DE1668233A1 - Process for the preparation of tricyclic secondary amines - Google Patents

Description

BRA. ING. T. WTJESTHO ** IMDPI ,. ING. G. PTJLS DR. E. τ. PECHMANN

FATBNTANWJtXTH 8 MUNICH ΘΟ

T668233 "

RAN 4008 / 22-011

ff. Hoffaami-Ia Roche & Co. Aktiengesellschaft in Basel (Switzerland)

Process citr preparation of tricyolic secondary amines

The present invention relates to tricyclic secondary ones Amines of the general formula

GH-CH ₂ -OH ₂ -IiH-R ₁

where the dotted bond shown can be hydrogenated •, Ri 'denotes the methyl or ethyl radical and R ₂ denotes hydrogen or halogen,

• 009834 / 1SSA

their salts as well as the compounds mentioned ent * holding drugs.

The invention also relates to a method for producing

position of the tricyclic, secondary amines of the formula This process is characterized in that a compound of the general formula -

II

CK-CH ₂ CH ₂ -HaI

wherein Rp has the same meaning as above and Hal represents a halogen atom, with a primary amine of the general formula

III

wherein R, has the same meaning as above, is reacted in a manner known per se and optionally the obtained connection in a known manner in a Acid addition salt transferred.

The starting compounds of the formula II required for the process according to the invention can be, for example win in the following ways:

909834/1554

-3 · - * ■

An optionally halogen-substituted dlbenzo [a, d] -cyclohepta [1,4] dien-5-one or bibenzo [a _t d] cyelohepta. [1,4 »6] ~ trien-5-one is converted by means of an organometallic reaction with one. Propenyl halide or reacted with an eropylene halide having an ether function.

Preferred

the reaction is carried out via a magnesium compound. Let us »stimulate the reaction by adding a suitable alkali halide, such as β · Β · methyl iodide or ethyl bromide ·

Examples of PropenyHialogenide or etherified Pro _r ^ iM pylhaiLog§3ä4flle the l-bromo-2 ^ pröpen '' and the 1-Ohlor- • J-methoxy-propane ·

The alkoxy group is in two ways a lower alkoxy group, such as methoxy, ethoxy, propoxy, butoxy, which is in the end position of the alkyl halide. &> - Methoxy- \ propyl-magnesium compounds are preferred starting materials. In addition to alkoxy, for example, aralkoxy can also be used.

interpret, such as benzyloxy or phenäthyloxy, or tetrahydro-. !

pyranyloxy. |

The reaction of the tricyclic ketones with a

909834/1554

An ether group or an organometallic compound bearing a terminal unsaturated group are obtained by hydrolysis into the tertiary carbinols Transferred which by treatment with suitable, with Water-immiscible organic solvents, such as ether, ethyl acetate, chloroform, methylene chloride., From the by-products of the reaction can be separated and isolated. The tertiary carbinols obtained in this way are solid, mostly easily crystallizable compounds.

In a further reaction stage, the ether function of the hydrolysis product obtained by one process variant is replaced by halogen with simultaneous dehydration of the carbinol. The same reaction product is obtained with simultaneous elimination of water by addition of hydrogen halide onto the terminally unsaturated propenyl radical formed according to the other variant. This sequence of reactions is advantageously carried out as described below:

1) The hydrolysis product is treated with hydrogen bromide, expediently with a concentrated aqueous solution of hydrogen bromide at boiling point or with a solution of hydrogen bromide in glacial acetic acid at room temperature, the corresponding 5- (b-bromopropylidene) derivative being formed.

I I

2) The hydrolysis product is be-909834/1554 with phosphorozychloride

acts, which happens with advantage at Eüokflusstemperatur. This creates the above-mentioned ö-fa-chloropropylidene) derivative. The 5 - («- halogen propylidene) derivatives are mostly viscous, partly crystallizable substances, which undecompose in a high vacuum et can be distilled.

The reaction of the products of the formula II with the amines of the formula III is expediently carried out in an inert organic Solvent such as benzene or toluene performed. It is best to work at a higher temperature, e.g. at Boiling point of the mixture, or in the case of slightly "" ' • volatile amines, in the containment tube, e.g. at a temperature of about 100 ° C. In addition, it is appropriate to start the reaction to be carried out in the presence of an inorganic or organic acid-binding agent. As an inorganic acid-binding agent Means such as anhydrous potassium carbonate can be used. The organic acid-binding agent is advantageously used the same amine that is used to react with the halogen compound. There is an expedient embodiment in that one uses 2 moles of amine for 1 mole of halogen compound. The amine of the formula III is advantageously used Mono-methyl-, ethyl-, iaopropyl- or benzylamine.

