NO143169B - WALL CONSOLE TO FIX PRIOR MARKET FITTINGS - Google Patents

Description

Process for the preparation of 5-(Y-secondary aminopropylidene)-dibenzoheptane compounds.

The present invention relates to a

process for the preparation of 5-(γ-secondary aminopropylidene)-dibenzoheptane compounds of the general formula

where the dotted bond may be

hydrated,

R, means one with up to 4 carbon atoms containing an alkyl residue, preferably methyl or ethyl, or

the benzyl residue,

R2 is hydrogen or halogen and

A" an optionally with a lower alkyl residue with up to 4 carbon atoms substituted ethylene residue,

and their salts.

The procedure is characterized by

that one transacts a connection with it

general formula

where A and R 2 have the meanings given above and Hal is a halogen atom, with a primary amine of the general formula

where R, has the meaning indicated above, and optionally transfers the obtained compounds to their acid addition salts.

The starting compounds of formula II required for the method according to the invention can be, e.g. obtain in the following way: An optionally halogen-substituted dibenzo [a,e] cyclohepta [1,5] dien-5-one or dibenzo [a,é] cyclohepta [1,3,5]-trien-5-one is reacted by means of an organometallic reaction with a propenyl halide or with a propylene halide which exhibits an ether function. These halides can be substituted in the carbon chain with an alkyl residue containing up to 4 carbon atoms. The conversion is preferably carried out via a magnesium compound. It is therefore appropriate to stimulate the turnover by adding a suitable alkyl halide, such as methyl iodide or ethyl bromide.

Examples of propenyl halides or etherified propyl halides are 1-bromo-2-propene, 1-chloro-2-methyl-2-propene, 1-chloro-3-methoxy-propane and 1-chloro-2-methyl-3-methoxy-propane .

The alkoxy group is suitably a lower alkoxy group, such as methoxy, ethoxy, propoxy, butoxy, which is located in the terminal position of the alkyl halide.

(o-methoxy-propyl-magnesium compounds are preferred starting materials. The ether function can be next to alkoxy, e.g. also aralkyloxy, such as benzyloxy or phenethyloxy, or also tetrahydropyranyloxy.

The condensation products obtained in the reaction of the tricyclic ketones with an organometallic compound bearing an ether group or an unsaturated group in the end position are transferred by hydrolysis to the tertiary carbinols, which can be separated and isolated by treatment with suitable, water-immiscible organic solvents, such as e.g. ether, acetic acid ethyl ester, chloroform, methylene chloride, from the by-products of the reaction. The tertiary carbinols thus obtained are solid, mostly easily crystallizable compounds.

In a further reaction step, the ether function in the hydrolysis product obtained according to a method variant is replaced, during simultaneous dehydration of the carbinol, with halogen. The same reaction product is obtained by simultaneous water splitting through the anchoring of halogen-hydrogen at the unsaturated propenyl residue formed in the end position according to the second variant. This reaction sequence is carried out with advantage as described in the following:

1) The hydrolysis product is treated with hydrogen bromine, suitably with a concentrated aqueous solution of hydrogen bromine at boiling temperature or with a solution of hydrogen bromine in glacial acetic acid at room temperature, whereby the corresponding 5-(M-bromopropylidene) derivative is produced. 2) The hydrolysis product is treated with phosphorus oxychloride, which is advantageously done at reflux temperature. Thereby the corresponding 5-(w-chloro-propylidene)r derivative is formed. The 5-(«-halo-propylidene) derivatives are mostly viscous, partly crystallisable substances, which can be distilled without cleavage in high vacuum. The production of compounds of formula II can be visualized through the following reaction scheme

In the formulas given above, R2, A and the dashed bond have the meanings given above and R3 and R4 mean hydrogen

or lower alkyl.

The reaction of the products of formula II with the amines of formula III is conveniently carried out in an inert organic solvent such as benzene or toluene. One works best at an increased temperature, e.g. at the boiling temperature of the mixture, or in the case of volatile amines, in a closed tube, e.g. at a temperature of approx. 100°C. Furthermore, it is appropriate to carry out the reaction in the presence of an inorganic or organic acid-binding agent. As an inorganic acid-binding agent, e.g. anhydrous potassium carbonate is used. The same amine, which is used for the reaction with the halogen compound, advantageously serves as an organic acid-binding agent. A suitable embodiment consists in using two moles of amine for one mole of halogen compound. As amine with formula III, monomethyl, ethyl, isopropyl or benzylamine is advantageously used.

