KR810000540B1 - Process for preparing tricyclic compounds - Google Patents

Abstract

3-Cyano-N-(N,N-dimethylamino-propyl)iminodibenzyl compd. or its acid-addition salt was prepd. by reacting compd. II (M = alkali metal) with III(Z = eliminable group) or IV with compd. V (R1,R2 = H, lower alkyl, 5- or 6-membered saturated hetero cyclic group) or by heating compd. VI or by reacting compd. VII with copper-I-cyanide. I had a ED50 for inhibition of serotonin uptake in rat brain in vitro 1.5X10-9 mol/L.

Description

Method for preparing tricycle compound

The present invention relates to a process for preparing 3-cyano-N- (N, N-dimethylamino-propyl) -iminodibenzyl compound or acid addition salt thereof having the following structural formula (I) having excellent antidepressant action.

3-Cyano-N- (N, N-dimethylamino-propyl) -iminodibenzyl and its acid addition salt, which are structural formula (I) compounds, have an excellent antidepressant effect, which strongly increases the resorption of serotonin in the nervous system in animal experiments. It is proven to inhibit. Therefore, it is used to treat internal or external depression.

A particular benefit is the minimal suppression of anticholinergic side effects that can cause dry mouth, constipation, swelling and illness.

In the present invention, 3-cyano-N- (N, N-dimethylamino-propyl) -imino dibenzyl and acid addition salts thereof are prepared by reacting compounds (II) and (III) of the following general structural formula.

M is an alkali metal atom and Z is a free group.

And reacting with 3-cyano-iminodibenzyl of formula (IV) and a compound of general formula (V).

Wherein R ₁ and R ₂ are each a hydrogen atom or a lower alkyl group, or R ₁ and R ₂ are each a five-membered or six-membered saturated heterocyclic group together with the attached nitrogen atom. And heating 3-cyano-iminodibenzyl-5-carboxylic acid (N, N-dimethylaminopropyl ester) of the following formula (VI).

And 3-bromo-N- (N, N-dimethylaminopropyl) -iminodibenzyl of the following structural formula is reacted with copper-I-cyanide and, if necessary, the base of the resulting structural formula (I) is acid addition salt. Switch to.

3-cyano-substituted starting materials of structures (II) and (IV) can be prepared from iminodibenzyl.

The latter is converted to 5-acetyl-iminodibenzyl by heating with acetylchloride in an inert organic solvent such as toluene. (5-acetyl-iminodibenzyl is converted to 5-acetyl-3-oxalyl-3-iminodibenzyl by a Friedel-Crafts reaction. For this purpose, 5-acetyl-iminodibenzyl is monohydroxy (lower alkyl) Reactions of ester chlorides and preferably monomethyl ester chlorides are carried out in the presence of Friedel Cleft catalysts such as aluminum trichloride, especially at room temperature in a preferred inert solvent such as methylene chloride or weanonated carbon. Partial esterification of the 3-oxalyl group of salyl-iminodibenzyl is carried out by acidic or alkaline hydrolysis of the reaction product in order to completely hydrolyze the ester with α-keto acid, for example, at room temperature. It is more preferred to alkaline hydrolyse the reaction product in the presence of aqueous sodium solution and methanol. 5-acetyl-3-oxalyl-imino di The acetyl group of benzyl is removed by hydrolysis, for example, with alkaline metal hydroxides in water or monohydroxy or polyhydroxy alcohols at the desired high temperature conditions (ie the boiling point of the mixture).

The resulting 3-oxalyl-iminodibenzyl is converted to its 3-oxime acid derivative which is treated with hydroxylamine acid addition salt (ie, hydroxylamine chloride) and acetic acid. This treatment is preferably carried out in weak alkaline or buffered conditions.

Upon proceeding, the mixture is acidified and then the 3-oxime acid derivative is separated in the aqueous phase together with an inert organic solvent such as tetrahydrofuran. The 3-oxime acid derivative is subsequently converted to 3-cyano-iminodibenzyl while the oil phase is separated into water. The preferred temperature to advance is 90 ° to 100 ° C.

Since 3-cyano-iminodibenzyl is a weak base, it is preferred to convert it to an alkali metal derivative of formula (II) before reacting with the starting material of formula (III). It is preferable to react with alkali metal amide or alkali metal hydride such as sodium, potassium or lithium hydride or amide when converting.

