°C (from ether/petroleum ether),

2-chloro-11-(4-methyl-1-piperazinyl)-dibenz/b,f/ /1,4/thiazepine with m.p. 116 - 120°C (from ether/petroleum ether),

6-(4-methyl-1-piperazinyl)-morphantridine with m.p. 138 - 139°C, from acetone/petroleum ether,

2-methyl-11-(^-methyl-1-piperazinyl)-dibenz/b , fj£\ -j^Ztiazepine with m.p. 99 - 107°C, from petroleum ether,

2-Chloro-11-(^-methyl-1-piperazinyl)-dibenz/b ,f_7/l ,^/oxazepine with m.p. 1-)+-110°C, from petroleum ether,

2-bromo-11-(^-methyl-1-piperazinyl)-dibenz/b ,j^/l ,^thiazepine with m.p. 138 - 139°C, "from acetone/petroleum ether,

2-nitro-11-(*f-methyl-1-piperazinyl)-dibenz/b, f_7/1 j^oxazepine with m.p. 192 - 193°C, from chloroform/acetone/petroleum ether,

.2-diraethylaminosulfonyl-11 -(i+-methyl-1 -piperazinyl)dibenz/b , £j£\ ,*+7-thiazepine with m.p. 192 - 193°C, from acetone/petroleum ether,'

2-Dimethylaminosulfonyl-11-(h-methyl-1-piperazinyl) dibsnz/Tb ,f_7/I , h7-oxazepine with m.p. 1^9 - 150°C, from ether/petroleum ether,

2-methylsulfonyl-11-(3-methyl-1-piperazinyl)-dibenz/b',f_7/"l j^oxazepine with m.p. 178 - 179°C, from .acetone/ether/petroleum ether,

2-trifluoromethoxy-11-(V-methyl-1-piperazinyl)-dibenz/b,f_7/T , k7-oxazepine dihydrochloride monohydrate with m.p. 200 -210 C, from alcohol/ether. '

7-chloro-k-(^-methyl-1-piperazinyl)-thieno/2,3-b_//T , ^/benzothiazepine with m.p. 162 - 16K°C, from ethyl acetate.

2-trifluoromethylsulfonyl-11-(3-methyl-1-piperazinyl)-dibenz/c,f7/1 tiazepine with m.p. 168 - 170°C (from ether/petroleum ether),

2-acetyl-11-C+-methyl-1-piperazinyl)-dibenz/b,f//l j^oxazepine with m.p. 116 - 118°C, from acetone/petroleum ether,

2-trifluoromethyl-11-(^-methyl-1-piperazinyl)-dibenz/b,f7/T,^/oxazepine whose fumarate melts at 211+ -216°C, from acetone/petroleum ether,

2-trifluoromethylsufonyl-11-(N-methyl-1-piperazinyl)-dibenz/c ,fJVl ,1+7-oxazepine below m.p. 120 - 122°C, from ether/petroleum ether,

2-methylsulfonyl-11-(3-ethyl-1-piperazinyl)-dibenz/b , t2D j^oxazepine with m.p. 190 - 191°C, from acetone/petroleum ether,

^-(^--methyl-1-piperazinyl)-thieno/2,3^b/7/T , ^/benzothiazepine with m.p. 112 - llVc, from abs. ethanol,

^-(^-Methyl-1-piperazinyl)-10H-thieno/3,;2-c7/1^benzazepine with m.p. 1<5>+5 - 1<1>+7°C, from ether/petroleum ether,

8-chloro-^-(1-piperazinyl)-10Ii-thieno/3,2-cJY1.7benzazepine with m.p. 80 - 100°C, from acetone/water in the presence of charcoal,

8-chloro-'+-(!+-(2-acetoxyethyl)-1-piperazinyl)-10H-thieno/3, 2- qJC\ J-benzazepine with m.p. 185 - 189°C, ether/petroleum ether,

8-chloro-^-C1!-- methyl-1 -piperazinyl)-1 OH-thiéno/3,2-q7A/kenzazepine with m.p. 193 - 195°C, from acetone/petroleum ether',

