JPS5838239A - Manufacture of tricyclic amine - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 9-(3-methylamino-zolopyl)-9 represented by the formula
, 10-dihydro-9,1o-ethanoanthracene and key acid addition salts. Compounds of formula (1) have been described, for example, in US Pat. The drug can be used in free base form, or preferably pharmaceutically. It is used in the form of recognized acid addition salts.

The method of the present invention comprises 9-(3-methylaton-1-zorobenyl)-9,10-dihydro-9,10-anthracene or a salt thereof, in which the aliphatic double bond thereof is saturated; Salt 11! was obtained by catalytic hydrogenation with glC! iv) Conversion into a commercially loadable acid addition salt or liberating the base from the resulting acid addition salt; vI# mold. II catalytic hydrogenation can be carried out by a conventional method, 1
Examples include using palladium or activated carbon as the catalyst and using ethanol (alcohol) as the solvent. Hydrochloride salts are particularly preferred as acid addition salts of the starting materials to be hydrogenated.

Depending on the reaction conditions and starting material (base or salt), the formula (
The compound represented by 1) can be obtained in free form or in the form of its acid addition salt. The free base VC can be used in a manner 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 bases obtained can be used to form salts with organic or inorganic compounds, such as those suitable for the production of acid addition salts, in particular in the form of pharmaceutically usable salts.
use.

Such acids include, for example, hydrohalic acid, sulfuric acid, phosphoric acid, nitric acid, persalt g*, aliphatic, alicyclic, aromatic compound carbon I [or sulfonic acid, such as acetic acid, zoatone, amber, glycol acid,
Lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid,
Maleic acid, hydroxymaleic! Or gilpine, phenylacetic acid, benzoin, ν-agi) benzoin, anthranilic acid, p-hydroxybenzoic acid, salicylic acid, p
-Aminosalicyl Shun, Embon @1 Methanesulfone Bandit,
Methanesulfonic acid, hydroxyethanesulfonic acid, and ethylenesulfonic acid.

The starting materials used in the process of the invention are new or can be prepared by methods known per se.

For example, a possible preparation method is the formula (wherein 2 is a reactively esterified hydroxyl group)
It consists of reacting a compound represented by with methylamine.

Reactively esterified hydroxyl groups 2 are preferably organic or inorganic strong acids, such as halodated water, such as hydrochloric acid, hydrogen bromide or hydroiodic acid, or arylsulfonic acids, such as lower alkyl sulfonic acids such as those mentioned above. a benzenesulfonic acid substituted with a group and an alkyl group or an atom such as 1, 2 or more chlorine or bromine atoms, such as p-)luenesulfonic acid or marbrobenzenesulfonic acid, or lower alkadisulfones; An example of this is a hydroxyl group esterified with methanesulfonic acid.

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 carbonic acid, tubes or tertiary compounds, such as triethylamine or pyridine.Other possible preparation methods are In 9-(3-methyl-ion)-1-propenyl)-9,10-zohydro-9,10-ethanoanthracene, the WL reduction is common since the methyl group is reduced to the methyl amino group. Preferably simple hydrides or complex hydrides such as c-ran,
Light metal hydrides or V-light metal hydrides such as sodium borohydride (5) or lithium aluminum hydride, or aluminum hydride: FdP sialium or water borohydride, are carried out with borohydride alkoxy, or borohydride. However, if conditions are left such that the double bond of the 1-propenyl group is not compromised,
The reduction can also be carried out with hydrogen in the presence of a catalyst such as a platinum, palladium or nickel catalyst, or a homogeneous catalyst such as a trout lozoyum compound such as a rhodium chlorotriphenyl-phosphoyne complex. Preferably, the absorption of hydrogen is followed by a change in volume, and the vkK hydrogenation is stopped when the calculated amount of hydrogen has been absorbed.

Another possible method of preparation consists of reacting 9-(3-methylamino-1-propenyl)-9,10-dihyroanthra7ane with ethylene. This via is carried out by the Diels-Alder method at an elevated temperature and (
or) under pressure.

The following examples illustrate the invention.

Example: 9-(3-methylami)-1(6)-propenyl)-9,10-dihydro-9,10-ethano-anthrone hydrochloride in alcohol 50R1 3.12#V10 palladium charcoal Hydrogenation is carried out under normal pressure at 25° C. in the presence of 0.311.Hydrogenation is stopped on the bale which has absorbed $234+++Jv of water.The molten S is filtered off and the solvent is evaporated.Thus 9- (3-methylamino-fazel)-9,10
-dihydro-9,10-ethanolanthracene hydrochloride is obtained as colorless crystals with a melting point of 240-24'5°C.

After recrystallization from isozolopanol, this hydrochloride has 2
Melting at 43-244"0.

The starting material is made as follows.

(IL) Orthoformic acid triethyl ester 137.1
gKBIF3・diethylniteller)0.8jlJt'
Add and stir to this anthracene-9-aldehyde 164.8. Add SrV little by little. When heated to 40-45°C, the resulting yellow paste is
Produces a viscous brown-red solution. For 2 hours, the flask contents were cooled and at the same time the temperature of the ethyl vinyl ether 63.4 #v reaction mixture was increased (rl) and then the salt of isozolopanol 161i1 and 21 i*s4-
and heated under reflux for 8 hours. The product begins to crystallize relatively quickly in the bales for about 1 to 2 hours.・Mixture? 5
It is cooled to 0.degree. C. and filtered off with suction as fine, dark yellow crystals.