The tricyclic compounds obtained by the process according to the invention exist if they are substituted in the aromatic rings by halogen and / or a

• 809834/1554

branched side chain sluggish, from a mixture of isomers. This can be carried out according to methods known per se, e.g. due to the different solubility of the bases or addition salts fractional crystallization, in the cis-trans and / or optically active antipodes are separated. "

The invention also encompasses the preparation of the acid addition salts the aforementioned tricyclic. Links. Such salts are, for example, 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.

Draw the compounds obtainable according to the invention are characterized by a variety of effects on the nervous system. So are narcosis-potentiating, adrenolytic, sedative, antihistamine-like, antiemetic, antipyretic, local anesthetic and hypothermic effects have been noted. The rapid onset of action on application is particularly striking

of these substances.

From the German patent specification No. 1,109,166 dibenzo [a _f d] cyclohepta [1,4] dlene and dibenzo [a, d] cyclohepta [1,4,6] trienes are already known, which are replaced in the 5-position by an ω-dialkylaminopropylidene radical, e.g. B. the Dimethylaminopropylidenrest are substituted. These compounds have an antidepressant effect. In contrast, the products of the process which are characterized by a monoalkylamino group in the ω-position of the ^ side chain have a considerably stronger antidepressant effect, this effect being considerably more rapid. · ■ 809834/1854. '■'

You can use compounds as remedies ε.S. in the form of pharmaceutical preparations use which ice or its salts in a mixture with a pharmaceutical, organic or inorganic inert carrier material suitable for enteral or parenteral administration, such as * · Β · Vasstr, gelatin, lactose, starch, magnesium stearate, talc, vegetable Oils, rubber, polyalkylene glycols, vaseline,

909834 / 1S54

etc .. included. The pharmaceutical preparations can be in solid form Form, e.g. as tablets, dragees, 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, .Stabilizers, wetting agents or emulsifiers, salts for modification osmotic pressure or buffer. The preparations preferably contain about 5-100 mg per dosage unit

of the active ingredients obtainable according to the invention. They can also contain other therapeutically valuable substances.

example 1

10 g of 5- (3'-bromo-propylidene) -dibenzo [a, d] cyclohepta [l, 4] -diene and 25 ml of a 20? Sigen, alcoholic methylamine solution are heated at 10O ⁰ C θ hours in sealed tube. 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 deposited oil with ether, drying and evaporating the ethereal solution, 5- (3'-methylaminopropylidene) -dibehzo [a, d] -cyclohepta [1,4] diene is obtained, which distills at 150-160 ° C / 0.3 mm.

The hydrochloride is recrystallized from alcohol-ether

.909834 / 155A

ORIGINAL INSPECTED

sates and melts "at 218-220 ⁰ C.

The 5- (3'-bromopropylidene) · di "benzo [a, d] oy.cia> hepta [l _# 4] diene used as the starting product can be prepared as follows:.

In a 2 liter three-necked flask equipped with a stirrer, dropping funnel and cooler, 15 g of magnesium shavings * are covered with 60 ml of dry ether and mixed with 0.5 ml of methyl "iodide." · ' ^: ·

After the lively reaction has subsided somewhat, a solution of 54 »6 g of l-chloro-3-methoxy-propah in 300 ml dry ether was added dropwise in such a way that the reaction mixture

is kept boiling. It is boiled under reflux ^{at 45 °} C. for a further 5 hours.

The reaction mixture is then cooled with ice water, a solution of 50 g of dibenzo [a, d] cyclohepta [l, 4] dien-5-one in 600 ml of dry ether is added dropwise over the course of one hour, and the whole thing is added dropwise at 40 ^° C. for a further 17 hours stirred under reflux. The following day, the mixture is cooled again with ice water and a cold saturated ammonium chloride solution is added to the reaction mixture. The organic layer is separated off and the aqueous phase is extracted twice with 150 ml of ether each time

909834/1554

and the combined portions of ether dried over sodium sulfate and evaporated. The residue gives after recrystallization from a mixture of high boiling and low-boiling .Petroläther colorless hei 88-89 ⁰ O-melting Kri stalle of S-hepta [l,] diene. Today

20 g of the 5-hydroxy-5 - (. 3'-methoxy-propyl) -dibenzo £ a, d] cycloheptadiene [1,4] diene and 50 ml of a 48% aqueous solution of hydrogen bromide are added for 12 hours vigorous stirring refluxed. After cooling, the reaction mixture is shaken twice with 100 ml of ether each time, the combined portions of ether are washed neutral with water, sodium bicarbonate solution and water and evaporated. After distillation in a high vacuum, the residue yields 5- (3'-bromopropylidene) -di "benzo [a, d] cyclohepta [l, 4] diene with a boiling point of 145-150 ° C./0.07 mm Bg in an oil which soon solidifies. It can be recrystallized from a mixture of high boiling and low boiling petroleum ether and then melts at 74-76 ⁰ C. yield 86.5 #.