2-methylthio-11-(^--methyl-1-piperazinyl)-dibenz/b ,£7/1 ,1+7oxazepine with m.p. 198 - 201 °C (maleinate), :w i.,

^--Ct-ter t. butyi-1 -piperazinyl) -1 OH-thieno/5,2-cJ7/1_7benzazepine with m.p. 1M7 - -176°C (maleinate), ■ ■- r. n./ r'-

7-methyl-lf-(lt-methyl-:1-piperazinyl.)-1 OH-thieno/5,2-q7/L7benzazepine with m.p. 180.-'181°C, from acetone/petroleum ether., ^ ■

7-Chloro-^-(^-methyl-1-piperazinyl)-10H-thieno/3,2.-c//\7benzazepine with m.p. 18^ - 185°C, from acetone,-

7-Chloro-[(C^-p-hydroxyethyl-i-piperazinyl)-1'0H-thieno/5,2-q7/\7-benzazepine with m.p. 192 - i9^°C, from ethyl acetate,

8-chloro-^-(1+-p-hydroxyethyl-1-piperazinyl)-1OH-thieno/3,2-c7/\7-benzazepine m.p. 202 - 203 C, from ethyl acetate,

2-trifluoromethylsulfonyl-11-/h-(p-penaoyloxyethyl)-1-pipaazinyl7-dibenz/b,£7/1 ,>t/oxazepln, whose oxalate melts at 213-216°C,

2-trifluoromethylsulfonyl-11-(^-(3-hydroxyethyl-1-piperazinyl)-dibenz/b,£7/T j^oxazepine with m.p. 121 - 123°C, from ether/petroleum ether,

2-trifluoromethylsulfonyl-11-(1-piperazinyl)-dibenz/b ,£7/1,1t7oxazepine with m.p. 183 - 186°C, from ether,

2-trifluoromethylsulfonyl-11-(^-(3-hydroxypropyl-1-piperazinyl)-dibenz-/&,£7,/l j^oxazepine with m.p. 132 - 18C, from ether/petroleum ether,

2-trifluoromethylthio-11-(h-(3-hydroxyethyl-1-piperazinyl)-dibenz/b ,£7 Æ} i7

-oxazepine with m.p. 121 - 123 QC, from petroleum ether, 2-trifluoromethylsulfonyl-11-(^t-p-oleyloxyethyl-1-piperazinyl)-dibenz-Zb,£7/1 ,^oxazepine (oil with Rf value=0.88 under use of chloroform/cyclohexane/diethylamine (5:<1>+:1) as eluent and detection with Dragendorff reagent), 1,U--dimethyl-11-(^-methyl-1-piperazinyl)-dibenz/b, f_7/i ,^oxazepine with m.p. IV3 - 1M+°C, from ether/petroleum ether,

3,^-dimethyl-1 1 -(^-methyl-1 -piperazinyl)-dibenz/b,£7/1 ,^1/oxazepine with m.p. 167 - 169°C, from acetone/petroleum ether,

2,8-dichloro-11-(^-methyl-1-piperazinyl)-dibenz/b ,£7/1 j^oxazepine with m.p. 130 - 131°C, from acetone/petroleum ether,

k,8-dichloro-11 -(^-methyl-1 -piperazinyl)-dibenz/b,£7/T,Voxazepine with m.p. 13"+ - 135 C, from acetone/petroleum ether,

■ >+-methyl-8-chloro-1 1 -(^--methyl-1 -piperazinyl)-dibenz/b ,£7/1 ,^oxazepine with m.p. 150 - 151 C, from ether, petroleum ether,

^-methyl-7-chloro-l 1 -(^--methyl-1 -piperazinyl)dibenz/b ,£2J,^oxazepine with m.p. 167 - 168°C, from acetone/petroleum ether,

2, k-dichloro-11-(^--methyl-1-piperazinyl)-dibenz/b ,f_7/l ,4/oxazepine with m.p. 135 - 138°C, from acetone/petroleum ether,

2-chloro-11-(1-piperazinyl)-dibenz/b,f7/J j^t/oxazepine with m.p.