The treatment is preferably carried out in a neutral solvent, in particular a polar neutral solvent such as dimethyl foramide.

The temperature is preferably advanced at about 20 to 100 ° C., especially at 50 ° C.

The free atom or group represented by Z in the starting material of formula (III) is preferably a lower aryl substituted with a halogen atom, a lower alkyl or a sulfonyloxy group. The lower alkyl or lower aryl groups present in the sulfonyloxy group of 1 to 4 carbons or 6 to 10 carbons are especially methyl or phenyl or P-tolyl. Halogen here means chlorine, bromine, especially chlorine.

The reaction of the compounds of formula (II) and (III) is carried out in an inert neutral solvent, in particular in an inert polar neutral solvent such as dimethyl foramide. The temperature is preferably run between 20 ° C. and 100 ° C., especially at 50 ° C.

In the starting material of formula (V), R ₁ and R ₂ are lower alkyl groups, with alkyl groups containing 1 to 4 carbon atoms such as methyl, ethyl, isopropyl or n-butyl being preferred. Both R ₁ and R ₂ to which nitrogen atoms are attached represent a saturated heterocyclic group of five-membered and six-membered rings, which are piperidino, pyrrolidino, or morpholino groups.

The reaction of the 3-cyano-iminodibenzyl of formula (IV) with the compound of formula (V) is preferably carried out in the absence of solvent between 200 ° C and 280 ° C, in particular at 250 ° C. If necessary, the reaction proceeds under reduced pressure. The reaction is preferably carried out in the presence of a base catalyst such as an alkali metal salt of weak acid such as acetic acid, formic acid, sodium of carbonate or phthalic acid, potassium salt.

The 3-cyano-iminodibenzyl-5-carboxylic acid (N, N-dimethylaminopropyl ester), the starting material of formula (VI), is new and part of the present invention. It is prepared by the reaction of 3-cyano-iminodibenzyl with phosgene followed by the reaction of the resulting 3-cyano-5-chlorocarbonyl-iminodibenzyl with dimethylaminopropanol.

The heating of the 3-cyano-iminodibenzyl-5-carboxylic acid (N, N-dimethylaminopropyl ester) is preferably between 150 ° C and 250 ° C, especially at reduced pressure.

The required 3-cyano-N- (N, N-dimethylaminopropyl) -iminodibenzyl of formula (I) can be obtained directly by this method. 3-Bromo-N- (N, N-dimethylaminopropyl) -iminodibenzyl, a starting material of the structural formula (VII), is used to prepare an alkali metal salt of 3-bromo-iminodibenzyl and a compound of formula (III). It is prepared by the same method as described above in connection with the reaction of the compound (II) and the compound of the formula (III).

The reaction of 3-bromo-N- (N, N-dimethylaminopropyl) -iminodibenzyl and copper-1-cyanide of the structural formula (III) is carried out at 100 ° C. in a neutral polar organic solvent such as dimethyl foramide. It is preferable to advance between boiling points.

The required 3-cyano-N- (N, N-dimethylamino propyl) -iminodibenzyl of Structural Formula (I) may contain starting materials and a small amount of 3-cyano-iminodibenzyl and 3-bromo-iminodibenzyl. Obtained together. The necessary 3-cyano-N- (N, N-dimethylamino propyl) -iminodibenzyl can be separated from the by-products of this mixture, which is extracted from acidic and organic solvents to alkalinize the aqueous phase, followed by extraction with organic solvents. The solvent is removed and the residue is distilled off.

3-Cyano-N- (N, N-dimethylaminopropyl) -iminodibenzyl of formula (I) is composed of inorganic acids (i.e., hydrochloric acid such as hydrochloric acid or hydrobromic acid and mineral acids such as sulfuric acid, phosphoric or nitric acid) and organic acids (i.e., tartaric acid). , Salts with citric acid, sulfuric acid camphor, sulfoic acid methane, sulfuric acid toluene, salicylic acid, ascorbic acid, tungumic acid, fumaric acid and mandelic acid).

Preferred salts are hydrogen halides, in particular hydrogen chloride. Acid addition salts are preferably prepared by treating the free base with the corresponding non-aqueous acid in a suitable solvent such as ethanol, acetone or acetonitrile.

3-Cyano-N- (N, N-dimethylamino propyl) -iminodibenzyl of formula (I) is a crystalline solid, which is a hydrocarbon substituted with dimethylsulfoxide, dimethylformamide, and chlorine (ie chloroform and methylene chloride). ), And relatively good solubility in alkanols (ie methanol and ethanol), ether and benzene.