Add this to iso/lovanol 5 (1 + j each for 2 @ 2 water 80
- and again once with Inzolopanol 801 and the 3-(9-anthryl)-7chlorein thus obtained is dried in a vacuum vessel at 80 DEG C./80 tmHg to constant weight for 12 hours. This substance is golden in color and has 6 parts?
, 174-175°C after being decomposed at 172-174°C and recrystallized once from a mixture of chloroform and ethyl acetate.
to melt. Yield is 1711 (92% of !1 theory).

((9) 5- (9-
Anthryl)-Acrolein 232# (1,0-, mol) is heated to 170-180°C with 1000M toluene. Next, put ethylene at 100 atmospheres in the tube and keep it at the pressure Wc for 20 hours.The pressure vessel 1 is cooled to 90°C, carefully evacuated, and the contents of the autoclave are mixed with 20L of activated carbon. Filter. The filtrate is reduced to about 3/5 of its volume and slowly cooled to 10°C. 9-(3-oxo-1-propenyl)-9,10-dihydro-9,10-ethano-anthracene is thus crystallized. This was suction filtered and the total amount was 400-
Wash this colorless crystal with ice-cold toluene and dry in a 4'l vacuum container to a constant weight of 80% Hg/IQ at 0°C (15 hours).The yield is 254.2 & CI
92 of Theory I], and the melting point is 174-176°C. Recrystallization once from a mixture of chloroform and ether gives colorless crystals with a melting point of 175.5-177°C. , such operations generally require a lot of effort and little benefit.

The above reaction can be carried out in the same way using iso/lobanol and a7toethryl as solvents (yields of 62.5% and 71.5(9)11), respectively, combined with dimethylformamide. With this method, only a trace of the desired product is obtained.

(e)? -(3-oxo-1-propenyl)-9゜10
-dihydro-9,10-ethanolanthrace V26.0
The mixture is stirred for 1 vfifi and 200 d, and gaseous methyl atom is introduced into the mixture while stirring. 0 heat is generated and the aldehyde is dissolved. The temperature of the reaction mixture rises to 50-55°C within a few minutes.

When the kernel 1a solution becomes strongly alkaline (wet instructions!I
IJtt), the introduction of methylamine is stopped and the mIW is stirred for 30 minutes. When IQQdl of water is added slowly, 9-C5-methylimino-1-propenyl)9e10-dihydro-9,1°-ethano-anthracene crystallizes. By cooling to 10°C and filtering with scissors, 26.2N colorless crystals with a melting point of 128-129°C are obtained.

9-(3-methishii 2 no 1-prope tool)-9,10
-Dihige a-9,10-No-anthracene can also be produced from the following steps (o') and CW)K instead of the steps (b) and (6).

(10) (♂) In absolute ethanol 80-! t-(9-anthryl)-acrolein 11.61i and methylane (7
) 331G-C//-kf11W19A11f) Namiai'? Stir for 20 minutes and then heat to 40°C.

When this transparent brown-yellow solution is cooled to *t'o C, dark yellow crystals precipitate out. It is filtered off with suction and recrystallized from a mixture of inzolopanol 151j and acetic acid ester 5d. Thus, 9-(3-methylimino-1-propenyl)-anthracene has a melting point of 122.5-124.5°C.
Obtained as yellow needle-like crystals.

In the autoclave 9-(5-methicy2-no-1-zoropaerun-anthracene 12.2! Mv toluene 15
Heat to 180°C in a vacuum. While hot, a pressure of 80 atmospheres is brought up with ethylene and the reaction mixture 'IIt' is kept under 80 atmospheres at 180 DEG C. for 20 hours. The mixture is cooled and evaporated in vacuo. In this way, the crude 9-(3-methyl-f
]-1-debenyl)-9,10-dihydro-9,10
-Ethano-anthracene 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 thus obtained colorless product had a melting point of 128-129°C.

The crystal of is the same as the substance described above in all respects.

←) 9-C5-methylano 1-2” Ropeel)-
9,10-zohydroEl-9,10-ethano-anthracene 15.65jrV///-KJl in 1501j. To this suspension, add 4.0% sodium borohydride dissolved in 15 WJ of water. The solution of OI is added dropwise with stirring and cooling with ice water. During the dropwise addition, the temperature of the contents of the flask should not exceed 15°C. During the course of this reaction, the Schiff base dissolves rapidly. The reduction ends after 30 minutes. Add 200 dv of water, methylene chloride 1004
Extract 3 times. The combined extracts were washed once with 50 liters of water, dried over 11 am of anhydrous sodium sulfate and removed in vacuo to give 9-(3-methylano-1-zolobenyl)-9e 1. o-Dihyro9,10-ethano-anthracene is obtained as a colorless viscous oil. This substance crystallizes if left standing (melting point 7
8-80°C).

By neutralizing this a7tone solution of the base with methanuronic acid, methanesulfonate with a melting point of 168-17
Obtained as colorless crystals at 1°C.

The hydrochloride of this base is made as follows.

That is, this base '1 is dissolved in 5 times the amount of atritone and neutralized by adding the appropriate amount of hydrogen chloride in ethyl acetate. Thus, the hydrochloride is recrystallized from several colorless crystals with a melting point of 241-243°C from a mixture of inzolopanol and ether, and the melting point rises to 243-244°C.

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Claims (1)

[Claims] 9-(6-methylaz)-1-propenyl)-9,10
-zohydro-4-9,10-emenoanthracene or a salt thereof is catalytically hydrogenated with 1 whose aliphatic double bond is saturated to produce 9-(6-methylinopropyl)-9 of the formula
* 10-dihydro El-9,10-emenoanthracene or its salt, and the ring group t obtained from WriilK Freeing the base from salting V*
A method for producing Sanno-style ain-katto or its salt expressed by the above formula (1), which is made into mold.