178 - 180°C, from acetone/petroleum ether.

The starting compounds for the production of 1 OH-thieno/5,2-c_7/1_7-benzazepines' can be obtained in the following way:

|+.i5-dihy_dro-1 0H-thieno^ i2-o7/fl,7benzazepin-j+-one

12.8 g of 2-(2-amino-phenyl)-thienone, 23.8 g of solid potassium hydroxide and 19.6 g of hydrazine hydrate are heated in 180 ml of diethylene glycol for 3 hours by boiling and under reflux. After diluting the reaction mixture with ice water, the solution is extracted with ether. The ether phase is washed three times with water, dried with sodium sulphate and evaporated. 2-(2-aminobenzyl)-thiophene is obtained in the form of a light yellow oil with a boiling point of 128 - 130°G/0.1 torr.

To a solution of 958 g of this product in 60 ml of toluene is added dropwise at -3°C and with stirring, +6 ml of a 20% solution of phosgene in toluene. Finally, the reaction mixture is heated to room temperature by introducing a stream of phosgene and is then further heated for -J- hour by refluxing. After removing excess phosgene with a stream of nitrogen, the reaction mixture is evaporated in vacuo and the residue is distilled. 10.8 g of 2-(2-isocyanato-benzyl)-thiophene with a boiling point of 108°C/0.05 torr are obtained.

10.5 g of 2-(2-isocyanato-benzyl)-thiophene (boiling point 108°C/0.05 torr) is heated to 110°C with 105 g of polyphosphoric acid for 1 hour with stirring. The solution is then made alkaline with concentrated ammonia cooling under internal and external ice cooling and the precipitate is filtered off. This is washed with water and after drying it is crystallized from acetone during treatment with activated charcoal. \, 5-dihydro-1 0H-tie.no/352-o7/lJ7benzazepin-l+-one is obtained in the form of grains with m.p. 225 - 236 o C (between 150 and 200 o C a transformation to light needles takes place).

8-chloro-henhv;__7-chloro=lfi5-dihyclro-1 0H;:thieno/3i2-c7/:l7rbenzazepin-1+-one

6 g of N-p-toluenesulfonyl-5-chloro-(or h-chloro)-anthranilic acid are heated to boiling with 10 ml of thionyl chloride for 1 g-hour under reflux. After evaporation in vacuo to dryness, the residue is recrystallized from methylene chloride/petroleum ether. The obtained N-p-toluenesulfonyl-5-chloro-anthranilic acid chloride melts at 13'-+ - 136°C and N-p-toluenesulfonyl-^f-chloro-anthranilic acid chloride melts at 135 - 1'1+0°C.

lii a mixture of 7 g of finely powdered N-p-toluenesulfonyl-5-chloro (or .f-chloro)-anthranilic acid chloride and 3.!+ g of thiophene in 25 ml of sulfur-carbon is added dropwise slowly at the boiling point temperature and 'on reflux a solution of 6 g of stannous chloride in 10 ml of sulfur charcoal. After the addition has been completed, the mixture is stirred for 2 hours

room temperature. The solvent is then evaporated in a vacuum, the residue is treated with ice water and hydrochloric acid and shaken out with vinegar. The acetic ester extract is washed with a solution of 2N hydrochloric acid, water and a saturated aqueous potassium bicarbonate solution, dried over sodium sulfate! and evaporated. The evaporation residue is distributed between ether and a 1N aqueous sodium hydroxide solution. The aqueous-alkaline solution is acidified with concentrated hydrochloric acid and the formed precipitate is sucked off. The residue in the Nutschen filter is washed with water and recrystallized from vinegar/petroleum ether. The obtained 2-(2-p-toluenesulfonamido-5-chloro-phenyl)-thienone melts at 1 6^4- - 167°C and 2-(2-p-toluenesulfonamido-^--chloro-phenyl)- thienone melts at 1^0 - J\ at°C.