The acid addition salt of 3-cyano-N- (N, N-dimethylamino-propyl) -iminodibenzyl of formula (I) is a crystalline solid. It has good solubility in dimethylsulfoxide, dimethyl poramide, alkanols (ie methanol and ethanol), chloroform, methylene chloride and water. However, the solubility is relatively poor in benzene, ether and n-hexane.

As described above, the iminodibenzyl derivatives provided by the present invention have excellent antidepressant activity and can be observed to inhibit serotonin reuptake in the rat brain nerves. To illustrate this antidepressant action, 3-cyano-N- (N, N-dimethylaminopropyl) -iminodibenzyl (substance A) is tested for known analogues according to the following experimental procedure.

Substance A:

3-cyano-N- (N, N-dimethylamino propyl) -iminodibenzylhydrochloride (material provided by the present invention)

Substance B:

N- (N, N-dimethylaminopropyl) -iminodibenzyl hydrochloride (base material)

Substance C:

3-Chloro-N- (N, N-dimethylaminopropyl) -iminodibenzyl hydrochloride (base material)

1. Inhibition of serotonin reuptake in vitro

Reabsorption of serotonin at the neuronal junction of the forebrain of rats is described by J. Pharmacol. exp. Ther. Experiment in accordance with 181, 36, 1972. The 50% inhibitory dose was determined as follows.

In this experiment, substance A is 52- and 42-fold more active than two matrixes B and C.

2. Inhibiting Serotonin Reuptake In Vitro

An experimental procedure similar to that in 1 is used. However, the test substance is injected intraperitoneally. Serotonin reuptake is measured after 1 hour. Untreated mice are used as controls. Then you can get ₅₀ ED.

In this experiment, substance A has the same activity at doses 21 times 2.4 times less than known substances B and C.

3. Inhibiting Serotonin Secondary Resorption in vivo

The so-called "membrane pump" action is Biochem. Pharmacc. Experiment by the method described in 20, 707, 1971. Then you can get ₅₀ ED.

Here substance A showed the same activity at doses 18 and 9 times lower than known substances B and C.

The following results on the inhibition of serotonin reuptake in rat platelets are more extensive than the antidepressant action of the iminodibenzyl derivatives provided herein.

4. Inhibiting Serotonin Reuptake In Vitro

0.5 ml of blood cavity is treated in 50 μl of physiological sodium chloride solution as a different concentration of test substance. After incubation at 37 ° C. for 5 minutes, serotonin (C ¹⁴ : 0.1 μM) is added and the mixture is incubated again at 37 ° C. for 5 minutes.

Serotonin concentration can be determined as C ¹⁴ for measurement.

Control experiments without the use of test substances are also performed. The concentration (ED ₅₀ ) that inhibits serotonin reuptake by 50% was measured separately for the three concentrations of the test substance.

A has 130 times and 20 times greater activity than known substances B and C.

5. Inhibiting Serotonin Reuptake In Vivo

Intraperitoneal injection of 5.0 mg / kg of the test substance twice a day for 4 days, the rat died 12 hours after the last administration. J. pharmacol exp. Ther. Serotonin was measured using a fluorescence spectrometer described in 117, 82 et seq, 1956 to determine the protein content of J. Biol. chem. It can be measured by the colorimetric method described in 193, 265 et seq, 1931.

The iminodibenzyl derivative provided by the present invention can be used as a medicine. For example, it may be made into a pharmaceutical formulation containing a drug in combination with an acceptable pharmaceutical carrier. These carriers are organic, inorganic inert carriers suitable for oral and parenteral administration, including water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gum arabic, polyalkylene glycols, petroleum jelly and the like. Pharmaceutical formulations may be in the form of solids such as tablets, sugars, suppositories or capsules, or in liquid forms such as liquids, suspensions or emulsions.

Pharmaceutical formulations may be sterile and may contain adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers and salts required for various osmotic or buffering. Another therapeutically necessary substance is included. Convenient formulations contain 1 to 200 mg of 3-cyano-N- (N, N-dimethylamino propyl) -iminodibenzyl or acid addition salts thereof of formula (I). Convenient oral dosages range from 1 mg / kg to 10 mg / kg.

Convenient parenteral dosages range from 0.1 mg / kg day to 1 mg / kg day.