The tricyclic compounds obtained according to the method according to the invention consist, provided that they are substituted with halogen in the aromatic rings and/or carry a branched side chain of an isomer mixture. These can be separated according to methods known in and of themselves, e.g. due to different solubility of the bases or addition salts by fractional crystallization in cis-trans and/or optically active antipodes.

The invention also covers the preparation of acid addition salts of the aforementioned tricyclic compounds. Such salts are e.g. those with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, and those with organic acids, e.g. acetic acid, oxalic acid, citric acid, lactic acid, tartaric acid.

The compounds obtained according to the invention are distinguished by their multiple effects on the nervous system. Thus, anesthetic potentiating, adrenolytic, sedative, antihistamine-like, anti-emetic, antipyretic, local anesthetic and hypothermic effects have been established. Particularly striking is the rapid onset of action when these substances are administered. The compounds can find use as pharmaceuticals, e.g. in the form of pharmaceutical preparations, which contain them or their salts in mixture with a pharmaceutical, organic or inorganic inert carrier material suitable for enteral or parenteral administration, such as e.g. water, gelatin, milk sugar, starch, magnesium stearate, talc, vegetable oils, rubber, polyalkylene glycols, vaseline, etc. The pharmaceutical preparations can be in solid form, e.g. as tablets, dragées, suppositories, capsules, or in liquid form, e.g. as solutions, suspensions or emulsions. If necessary, they are sterilized and/or contain auxiliary substances, such as preservatives, stabilisers, wetting agents or emulsifiers, salts to change the osmotic pressure or buffers. The preparations contain per administration unit preferably 5-100 mg of the active substances obtained according to the invention. They may also contain other therapeutically valuable substances.

Example 1.

10 g of 5-(3'-bromopropylidene)-dibenzo-[a,e]cyclohepta[1,5]diene and 25 ml of a 20% alcoholic methylamine solution

heated for 8 hours in a closed tube at 100°. After cooling, the alcohol is distilled off under reduced pressure, the residue is taken up in ether, the ethereal solution is washed with water and shaken with dilute hydrochloric acid. By treating the aqueous, acidic solution with excess potassium carbonate, extracting the separated oil with ether, drying and evaporating the ethereal solution, 5-(3'-methylaminopropylidene)-dibenzo[a,e]-cyclohepta[l,5 ]dien, which distils at 150—160<o>/0.03 mm.

The hydrochloride is recrystallized from

alcohol-ether and melts at 218—220°.

The 5-(3'-bromo-propylidene)-dibenzo[a,e]cyclohepta[1,5]diene introduced as starting product can be prepared as follows: In a 2 liter three-necked flask equipped with a stirrer, dropping funnel and cooling Then cover 15 g of magnesium shavings with 60 ml of dry ether and add 0.5 ml of methyl iodide.

After the lively reaction has subsided, a solution of 54.6 g is added

1-chloro-3-methoxy-propane dropwise in 300 ml

dry ether in such a way that the reaction mixture is kept at a boil. It is boiled for a further 5 hours under reflux at 45°.

The reaction mixture is then cooled with ice water, a solution of 50 g of dibenzo[a,e]cyclohepta[1,5]dien-5-one is added dropwise in 600 ml of dry ether over the course of one hour and the whole is stirred for a further 17 hours under reflux at 40°. The following day, it is cooled once again with ice water and a cold saturated ammonium chloride solution is added to the reaction mixture. The organic layer is separated, the aqueous phase is shaken out twice, each time with 150 ml of ether and the combined ether portions are dried over sodium sulphate and evaporated. The residue gives, after recrystallization from a mixture of high-boiling and low-boiling petroleum ether, colorless crystals of 5-hydroxy-5-(3'-methoxy-propyl)-dibenzo[a,e]cyclohepta[1,5]diene melting at 88-89° . Yield 88%.