909834/1554

. ■ -.ία - ■

Example 2

50 g-ethylamine, 100 nil of dry toluene and 20 g of 5- (3'-bromo-propylidene) -dibenzo [a, d] cyclohepta [1,4] diene (according to Example 1) are mixed at -15 ⁰ C and in an autoclave under 20 atmospheres nitrogen for 7 hours at 100-110 ⁰ C shaken. After cooling, the toluene and the excess ethylamine are distilled off, the residue is shaken with ether and dilute sodium hydroxide solution, the ethereal solution is separated off, washed with water, dried over sodium sulfate and evaporated. Distillation of the residue yields under a pressure of 0.1 ram Hg at 160 ⁰ C, the 5- (3'-ethylamino-propylidene) -dibenzo [a, d] cyclohepta [l, 4] diene. The hydrochloride is recrystallized from ethanol-ether and melts at 262-264 ⁰ C.

example τ

To a mixture of 100 ml of dry toluene and 40 g of methylamine, 20 g of 5- (3'-bromopropylidene) -dibenzo [a, d] cyclohepta [1.4 _t 6] triene are added at -20 °. The reaction mixture

is in an autoclave under 20 Atü nitrogen for 7 co

Heated to 10O ⁰ C ^ hours. After cooling down, the over-

The excess amine and the toluene are removed under reduced pressure. ^ distilled and the residue with ether and aqueous potassium carbonate shaken. The ethereal solution is separated off, washed with water and dried over sodium sulfate. the end

the residue is obtained by distillation in a high vacuum 5- (3'-methylamino-propylidene) -dibenzo [a, d] cyclohepta [1.4 »6] -triene with a boiling point of 150 ° C./0.1 mm Hg. The hydrochloride is from ethanol-ether umkristallieiert and melts at 181-183 ⁰ C. The used as starting material 5- (3'-bromo-propylidene) -dibenzo [a, d] cyclohepta [1,4,6] may trien be prepared as follows:

In a 1 liter three-necked flask fitted with a stirrer, dropping funnel and cooler is provided, 7.5 g of magnesium shavings are covered with 30 ml of dry ether and with 10 drops of methyl iodide offset. ι. .

- After the lively reaction has subsided somewhat, a solution of 27.3 g of 1-chloro-3-methoxypropane in 150 ml of dry ether is added dropwise over the course of an hour. ^{It is boiled at 45 0} C on the reflux condenser for a further 3 hours. Then a solution of 21 g of dibenzo [a, d] cyclohepta [l, 4,6] -trien-5-one in 300 ml of dry ether is added dropwise over the course of one hour to the reaction mixture cooled with ice water, and the whole thing is continued for 3 hours on Reflux condenser boiled. The following day, the mixture is cooled again with ice water and a cold saturated ammonium chloride solution is added to the reaction mixture. The organic layer is separated off, the aqueous phase is extracted twice with 3L00 ° 1 ether and the combined portions of ether are dried over sodium sulfate and evaporated. Of the

■. . 809834/1554

- ig · -

The residue gives, after crystallization from petroleum ether, colorless crystals of 5 ~ hydroxy ~ 5- (3 ^l -methoxy-propyl) -dibenzo [a, d] cyclohepta [l, 4- _i 6] triene which melt at 90-91 ° C . 3ine another crystal form of melting point 78-79 ⁰ C may occasionally occur / but can warden easily converted by intimately trituration of a mixture of the two forms in the higher melting form. yield 77 $.

15 g S-

Hepta £ 1, 4, 6] triene and 40 ml of a 48% aqueous solution of hydrogen bromide are refluxed for 20 hours with vigorous stirring. After cooling, the reaction mixture is shaken twice with 100 ml of ether each time, the combined portions of ether are washed neutral with water, with sodium bicarbonate solution and with water and evaporated. After distillation in a high vacuum, the residue gives 5- (3'-broin-propylidene) -dibenzo [a, d] cyclohepta [l, 4,6] triene with a boiling point of 150 ° C./0.1 mm Bg as a yellow oil, the soon becomes solid. Yield 675 *.