The above-mentioned dosage range is determined according to the circumstances of each individual or the instructions of a doctor.

The following example illustrates the process provided by the present invention.

Example 1

230 g (4.8 moles) of 50% sodium hydride dried in molecular sieve three times with 1 l of n-hexane and 4.5 l of dimethyl foramide in mineral oil and 20 l 4 balls with stirrer, capacitor, thermometer, dropping funnel and inert gasifier Fill the flask.

To this suspension was added dropwise a solution of 919 g (4.2 moles) of 7 L of 3-cyano-iminodibenzyl in dimethylporamide in about 2 hours at room temperature. The mixture is stirred at 50 ° C. for 0.5 h and then cooled and added dropwise to a solution of 1120 g of N, N-dimethylaminopropyl chloride of 2.5 L of dimethylporamide within about 1 hour at 20 ° to 25 ° C. The mixture is again warmed to 50 ° C. and stirred at this temperature for 3 hours. Then continue to stir overnight at room temperature. After complete reaction, excess sodium hydride is decomposed by the slow dropwise addition of 2.5 liters of water while passing through nitrogen. The mixture is then poured into 12 liters of cold water and extracted once with 20 liters of ethyl acetate and once with 10 liters of ethyl acetate. The ethyl acetate solution is washed once with 6 liters of water, mixed and extracted once with 6 liters of 1-N hydrochloric acid and once with 8 liters of water. The acid solution is brought to pH with cooling with concentrated sodium hydroxide. The mixture is extracted once with 20 liters of ethyl acetate and once with 10 liters of ethyl acetate. The oil phase is washed once with 6 liters of water. Ethyl acetate solution is evaporated without drying in vacuo. The obtained residue was filtered with toluene while passing through 6 kg of aluminum oxide (activity II: neutral). The same portion of thin layer chromatography is collected and evaporated. Obtain about 1230 g of base, which is dissolved in 10 l of isopropanol and treated with 500 ml of 30% alkanolic hydrochloric acid until a Congo-red reaction occurs. The solution is warmed to 40 ° to 50 ° for 2 hours to crystallize the hydrochloride. The mixture is then slowly cooled to room temperature and subsequently cooled to 0 ° C. The crystals are filtered off and washed with 3 liters of ice-cold isopropanol each time and twice with 2.5 liters of anhydrous ether. The product is dried over sodium hydroxide in a drying oven for 16 hours at 40 ° C. vacuum. 3-Cyano-N- (N, N-dimethylamino propyl) -iminodibenzyl hydrochloride is obtained and further purified and then recrystallized as follows.

1095 g of 3-cyano-N- (N, N-dimethylamino propyl) -iminodibenzyl hydrochloride is dissolved in 2.6 L of hot anhydrous ethanol and treated with 2.6 L of anhydrous ether to stir the product to crystals. Crystal further for 1 hour at room temperature and stirred for 3 hours at 0 ° C. The crystals are suction filtered, washed with 1.5 liters of ether / ethanol (1: 1) and dried over sodium hydroxide for 16 hours at 40 ° C. vacuum.

3-Cyano-N- (N, N-dimethylamino propyl) -iminodibenzyl hydrochloride is obtained having a melting point of 200 ° to 202 ° C. Starting material 3-cyano-iminodibenzyl is prepared as follows.

585 g (3 mol) of iminodibenzyl are dissolved in 2000 ml of toluene at 80 ° C. in a 6 L four-necked flask equipped with a stirrer, capacitor, thermometer and dropping funnel.

370 ml (408.4 g: 5.2 mol) of acetyl chloride were added dropwise within 0.75 hours at 80 ° C. The mixture is then cooled to room temperature using an ice bath and excess acetylchloride is destroyed by the dropwise addition of 200 ml of ethanol and 100 ml of water. The mixture is also treated with 500 ml of ether. The aqueous phase is separated and reextracted once with 1500 ml of ether. The organic phase is washed three times with 1000 ml of water each time. The combined organic phases are treated with 50 g of carbon, dried over sodium sulfate and evaporated to dryness in vacuo. The resulting crude product is dissolved in 1000 ml of ether with stirring and the solution is stirred overnight to crystallize the product. The crystals are filtered off and washed with a small amount of ice cold ether. 539 g of 5-acetyliminodibenzyl having a melting point of 95 ° to 96 ° C is obtained.