20 g of the obtained 5-hydroxy-5-(3'-methoxy-propyl)-dibenzo[a,e]cyclohepta-[1,5]diene and 50 ml of a 48 °/o aqueous solution of hydrogen bromide are boiled for 12 hours under vigorous stirring during reflux. After cooling, the reaction mixture is shaken twice, each time with 100 ml of ether, the combined ether portions are washed neutrally with aqueous sodium bicarbonate solution and water and evaporated. The residue gives, after distillation in high vacuum, 5-(3'-bromo-propylidene)-dibenzo [a,e] cyclohepta [1,5] diene with boiling point 145-150°/ 0.07 mm Hg in the form of an oil, which quickly hardens. It can be recrystallized from a mixture of high-boiling and low-boiling petroleum ether and then melts at 74-76°C. Yield 86.5%.

Example 2.

A mixture of 20 g of 5-(3'-bromopropylidene)-dibenzo[a,e]cyclohepta[1,5]diene (according to Example 1), 100 ml of dry toluene and 50 g of isopropylamine is heated in a shaking autoclave under 20 atii nitrogen for 7 hours at 100°. After cooling, the toluene and the excess isopropylamine are distilled away under reduced pressure, the residue is shaken with ether and diluted caustic soda, the ethereal solution is separated, washed neutral with water, dried over sodium sulfate and evaporated. Distillation of the oily residue under a pressure of 0.05 mm Hg at 165° yields 5-(3'-isopropylamino-propylidene)-dibenzo[a,e]cyclohepta^,5]diene. The hydrochloride is recrystallized from alcohol-ether and melts at 239-242°.

Example 3.

50 g of ethylamine, 100 ml of dry toluene and 20 g of 5-(3'-bromo-propylidene)-dibenzo[a,e]-cyclohepta[1,5]diene (according to example 1) are mixed at -15° and shaken in a autoclave under 20 atii nitrogen 7 hours at 100— 110°. After cooling, the toluene and the excess ethylamine are distilled away, the residue is shaken with ether and diluted caustic soda, the ethereal solution is separated, washed with water, dried over sodium sulfate and evaporated. The distillation of the residue gives under a pressure of 0.1 mm Hg at 160° the 5-(3'-ethylamino-propylidene)-dibenzo [a,e]cyclohepta [1,5] diene. The hydrochloride is recrystallized from ethanol-ether and melts at 262-264°.

Example 4.

14 g of 5-(3'-bromo-propylidene)-dibenzo-[a,e]cyclohepta[1,5]diene (according to example 1) and 50 g of benzyl amine are dissolved in 100 ml of dry xylene and the solution is boiled for 5 hours under reflux . After cooling

dilute with 200 ml of ether, wash several times with water, dry over sodium sulphate and first distill the ether and

the xylol under water tr eel pump vacuum,

then the excess benzylamine under a pressure of 0.05 mm Hg at a bath temperature of 160°. The 5-(3'-benzylamino-propylidene)-dibenzo[a,e]cyclohepta[1,5]diene, which remains as a thick oil, is converted to the hydrochloride. This melts after recrystallization from ethanol-ether at 174-176°.

Example 5.

To a mixture of 100 ml of dry toluene and 40 g of methylamine is added at -20° 20

g 5-(3'-bromopropylidene)-dibenzo[a,e]-cyclohepta[1,3,5]triene. The reaction mixture is heated in an autoclave under 20 ati of nitrogen for 7 hours to 100°. After cooling, the excess amine and toluene are distilled away under reduced pressure and

the residue is shaken with ether and aqueous potassium carbonate. The ethereal solution is separated, washed with water and dried over sodium sulfate. From the residue, you get 5-(3'-methylamino-propylidene)-dibenzo [a,e]cyclohepta[1,3,5]triene with a boiling point of 150°/0.1

mm Hg. The hydrochloride is recrystallized from ethanol-ether and melts at 181-183°. The 5-(3'-bromopropylidene)-dibenzo[a,e]cyclohepta[1,3,5]triene introduced as starting product can be prepared as follows: In a 1 liter three-necked flask equipped with a stirrer, dropping funnel and cooler, cover 7.5 g of magnesium shavings with 30 ml of dry ether and add 10 drops of methyl iodide. After the lively reaction has subsided, a solution of 27.3 g of 1-chloro-3-methoxy-propane in 150 g of dry ether is added dropwise over the course of one hour. It is boiled for a further 3 hours at 45° under a reflux condenser. A solution of 21 g of dibenzo [a,e]cyclohepta[1,3,5]trien-5-one in 300 ml of dry ether is then added over the course of one hour to the ice-water-cooled reaction mixture and the whole is boiled for a further 3 hours during reflux cooling. The following day, it is cooled once more with ice water and a cold saturated ammonium chloride solution is added to the reaction mixture. The organic layer is separated, the aqueous phase is shaken out twice, each time with 100 ml of ether and the combined ether portions are dried over sodium sulphate and evaporated. The residue gives, after recrystallization from petroleum ether, f heirless crystals of 5-hydroxy-5-(3'-

