JPS594412B2 - Process for producing tricyclic amines - Google Patents

Description

Detailed Description of the Invention 15 The present invention provides 9-(3-methylamino-propyl)-9 represented by the formula / CH2-CH2-CH2-N 70□ ”H(l)
・10-dihydro 9 ・10-ethanoanthoph 5
A method for producing a helix and an acid addition salt thereof is provided.

Compounds represented by formula (I) are described, for example, in US Pat. No. 339
No. 9201, which exhibits valuable pharmaceutical properties, in particular antidepressant activity, and therefore in the free base form for the treatment of psychological depression, and 90 is preferably a pharmaceutically acceptable acid addition. Used in salt form. The method of the present invention is 9 (3-methylamino-1-propenyl)-9.1
Catalytically hydrogenating the 0-dihydro9-10-ethanoanthracene or its salt until its aliphatic '15 double bond is saturated and optionally converting the resulting base into a pharmaceutically acceptable acid addition salt. or the base is liberated from the resulting acid addition salt.

Catalytic hydrogenation can be carried out by conventional methods, in one example using palladium or activated carbon as a catalyst and ethanol (alcohol) as a solvent. Hydrochloride salts are particularly preferred as acid addition salts of the starting materials to be hydrogenated. Depending on the reaction conditions and the starting materials (bases or salts), the compounds of formula (1) can be obtained in free form or in the form of their acid addition salts. This acid addition salt can be converted into the free base by methods known per se, for example by treatment with a basic substance such as an alkali or an ion exchanger. On the other hand, the free base obtained can form salts with organic or inorganic acids. For preparing acid addition salts, in particular acids are used which are suitable for the formation of pharmaceutically usable salts. Such acids include, for example, hydrohalic acids, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, or aliphatic, cycloaliphatic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic acid, acetic acid, propionic acid. , succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic or pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, anthranilic acid, p-hydroxybenzoic acid , salicylic acid, p-aminosalicylic acid,
These are embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid and ethylenesulfonic acid. The starting materials used in the process of the invention are new, but can be prepared by methods known per se.

For example, a possible preparation method is the formula (where Z is a reactively esterified hydroxyl group)
It consists of reacting a compound represented by with methylamine.

Reactively esterified hydroxyl groups z are preferably organic or inorganic strong acids, in particular hydrohalic acids such as hydrochloric acid, hydrobromic acid or hydroiodic acid, or arylsulfonic acids such as lower alkyl and alkoxy groups as mentioned above. or a halogen atom such as a chlorine atom or a bromine atom 1
Hydroxyl groups esterified with benzenesulfonic acids, such as p-toluenesulfonic acid or p-bromobenzenesulfonic acid, or lower alkanesulfonic acids, such as methanesulfonic acid, which are substituted with 2, 2 or more.

The reaction is carried out in a conventional manner, preferably in the presence of a solvent and optionally a condensing agent, such as a basic condensing agent, preferably at elevated temperature and optionally under pressure.
It is done in a closed container.

Basic condensing agents are, for example, alkali metal hydroxides or carbonates, such as sodium hydroxide or potassium carbonate, or tertiary amines, such as triethylamine or pyridine. Another possible preparation method consists in reducing the methylimino group to the methylamino group in 9-(3-methylimino-1propenyl)-9,10-dihythro-9,10 ethanolanthracene.

The reduction is carried out in a conventional manner, preferably using simple hydrides or complex hydrides such as borane, light metal or di-light metal hydrides such as sodium borohydride or lithium aluminum hydride, or alkoxyaluminum hydride or alkoxy borohydride, or Performed with formic acid. However, if conditions are chosen such that the double bond of the 1-propenyl group is not violated, the reduction may be carried out using a catalyst such as a platinum, palladium or nickel catalyst, or a homogeneous catalyst such as a copper-rhodium compound such as a rhodium chlorotriphenylphosphine complex. It can also be carried out with hydrogen in the presence of. Preferably, the absorption of hydrogen is followed by the change in capacity, and the hydrogenation is stopped after the calculated amount of hydrogen has been absorbed. Another possible preparation method is 9-(3-methylamino-1
-propenyl)-9,10-dihydro-anthracene with ethylene.

This is suitably carried out by the Diers-Alder method, advantageously at elevated temperature and/or under pressure. The following examples illustrate the invention.

Example: In 50ml of alcoholic beverage, 3.12y of 9-(3-methylamino-1propenyl)-9,10-dihythro9,10ethanoanthracene hydrochloride is added to 0.3y of 10% palladium on charcoal.
Hydrogenation is carried out at 25° C. under normal pressure in the presence of f.

Hydrogenation is stopped after absorbing 234 ml of hydrogen. The catalyst is filtered off and the solvent is evaporated. Thus 9-(3-methylamino-propyl)-9,10-dihydro9,1
0-ethanolanthracene hydrochloride has a melting point of 240-243
Obtained as colorless crystals at °C. After recrystallization from isopropanol, this hydrochloride salt melts at 243-244°C. The starting material is made as follows.

(a) B to orthoformic acid triethyl ester 137.17
Add 0.8 ml of F3 diethyl etherate and add anthracene-9 aldehyde 16 while stirring.
4. Add 8y little by little.

When the yellow paste thus produced is heated to 40-45°C, it gradually forms a viscous brown-red solution. After 2 hours, the contents of the flask are cooled and at the same time ethyl vinyl ether 63,4y is added dropwise at such a rate that the temperature of the reaction mixture does not exceed 20°C.

Two hours later? 161 ml of isopropanol and 24 ml of 2N hydrochloric acid are added and heated under reflux for 8 hours.