The mother liquor is evaporated in vacuo and treated with 200 ml of ether. This is poured into about 70 ml of petroleum ether, which is a low boiling point, with slight stirring until turbidity occurs, and stirred for 4 hours. Suction filtration and washing of the crystals with a small amount of cold ether gave 5-acetyl iminodibenzyl again with a melting point of 94 ° to 96 ° C.

1800 g (13.5 mol) of 3600 ml of aluminum chloride (13.5 mol) of methylene chloride are dried in a molecular sieve and placed in a 20 L round flask equipped with a dropping funnel with stirrer, capacitor, thermometer, gas introduction tube and hydrochloric acid gas consumption under inert gas. To this mixture is added dropwise a solution of 712 g of 5-acetyl-iminodibenzyl 1800 ml of methylene chloride dried in the molecular sieve within about 0.5 hours at room temperature, and the resulting mixture is further stirred for about 10 minutes. In addition, 830 ml (9 mol) of a monomethyl ester chloride solution of hydroxyl and 1200 ml of methylene chloride were added dropwise within 0.5 hours at room temperature. In doing so, the internal temperature is gradually raised to 33 ° C. The mixture is stirred overnight at room temperature or for 16 hours. After completion of the reaction, 3000 ml of 3-N hydrochloric acid is slowly added dropwise while cooling the temperature well with ice not to exceed 20 ° C. Doing so makes the contents of the flask so thick that it cannot be stirred and must be diluted with 5000 ml of ethyl acetate. The mixture should be treated carefully with 2000 ml of distilled water with vigorous stirring. The flask contents were transferred to a 30 L agitation vessel, treated again with 5000 ml of ethyl acetate and stirred. The aqueous phase is reextracted once with 4000 ml of ethyl acetate. The organic phase is washed five times with 4000 ml of diluted sodium chloride solution each time (2000 ml of saturated sodium chloride solution and 2000 ml of water). And concentrated in vacuo without drying. Water is azeotropically distilled with 1500 ml of toluene. On complete evaporation, a resin is obtained which is dissolved in 3800 ml of methanol in a steam bath and placed in a 20 L stirred flask. The methanol solution cooled in the ice bath is cooled further and treated with 4550 ml of 1N sodium hydroxide while the temperature does not exceed 15 ° C.

After complete saponification, the flask contents are poured into 8000 ml of cold water and brought to Congo acid with about 850 ml of concentrated hydrochloric acid with stirring. The mixture is extracted once with 12 liters of ethyl acetate and once with 4 liters of ethyl acetate. The organic phase is washed six times with 4 liters of water each time. The ethyl acetate phases were combined and concentrated to 1-2 liters in vacuo without drying, but the water still remained azeotropic with toluene. The crystals obtained after concentration are cooled to room temperature with stirring, stirred for 2 to 3 hours at this temperature, and then filtered by suction. The filtered cake is partially washed with 1 L of ice cold ethyl acetate and dried in vacuo at 40 ° C. In thin layer chromatography, 5-acetyl-3-oxalyl-iminodibenzyl having the same melting point of 205 ° C is obtained.

658 g (11.7 mol) of potassium hydroxide are dissolved in 5 l of water by raising the temperature to 45 ° C in a 20 l four-necked flask with a stirrer, a capacitor, a thermometer and an inert gas introduction tube.

1000 g (3.2 mole) of 5-acetyl-3-oxalyl-iminodibenzyl are introduced into the solution with an inert gas and the mixture is stirred in an oil bath at 135 ° C. for 24 hours until saponification occurs completely. The flask contents are cooled to room temperature and treated with 100 ml of ethyl acetate without bubbles. And within 1.5 hours at 15 ° C to 20 ° C dropwise to a solution consisting of 2 L of water, 540 ml of glacial acetic acid and 488 g (6.5 mol) of hydroxylamine hydrochloride. After complete dropwise addition, the mixture is stirred for 5.5 hours and the flask contents are stirred and combined with 12 liters of ethyl acetate. The mixture is brought to pH 1-2 with concentrated hydrochloric acid, the aqueous phase is separated off and reextracted once with 5 liters of ethyl acetate. The organic phase is washed five times with 5 liters of water each time for a total of 25 liters, dried over sodium sulfate and evaporated. The crude product thus obtained was dissolved in 3 L of tetrahydrofuran and added dropwise to 12 L of boiling water in a 20 L stirring flask within about 1.5 to 2 hours. At this time, the tetrahydrofuran was stirred while keeping the internal temperature between 85 ° C and 95 °. Distill.