methoxy-propyl )-dibenzo [a,e] cyclohepta-[1,3,5]triene, which melts at 90—91° Another crystal form with melting point 78 —79° may occasionally appear, which, however, easily by intimate tearing of a mixture of both forms can be transferred in the higher molten form. Dividend 77 o/o.

15 g of 5-hydroxy-5-(3'-methoxy-propyl)-dibenzo[a,e]cyclohepta[1,3,5]triene and 40 ml of a 48% aqueous solution of hydrogen bromide are boiled for 20 hours under vigorous stirring under reflux. After cooling, the reaction mixture is shaken twice, each time with 100 ml of ether, the combined ether portions are washed neutrally with water, sodium bicarbonate solution and water and evaporated. The residue gives, after distillation in high vacuum, 5-(3'-bromopropylidene)-dibenzo[a,e]cyclohepta[1,3,5]triene with a boiling point of 150°/0.1

mm Hg as yellow oil, which quickly solidifies. Yield 67%.

Example 6.

To a mixture of 30 ml of dry toluene and 40 g of methylamine is added at -10 to -20° 3-chloro-5-(3'-bromo-propylidene ^dibenzo [a,e] cyclohepta [1,5] diene and the whole heated for 7 hours in an autoclave at 100°. After cooling, the excess methylamine and toluene are distilled off under reduced pressure, the residue is shaken with ether and dilute sodium hydroxide solution, the ethereal solution is separated, washed with water, dried over sodium sulfate and evaporated. 3- chloro-5-(3'-methylamino-propylidene ^dibenzo [a,e] cyclohepta [1,5] diene remains as a thick oil and is converted to the hydrochloride. Melting point, after recrystallization from ethanol, 260—262°.

The 3-chloro-5-(3'-bromo-propylidene)-dibenzo[a,e]-cyclohepta[1,5]diene introduced as starting product can be prepared as follows: In a 2 liter three-necked flask, which is fitted with a stirrer , dropping funnel and cooler, cover 15 g of magnesium shavings with 60 ml of dry ether and add 0.5 ml of methyl iodide.

After the lively reaction has subsided, a solution of 41 g of 1-chloro-3-methoxy-propane in 300 ml of dry ether is added dropwise so that the reaction mixture is kept at a boil. It is boiled for a further 5 hours at 45° under reflux.

The reaction mixture is then cooled with ice water, a solution of 47.8 g of 3-chloro-dibenzo[a,e]cyclohepta[1,5]dien-5-one in 600 ml of dry ether is added dropwise over the course of one hour and the whole is stirred further for 17 hours at 40° under reflux. The following day, it is cooled once more with ice water and a cold saturated ammonium chloride solution is added to the reaction mixture. The organic layer is separated, the aqueous phase is shaken out twice, each time with 150 ml of ether and the combined ether portions are dried over sodium sulphate and evaporated. The residue gives, after recrystallization from high-boiling petroleum ether, colorless crystals of 3-chloro-5-hydroxy-5-(3'-methoxy-propyl)-dibenzo[a,e]-cyclohepta[1,5]diene melting at 67

-69°. Yield 80%.

30 g of the 3-chloro-5-hydroxy-5-(3'-methoxy-propyl)-dibenzo[a,e]cyclohepta[1,5]diene obtained is added portionwise to 100 ml of a cold saturated hydrogen bromide solution in glacial acetic acid. While stirring, the temperature is slowly raised to 25° and left overnight at this temperature. The following day, the mixture is cooled again with ice water, saturated once more with dry hydrogen bromide and allowed to stand at room temperature for 20 hours. It is then diluted with 2 liters of ice water, the oil is extracted once more with ether, the ether portions are washed with water, sodium bicarbonate, water, dried over sodium sulphate and evaporated. The residue gives, after distillation in high vacuum, 3-chloro-5-(3'-bromo-propylidene)-dibenzo[a,e]cyclohepta[1,5]diene with a boiling point of 195/0.04 mm Hg.

Example 7.