The product begins to crystallize relatively quickly after about 1-2 hours.
The mixture is cooled to 5° C. and the dark yellow fine crystals are filtered off with suction. This was mixed twice with 80 ml of isopropanol, once with 80 ml of water, and again with 80 ml of isopropanol.
1, and the 3-(9-anthryl)-acrolein thus obtained was washed at 80°C/80ml in a vacuum container.
Dry with Hg for 12 hours to constant weight. This material is golden in color and melts at 172-174°C and after one recrystallization from a mixture of chloroform and ethyl acetate.
Melts at 74-175°C. The yield is 171y (theoretical 9
2%). (b) 3-(.9-anthril)-acrolein 2327(1) in a stirring autoclave.
．． 0 mol) with 1000 ml of toluene to 170-18
Heat to 0°C.

Next, ethylene was introduced to 100 atm, and at this pressure 20
Keep time. The pressure vessel is cooled to 90° C., carefully evacuated and the autoclave contents are mixed with 20 V of activated carbon and the hot solution is filtered. The filtrate is concentrated to about three-fifths of its volume and slowly cooled to 10°C. In this way, 9-(3-oxo-1-propenyl)-9,10-dihythro-9,10-ethanoanthracene is crystallized.

This is filtered off with suction and washed with a total volume of 400 ml of ice-cold toluene. This colorless crystal was heated to 80 muH in a vacuum container.
Dry at g/100℃ until constant weight (15 hours)
. The yield is 234.2f (92% of theory) and the melting point is 174-176°C. One recrystallization from a mixture of chloroform and ether gives a melting point of 175.5-17.
Colorless crystals at 7° C. are obtained. By concentrating the above mother liquor, more pure product can be obtained, but such operations are generally laborious and less profitable.

The above reaction can be carried out in the same way using isopropanol and acetyutrile as solvents (yields 62.5% and 71.5%, respectively).

Also, with dimethylformamide, at most only traces of the desired product are obtained. c) 9-(3-oxo-1-propenyl)-9,10-dihythro9,10-
Ethanoranthracene 26.07 methanol 200W
11, and gaseous methylamine is introduced into this with stirring.

Heat is generated and the aldehyde melts. The temperature of the reaction mixture rises to 50-55°C within a few minutes. When the solution becomes strongly alkaline (tested with wet indicator paper), the introduction of methylamine is stopped and the solution is allowed to stand for 30 minutes. When 100 ml of water is slowly added, 9(3-methylimino-1-propenyl)-9,10-dihythro-9,10-ethanoanthracene is crystallized. By cooling to 10°C and filtering with suction, the melting point is 128-129.
Colorless crystals at 26.27 °C are obtained.

9-(3-methylimino-1-propenyl)9,10-
Dihythro-9,10-ethanolanthracene can also be produced by the following steps (c') and (b') instead of the above steps (b) and (c).

(c!) 11.6y of 3-(9-anthryl)-acrolein and 3 of methylamine in 80ml of absolute ethanol.
The mixture with 3% ethanol solution 9.1f is stirred for 20 minutes and subsequently heated to 40°C. When this clear brown-yellow solution is cooled to 0° C., dark yellow crystals precipitate out. This was filtered with suction and 15ml of isopropanol was added.
and 5 ml of acetic ester. 9-(3-Methylimino-1-propenyl)-anthracene is thus obtained as yellow needle-like crystals with a melting point of 122.5-124.5°C. 9-(3-Methylimino-1-propenyl)-anthracene in an autoclave 12.2
5t is heated to 180° C. in 150 ml of toluene. A pressure of 80 atmospheres is brought up with ethylene while hot and the reaction mixture is kept under 80 atmospheres at 180° C. for 20 hours. The mixture is cooled and evaporated in vacuo. In this way, the crude 9-(
3-Methylimino-1-propenyl)-9,10-dihythro-9,10-ethanoanthracene is obtained as a brownish amorphous material. This can be used in the next reaction without further purification. For characterization, the sample is crystallized from methanol and recrystallized. The colorless crystals thus obtained with a melting point of 128 DEG -129 DEG C. are identical in all respects to the substance described above. (d) 9-(
3-Methylimino-1-propenyl)-9,10-dihythro9,10-ethanol ninthracene 13.65
t in 150 ml of methanol.

A solution of 4.0 f sodium borohydride in 15 ml of water is added dropwise to this suspension while stirring and cooling with ice water. During the addition, the temperature of the flask contents should not exceed 15°C. During the course of this reaction, the Schiff base rapidly dissolves. The reduction ends after 30 minutes.

Add 200 ml of water and extract three times with 100 ml each of methylene chloride. The combined extracts are washed once with 50 ml of water, dried over anhydrous sodium sulfate and freed from the solvent in an aspirator vacuum. 9-(3-Methylamino-1propenyl)-9,10-dihythro-9,10-ethanolanthracene is thus obtained as a colorless viscous oil.
This substance crystallizes if left alone (melting point 78-8'C)
. By neutralizing this acetone solution of the base with methanesulfonic acid, methanesulfonate with a melting point of 168-1
Obtained as colorless crystals at 71°C.

The hydrochloride of this base is made as follows.

Claims (1)

[Claims] 1 9-(3-methylamino-1-propenyl)-9.
10-dihydro-9,10-ethanoanthracene or its salt is catalytically hydrogenated until its aliphatic double bonds are saturated, and the formula ▲ has mathematical formulas, chemical formulas, tables, etc. ▼ (I)
9-(3-methylamino-propyl)-9 represented by
- 10-dihydro-9,10-ethano-anthracene or a salt thereof, and optionally converting the obtained base into a pharmaceutically acceptable acid addition salt or liberating the base from the obtained acid addition salt. The above formula (
I) A method for producing a tricyclic amine or a salt thereof.