Then, within 0.25 hours, 28.6 g (0.4 mol) of a 200 ml hydroxylamine hydrochloride solution of water was added dropwise, and the resulting mixture was stirred at 90 ° to 95 ° C. for 5 hours. At this time, a resinous precipitate is formed and the water phase is cleared. When this is done the mixture is treated as follows.

Just pour off the clear aqueous solution that floated on the surface. The remaining residue is dissolved in 12 l of methylene chloride and washed twice with 5 l of water each time. The aqueous phase is extracted again with 2 liters of methylene chloride. All organic phases are concentrated to about 5 L and nitrile crystallized. To crystallize completely, the mixture is frozen overnight and the crystals are then filtered. The obtained mother liquor is filtered through a column containing methylene chloride and 4.5 kg of aluminum oxide (active hair II; neutral), and the same portions of thin layer chromatography are collected and evaporated in vacuo. The residue obtained here is suspended in about 1 liter of ether / methylene chloride (3: 1) in combination with the above-mentioned drawbacks. The suspension is filtered and the crystals are washed again with a small amount of ether / methylene chloride (3: 1). The same 3-cyano-iminodibenzyl is obtained in thin layer chromatography with a melting point of 164 ° -165 ° C. after drying in 40 ° C. vacuum.

Example 2

1.10 g (0.005 mol) of 3-cyano-iminodibenzyl and 0.25 g (0.0025 mol) of potassium acetate are heated to 210 ° C. At this temperature, 1.74 g (0.010 mol) of dimethylaminopropyl dimethylcarbamate are added dropwise within 15 minutes. The mixture is cooled to room temperature. Treat with 20 ml of water and extract twice with 20 ml of chloroform each time. The combined chloroform phases are washed with 20 ml of water and each time extracted with 10 ml of 5% methanesulfonic acid to separate the base composition from the neutral composition. The aqueous phase is alkaline with 28% aqueous sodium hydroxide solution and extracted with chloroform. After drying over magnesium sulfate, it is concentrated under reduced pressure. The residue is distilled at 200 ° C / 0.05mmHg. The light yellow distillate produced crystallizes naturally. 3-Cyano-N- (N, N-dimethylaminopropyl) -iminodibenzyl is obtained having a melting point of 55 ° to 57 ° C.

Example 3

1.30 g (0.0036 mol) of 3-bromo-N- (N, N-dimethylaminopropyl) -iminodibenzyl and 0.41 g (0.0046 mol) of copper-I-cyanide were refluxed for 6 hours in the presence of 5 ml of dimethylporamide. Boil it while making it. The mixture is cooled to room temperature, 20 ml of chloroform are added and the resulting mixture is filtered.

As a residue, brown oil with the following composition by gas chromatography is left. 3-cyano-N- (N, N-dimethylaminopropyl) -iminodibenzyl 72%, 3-bromo-N- (N, N-dimethylaminopropyl) -iminodibenzyl 4%, 3-cyano 16% iminodibenzyl and 1% 3-bromoiminodibenzyl.

Purification of the crude product is carried out as follows.

Brown oil is dissolved in 20 ml of chloroform and extracted three times with 10 ml of 5% methanesulfonic acid. The acid portion is washed with 20 ml of ethyl acetate and alkaline with concentrated aqueous sodium hydroxide solution. The resulting suspension is extracted twice with 20 ml of chloroform each time. The chloroform phases are combined, washed with 50 ml of water, dried over magnesium sulfate and evaporated under reduced pressure. The oil residue is distilled off under strong reduced pressure. 3-cyano-N- (N, N-dimethylaminopropyl) -iminodibenzyl of yellow oil having a boiling point of 240 ° C./0.12 mmHg is obtained, which is crystallized overnight with a melting point of 53 ° to 55 ° C.