Example 4

To a mixture of 30 ml of dry toluene and 40 g of methylamine is carried out at -10 to -2O ⁰ C 20 g of 3-chloro-5- (3'-brompropyliden) -dibenzo [a, d] cyclohepta [l, 4] diene added and the whole is -erwärmt 7 hours in an autoclave at 100 ⁰ C.

• 909834/1554

After cooling, the excess methylamine and "the toluene" are distilled off under reduced pressure, the residue is shaken with ether and dilute sodium hydroxide solution, the ethereal solution is separated off, washed with water, dried over sodium sulfate and evaporated - (3 ^{-methyl-l-propylidene)} -dibenzo [a, d] cyclohepta [l, 4] -diene zurückt remains as a thick oil, and is converted into the hydrochloride, melting point after recrystallization from ethanol, 260-262 ⁰ C,.

The 3-chloro-5- (3'-bromo ~ Propylidene) dibenzo [a, d] cyclohepta [l, 4] diene can be prepared as follows:

In a 2 liter three-necked flask fitted with a stirrer, dropping funnel and cooler is provided, 15 g of magnesium shavings are covered with 60 ml of dry ether and with 0.5 ml of methyl iodide offset.

After the lively reaction has subsided somewhat, a solution of 41 g of 1-chloro-3-methoxy-propane in 300 ml of dry ether is added dropwise in such a way that the reaction mixture is kept boiling. It wirörnoch boiled for 5 hours at 45 ⁰ C to reflux.

The reaction mixture is then cooled with ice water, a solution of 47.8 g of 3-chloro-dibenzo [a, d] cyclohepta [1,4] is used

Θ0983Α / 1554

Pull 5-one in 600 ml of dry ether in the course of an hour. drops and the whole thing stirred under reflux ^{at 40 0 C for a further 17 hours.} The following day, the mixture is cooled again with ice water and a cold, saturated ammonium chloride solution is added to the reaction mixture. The organic layer is separated off, the aqueous phase is shaken out twice with 150 ml of ether each time and the combined portions of ether are dried over sodium sulfate and evaporated: the residue, after recrietallization from high-boiling petroleum ether, gives colorless 3-chlorine crystals ^{that melt at 67- • 69 0 O} -5 - hydroxy-5- (3 ^l -methoxypropyl) -dibenzo [a, d] cyclohepta [1,4] diene. Yield £ 80.

30 g of the 3-chloro-5-hydroxy-5- (3'-methoxypropyl) -dibenzo [a, d] cyclohepta [l _t 4] diene obtained are added in portions to 100 ml of a cold, saturated hydrogen bromide solution. added in bite vinegar. While stirring, the temperature is allowed to rise slowly to 25 ^° C. and then stand at this temperature overnight. The following day the mixture is cooled again with ice water, saturated again with dry hydrogen bromide and left to stand for 20 hours at room temperature. The oil is then diluted with 2 liters of bis water, the oil is extracted again with ether, the portions of ether are washed with water, sodium bicarbonate solution and again with water, dried over sodium sulfate and evaporated. (S ¹ -bromopropylidene) ~ dibenzo [a,: dlcydohepta [l, '4] dien. From. Boiling point .195 ° C / 0.04 mm Hg.

909834/1554

Example 5 - "'

10 g 5- (3

diene and 30 ml of a 20 # strength, alkaholischen Methylaminlös-ung are heated for 8 hours in a sealed tube at 10O ⁰ C. 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 sulfate and evaporated. ^{The 5- (3 l} -methylamino-propylidene) -dibenzo [a, d] cyclohepta [lj4] diene described in Example 1 is obtained with a boiling point of 150-

• 160 ° C / 0 _# 03 mm Hg. Melting point of the hydrochloride 218-22O ⁰ C. -

The 5- (3'-chloro-propyIiden) -dibenzoXa, d.] CyclOhepta [l, VI-] Ä.ien used as starting material can be prepared as follows :. . : ■ '■ - ■■■■

10 g of 5 ~ hydroxy-5- ^{(3-methoxy-l-propyl)} -dibenzo [a, d] cyclohepta [l, 4jdien (according to Example 1) are dissolved in 25 ml phosphoric ¹ · oxychlosid and the solution for 3 hours under reflux cooked. The phosphorus-xychloride is then evaporated off under reduced pressure, the resinous residue is shaken with ether and ice-water.

• carbonate solution, again with V7asser, dries and concentrates. By distilling the residue under a pressure of 0.1 mm

9 0 9 8 3 4/1554, ORIGiNAL INSPECTED

) Diene, which was recrystallized from a mixture of low-boiling and high boiling petroleum ether; Hg and at a bath temperature of 200-22O ⁰ C erhälx one 5- (3'-chloro-propylidene) -dibenzo [a, d] cyclohepta [1,4 , forms colorless crystals of melting point 83-85 ⁰ C. Yield 12%,

Example 6

In a 1 liter 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-3rom-2-propene is added over the course of 2 hours while stirring. It is stirred for 5 hours at 2O ⁰ C.