10 g of 5-(3'-chloro-propyhdene)-dibenzo-[a,e]cyclohepta[1,5]diene and 30 ml of a 20% alcoholic methylamine solution

heated for 8 hours in a closed tube at 100°. After cooling, the alcohol is distilled off under reduced pressure, the residue is shaken with ether and aqueous potassium carbonate, the ethereal solution is washed with water, dried over sodium sulphate and evaporated. The 5-(3'-methylamino-propylidene)-dibenzo[a,e]-cyclohepta[1,5]diene described in example 1 is obtained with a boiling point of 150-160°/0.03 mm Hg. Melting point of the hydrochloride 218-220°.

The 5-(3'-chloropropylidene)-dibenzo[a,e]cyclohepta[1,5]diene introduced as starting product can be prepared as follows.

10 g of 5-hydroxy-5-(3'-methoxy-propyD-dibenzo[a,e]cyclohepta[1,5]diene (according to example 1) are dissolved in 25 ml of phosphorus oxychloride and the solution is boiled under bake for 3 hours, then evaporate the phosphorus oxychloride under reduced pressure

pressure, shakes the resin-like residue with ether and ice water until everything has dissolved, separates the ethereal solution, washes it with water, sodium bicarbonate solution, again with water, dries and concentrates. By distilling the residue under a pressure of 0.1 mm Hg and at a bath temperature of 200-230°C, 5-(3'-chloro-propylidene)-dibenzo[a,e] cyclohepta [1,5] diene is obtained, as ora-crystallized from a mixture of low-boiling and high-boiling petroleum ether, forms colorless crystals of melting point 83 —85°. Yield 72%.

Example 8.

In a 1-litre three-necked flask equipped with a stirrer, dropping funnel and cooler, 18 g of magnesium shavings are covered with 50 ml of dry ether and a solution of 30 g of l-bromo-2-propene is added over the course of 2 hours while stirring. It is stirred for a further 5 hours at 20°.

The reaction mixture, which still contains some excess magnesium, is then cooled with ice water, a solution of 52 g of dibenzo[a,e]cyclohepta[l,5]dien-5-one in 100 ml of dry ether is added dropwise over the course of an hour and the the whole is stirred for a further two hours at 20° and allowed to stand overnight.

The following day, it is cooled once more with ice water and a cold saturated ammonium chloride solution is added to the reaction mixture. The organic layer is separated, the aqueous phase is shaken out twice, each time with 100 ml of ether and the combined ether portions are dried over sodium sulphate. Evaporation gives 5-hydroxy-5-(2'-propenyl)-dibenzo[a,e]cyclohepta-[1,5]diene as a yellow, thick oil. 30 g of 5-hydroxy-5-(2'-propenyl)-dibenzo[a,e]cyclohepta[1,5]diene are dissolved in 200 ml of dry chloroform and the solution is saturated while cooling with ice water with dry hydrobromic acid. The solution is evaporated under reduced pressure, the residue is once again dissolved in 200 ml of chloroform and saturated with dry hydrobromic acid at 0°. After a few hours it is evaporated under reduced pressure, the residue is dissolved in ether, the ethereal solution is washed with water, sodium bicarbonate, water, dried over sodium sulphate and evaporated, whereby 5-(3'-bromo-propylidene)-dibenzo-[a ,e] cyclohepta [1,5] diene remains as a residue.

This 5-(3'-bromo-propylidene)-dibenzo-[a,e] cyclohepta [1,5] diene can be introduced

as starting product for the syntheses according to examples 1-4.

Claims (2)

1. Process for the preparation of 5-(γ-secondary amino-propylidene)-di-benzoheptane compounds with the general formula where the dotted bond may be hydrogenated, Rj means one with up to 4 carbon atoms containing alkyl residue, preferably methyl or ethyl, or the benzyl residue, R2 hydrogen or halogen and A optionally with a lower alkyl residue with up to 4 carbon atoms substituted ethylene residue, and their salts, characterized by reacting a compound of the general formula where A and R 2 have the above meaning and Hal is a halogen atom, with a primary amine of the general formula where R] has the above meaning, and possibly transferring the obtained compounds to their acid addition salts . 2. Process according to claim 1, characterized in that as halogen compound of formula (II) one is used, in which =CH—A— means the propylidene group and that as amine of formula (III) methylamine or ethylamine is used.