The preparation of 3-bromo-N- (N, N-dimethylaminopropyl) -iminodibenzyl used as starting material is as follows;

1.50 g of sodium hydride suspension of 50% mineral oil is washed with 10 ml of n-hexane and suspended in 5 ml of N, N-dimethylporamide. This suspension is added dropwise to a 2.2 g solution of 3-bromo-iminodibenzyl 5 ml of dimethylporamide within 10 minutes at room temperature. The resulting solution is stirred at 70 ° C. for 0.25 h, cooled to rt and added dropwise to a solution of 3.67 g of N, N-dimethylaminopropyl chloride of 4 ml dimethylporamide. The mixture is stirred at 60 ° C. for 16 h and then treated with 40 ml of water. The resulting suspension is extracted twice with 20 ml of ethyl acetate. Collect ethyl acetate extracts, wash eight times with 50 ml of water and extract three times with 20 ml of 10% methanesulfonic acid. The acid portion is washed twice with 20 ml of ethyl acetate and again alkaline with concentrated sodium hydroxide solution.

The base product is extracted twice with 30 ml of chloroform, dried over magnesium sulfate and concentrated under reduced pressure. The brown oil residue is distilled off under strong reduced pressure. 3-Bromo-N- (N, N-dimethylaminopropyl) -iminodibenzyl is obtained with a boiling point of 230 ° C./0.008 mmHg.

Example 4

1.90 g of 3-cyano-iminodibenzyl-5-carboxylic acid (N, N-dimethylaminopropyl ester) is heated at 170 ° C. for 3 hours at 210 ° C. for 1 hour under reduced pressure. The obtained brown oil is combined with 30 ml of chloroform and extracted twice with 20 ml of 1N methanesulfonic acid. The acid extract is washed with 30 ml of ethyl acetate and subsequently alkalined with concentrated sodium hydroxide solution. The resulting base product is extracted twice with 20 ml of chloroform each time. The organic solution is washed with water, dried over magnesium sulfate and evaporated. At this time, 3-cyano-N- (N, N-dimethylaminopropyl) -iminodibenzyl having a melting point of 53 to 55 ° is obtained.

The method for preparing 3-cyano-iminodibenzyl-5-carboxylic acid (N, N-dimethylaminopropyl ester) used as a starting material is as follows.

2.70 g of 3-cyano-iminodibenzyl are dissolved in 20 ml of orthoxylene. Dry in sulfuric acid and introduce a light phosgene stream into the solution and hold it at 100 ° C. for 7 hours. Subsequently, the solvent is evaporated while stirring the solution at the same temperature for 3 hours. 3-Cyano-5-chlorocarbonyl-iminodibenzyl having a melting point of 129 ° to 130 ° is obtained.

Dissolve 2.89 g of 3-cyano-5-chlorocarbonyl-iminodibenzyl and heat the mixture at 1.13 g of 3-dimethylaminopropanol and 20 ml of benzene while refluxing under argon for 18 hours. The resulting solution is alkaline with 5 ml of 2N aqueous sodium hydroxide solution and washed four times with 70 ml of water each time. The benzene phase is extracted twice with 50 ml of 1-N methanesulfonic acid each time and the aqueous phase is washed with 20 ml of ethyl acetate. The aqueous phase is collected, alkalined with concentrated sodium hydroxide, and extracted twice with 30 ml of chloroform each year. The chloroform phases are combined, washed with water, dried over magnesium sulphate and concentrated under reduced pressure. 3-Cyano-iminodibenzyl-5-carboxylic acid (N, N-dimethylimino propylester) is obtained in the form of a brown oil.

The following items each describe the present invention.

1. A process according to the claims for converting the base of formula (I) to hydrochloride.

2. Process according to claim 1 or 1 above, wherein N-sodium-3-cyanoiminodibenzyl is reacted with N, N-dimethylamino-propylchloride.

3. The process according to 2 above, which is reacted in the presence of dimethylformamide at a temperature of 20 ° to 100 ° C.

4. A process for the production of tricyclic compounds by selecting any of the methods of the above examples.

5. A method of treating neurological diseases by administering an effective amount of a tricyclic compound to a human body.

Claims (1)

Reacting a compound of formula (II) with a compound of formula (III) or 3-cyano-iminodibenzyl of formula (IV) with a compound of formula (V) or 3-cyano- of formula (VI) Heat the iminodibenzyl-5-carboxylic acid (N, N-dimethylaminopropylester) or with 3-bromo-N- (N, N-dimethylaminopropyl) -iminodibenzyl A method for producing a tricyclic compound having the structural formula (I) or an acid addition salt thereof by reacting with copper-I-cyanide.

In the above structural formula M is an alkali metal atom Z is a tally R ₁ and R ₂ are each hydrogen or a lower alkyl group or R ₁ and R ₂ connected with a nitrogen atom are pentagonal or hexagonal saturated heterocyclic groups.