Then the reaction mixture, which still contains a little excess magnesium, is cooled with ice water, a solution of 52 g of dibenzo [a, d] cyclohepta [1,4] dien-5-one in 100 ml of dry ether is added dropwise over the course of one hour, and the whole thing is two more Stirred for hours at 20 ^° C. and left to stand overnight.

The next day it is again cooled with ice water and the reaction mixture with. a cold saturated axsaionium chloride solution offset. The organic layer is separated off and the aqueous phase is extracted twice with 100 ml of ether each time and the combined portions of ether over sodium

0.9 834/1554

sulfate dried. Evaporation yields the 5-hydroxy-5- (2 ^l -propenyl) -di ^< ben2o [a, d] cyclohepta [1,4] diene as a yellow, thick oil.

30 g of 5-hydroxy-5- (2'-propenyl) -dibenzo [a, d] cyclohepta- [1,4] diene are dissolved in 200 ml of dry chloroform and the solution, while cooling with ice water, is acidified with dry hydrogen bromide β saturated. The solution is evaporated under reduced pressure, the residue redissolved in 200 ml of chloroform and saturated with dry hydrobromic acid at ⁰ ° C. After several hours, the residue is evaporated under reduced pressure, dissolved in ether, the ethereal solution with VJasser, l ^ ^{triumbicarbonaiaoaung:} undn9chmals mitVfesssr, dried over sodium sulfate and evaporated to give 5- (3'-bromo-propylidene) -diben2o [ a, a] cyclohepta [l, 4] diene remains as a residue.

Example 7

100 g ^ oa ^ hept _a [l, 4] diene hydrochloride, I ₅₀ Ig Aerosil composite, 420 g corn starch ^ ₃ 00 g lactose and _{50 ß} Ta ^ are intimately mixed with one another and _{pressed into tablets of 3} e 100 mg.

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- · · - Example 8 .

50 g of 5- (3'-methylamino-propylidene) -dibenzo £ a, d] cyclohepta- [1,46] triene hydrochloride, 110 g of corn starch,. 120 g of lactose and 20 g of talc are intimately mixed with one another and pressed into tablets of 300 mg. .

I ^v . .

. '·. · ■ ·,. Example 9 ^;%

A solution of 0.8 g of SC ^ '- methylamino-propylidenJ-dibenzo- [a, d] cyclohepta [l, 4] diene hydrochloride in 100 ml of double-distilled water is added 0.08 g of nipagin and 0.01 g Nipasol filled with nitrogen gas in ampoules of 2.2 ml each.

9Ό9834 / 1554

Claims (5)

668233 claims 1. Process for the production of antidepressant effective, tricyclic secondary amines of the general formula OH-CIH ₂ -OH ₂ -IIH-H ₁ in which the bond shown in dotted lines can be hydrogenated, R, the methyl or ethyl radical and IU Mean hydrogen or halogen, and their salts, characterized in that one is a compound the general formula II CH-CH ₂ CH ₂ -HaI wherein R _{2 has the} same meaning as above and Hal represents a halogen atom, 909834 / 155.4 with a primary amine of the general formula III in which R _{1 has the} same meaning as above, is reacted in a manner known per se and, if appropriate, the compound obtained is converted into an acid addition salt in a manner known per se. ■ 2. The method according to claim 1, characterized in that the halogen compound of the formula II used is one in which R _{2 is} hydrogen, and that the amine of the formula III used is methylamine. 3. iricyclic secondary amines of the general formula .903934 / 1554 in which the dotted line shown may be hydrogenated, R ₁ denotes the methyl or ethyl radical and R ₂ denotes hydrogen or halogen, and salts of these compounds. 4. 5- (3'-Methylamino-propylidene) -dibenzo [a, d] cyclohepta · - [1,4] dienes and salts of this compound, 5. Agents with antidepressant properties characterized by a content of 'a tricyolic secondary amine general formula CJH-CH ₂ -CH ₂ -NH-H ₁ '" wherein the bond shown in dotted lines is hydrogenated can be / R ₁ denotes methyl or ethyl acetate and B «denotes hydrogen or halogen, or on a salt of this compound. . 6, agent according to claim 5, characterized in that it contains 5- (3 ^l -Methylaminopropyliden) -dibeBZQfa _l d] oyeloheptaCl, 4] diene or a salt of this compound * 169834/1614