8.*f g 2-(2-p-toluenesulfonamido-5-chloro (respectively V-chloro)-phenyl)-thienone is stirred at room temperature with 100 ml of concentrated sulfuric acid for h hours. Finally, the reaction product is poured into ice and the resulting mixture is made alkaline with concentrated aqueous sodium hydroxide solution while cooling. This forms a precipitate, which is dissolved in ether. The ether solution is washed with water, dried with sodium sulphate and evaporated, whereby a residue is obtained. After recrystallization from ether/petroleum ether in the presence of charcoal and alumina, 2-(2-amino-5-chloro-phenyl)-thienone melts at 97 - 98°G and 2-(2-amino-^-chloro-phenyl)-thienone at 66 - 72°C.

15.5 g of 2-(2-amino-5-chloro(resp..h-chloro)-phenyl)-thienone, 23.8 g of solid potassium hydroxide and 19.6 g of hydrazine hydrate are heated to reflux for 2 hours at 180 ml diethylene glycol. After diluting the reaction mixture with ice water, the solution is extracted with ether. The ether phase is washed three times with water, dried with sodium sulphate and evaporated. 2-(2-amino-5-chloro-benzyl)-thiophene is obtained in the form of an oil with a boiling point of 150 -'157°C/0.1 torr. and 2-(2-amino-If-chloro-benzyl)-thiophene with boiling point 1 37 - 1lf0°C/0.05 torr.

To a solution of 11 g of 2-(2-amino-5-chloro (or h-chloro)-benzyl)-. thiophene in 60 ml of toluene is added dropwise at -3°C with stirring \S ml of a 20% solution of phosgene in toluene. Finally, the solution is allowed to warm up to room temperature under the introduction of a phosgene stream and is then further heated for half an hour to reflux. After removal of excess phosgene by means of a stream of nitrogen, the reaction mixture is evaporated in vacuo and the residue is distilled. 2-(2-isocyano-5-chloro-benzyl)-thiophene with a boiling point of 137 - 139°C/0.1 torr and 2-(2-isocyahato-^-chloro-benzyl)-thiophene with a boiling point of 12 *+ - 125°C/0.05 torr.

By cyclization of 2-(2-isocyanato-5-chloro (or 1f-chloro)-benzyl-thiophene using the method described at the end in example 2, 8-chloro-^-,5-dihydro-10H-thieno is obtained /3 12- cjnjroenzazep±n- k~ one with m.p. 280 - 281°C (after recrystallization from dioxane/acetone) and 7-chloro-i+, 5-dihydro-1 0H-thieno/3,2-07/iybenzazepine -^-one with m.p. -26^ - 266°C (after recrystallization from acetone).

Claims (1)

1. Process for the preparation of tricyclic compounds with the general formula I in which R^ stands for hydrogen, alkoxyalkyl with a total of at most 6 carbon atoms, alkyl or hydroxyalkyl of up to 4 carbon atoms since the hydroxyalkyl group can optionally be further acylated, R^ stands for hydrogen, alkyl, alkoxy or alkylthio, in which the alkyl groups have 1-4 carbon atoms, or stand for halogen or trifluoromethyl, and A stands for the structures in that, a) when A- stands for Zl, X means a -CH2~, -O-, -S-, -NH- or an -N-alkyl group in which alkyl has 1-3 carbon atoms, R2 stands for for hydrogen, alkyl, dialkylaminosulfonyl, alkylsulfonyl, in that the alkyl groups have 1-4 carbon atoms, alkoxy or alkylthio with 1-4 carbon atoms, halogen, nitro, trifluoro methylsulfonyl, trifluoromethoxy, trifluoromethylthio, acetyl, cyano or trifluoromethyl and R^ stands for hydrogen, halogen or alkyl with 1-4 carbon atoms, resp. b) when A stands for Z2, X means a -CH2~ or an -S group, characterized in that a compound of formula II wherein X, A and R^ have the above meaning, is reacted with a metalamine complex consisting of titanium or zirconium and a compound of the general formula III in which R^ has the above-mentioned meaning, and obtained compounds of formula I, in which R^ stands for an acylated hydroxyalkyl group, are optionally saponified, respectively obtained compounds of formula I, in which R^ stands for a hydroxyalkyl group, are esterified.