Method of preparing isoquinoline derivatives of their salts

专利摘要:
The invention relates to a process for preparing compounds of the formula I, <IMAGE> in which R1, R2 and R3 have the meaning given in the description, by the elimination of water from the corresponding octahydro-6-ol derivatives. The compounds of the formula I possess the properties of inhibiting aggression and depressing the central nervous system.
公开号:SU852172A3
申请号:SU782571448
申请日:1978-01-23
公开日:1981-07-30
发明作者:Мишель Бастьян Жан
申请人:Сандос Аг (Фирма)；
IPC主号:

专利说明:

(54) METHOD FOR OBTAINING DERIVATIVES OF IEOCHINOLINE OR THEIR SALTS The invention relates to a method for producing new derivatives of eoquinoline of general formula R - a hydrogen atom, a halogen atom with an atomic weight from 9 to 35 or 9 to 35 or C -C-alkyl hydrogen atom, - alkyl, free or monosubstituted with C, -Sglyl or C-C, -alkoxy-phenyl; Na-C-C-alkyl, cyclopropylmethyl, phenylethyl, substituted in the phenyl ring with chlorine, or their salts, KOTOfMJe can be used in the chemical-pharmaceutical industry. A known reaction of dehydration of spins in the presence of mineral acid 11. The purpose of the invention is the development, on the basis of a well-known method, of a method for the preparation of new yzoquino derivatives, which possess valuable pharmacological properties. This goal is achieved by the fact that in the method of producing isoquinoline derivatives of the above formula 1, a compound of the general formula in which R ,, K, and Rj have the values already indicated, undergo dehydration and the target product is isolated in free form or in salt form. Strong acids, anhydrides or acid halides are used as a dehydrating agent. The compounds of the general formula T are liberated in the form of a free base or salts with inorganic acids; aaiu iiMejp maleic. . . Pr and measures 1. trans-1,2,3,4,4a, 10b-Hexahydro-3, b-dimethylbenz (f) isoquinoline. a) A mixture of 14.6 g solutions-, 2,3,4, 4a, 5, b, 10′-octahydro-3 (6-dimethylbenz (f). ох and eo-linolin-6-ol in 20 ml of isopropanol, and 30 ml of 5 N The secoprol solution of chlorofluoride Brola is heated to 6 atmosphere of aert for 30 minutes before boiling.The resulting suspension is cooled about and the crystallized hydrochloride of the desired compound is filtered from ethanol / isopropanol T mixture, pl 302-303 ° C {decomposed), 302-303 ° C (decomposed), 302-303 ° C (decomposed), pl 302-303 ° C (decomposed), pl 302-303 ° C {decomposed), melted
 The original product can be obtained. Thus,
In 1500 anhydrous chloroform slowly, a solution of 39 g of tconyl chloride in 30 ml of anhydrous chloroform is added dropwise at. The reaction mixture is stirred at room temperature for 1 hour, then for 1 hour at and immediately thereafter for 3 hours at a temp; boiling point, the solvent is distilled to dryness and the residue is combined with a large amount of ether. Solid 3-chloromethyl-1-methyl-4-phenylpiperidine-hydrochloride is sucked off on a filter to a high T11I in vacuum, mp 203211 ° C.
b) The resulting product is sodium hydroxide converted to a base, which is extracted with methylene chloride. After drying over sodium sulfate, the organic phase is evaporated to dryness 51, g of the residue after evaporation and 13.4: sodium cyanide are suspended in 40 ml of dimethylformamide and heated for 2 hours under strong washing to boil. After cooling to room temperature, the reaction mixture is diluted with 200 ml of water, extracted with chloroform, the extract is washed with water, dried over sodium sulfate and the solvent is evaporated. The 1-methyl-4-phenyl-type of fidin-3-yl cetonitrile remaining in the thick oil type (i.e. sol. Caftalin-1, amp -disulfonic acid: 292 296C (decomposed)) is used without further purification,
B) A solution of 85 g of the product obtained is in 150 ml of absolute ethanol and saturated with hydrogen chloride. The dark reaction solution is then stirred for 24 hours at boiling point, the solvent is evaporated to dryness, the residue is mixed with 200 ml of anhydrous benzene and the benzene is evaporated to dryness. The residue after evaporation is taken up in 290 ml of absolute ethanol, mixed with 7.2 ml of water and heated for 2 hours until boiling. After evaporation of the solvent, the residue is dissolved in chloroform, mixed with water and the pH is adjusted to sodium alkaline. chloroform solution, the aqueous solution is shaken again with chloroform, the extracts are punched with 10% sodium bicarbonate solution and WATER, dried with sodium sulfate and the solvent is evaporated
dry up The residue is distilled under high vacuum; isolating 1-methyl-4-phenyl-piperidin-3-yl-acetic acid ethyl ester at 118-123 ° C, 0.08 mm Hg, 1.5220,
e) To a preheated 85 g of polyphosphoric acid and 25 MP anhydrous xylene, with vigorous stirring, a solution of 16.8 g of 1-methyl-4-phenylpiperidin-3-yl-acetic acid ethyl ester in 10 ml of anhydrous xylene is added over 15 min. The reaction mixture is stirred for another 2 hours at 12 ° –125 ° C, it is cooled to approximately 80 ° C, and poured into 300 ml of water. The resulting aqueous solution is washed with ether, basified with 20% sodium hydroxide solution and extracted with chloroform. The chloroform solution is washed with water until the reaction takes place, dried over sodium sulfate, evaporated, the residue is dissolved in methylene chloride / methanol 9: 1, filtered through alumina and evaporated to dryness. The remaining oil in the form of 1,2,3,4,4a, 10'-hexahydro-3-methylbenz (f) isoquinoline-b- (5H) -one, mixture of isomers, is distilled at 0.08-0.1 mm Hg .st.
Isomer separation: the trans-form is crystallized from ether-petroleum ether, m.p., 84-85 s (ether / petroleum ether); hydrochloride t, pl. 300-302 0 (with decomposition, from methanol).
Dysfyrm is isolated from the mother liquor in the form of acid fumarate. M.p. before recrystallization 172 ° C. Mp, 175177 ° C (from ethanol ester),
3) To a solution of 115 ml of 2 M, methyl lithium in ether and 400 ml of anhydrous ether, 20.0 g of trans-1,2,3,4,4a are added dropwise over 45 minutes at room temperature with stirring, under nitrogen atmosphere, 10b-hexahydro-3-methylbene (f) -isoquinoline-6- (5H) -one in 400 ml of anhydrous benzene. The reaction mixture is stirred for 2 hours at room temperature, poured into 1 ml of 20% ammonium chloride solution, section The organic phase and the aqueous solution are extracted with methylene chloride. The organic phase is washed with water, dried over sodium sulfate and the solvent is evaporated. The remaining trans -1,2,3,4,4a -5, Y-octahydro-3, b-dimethylbenz (f) isoquinolin-6-ol is recrystallized from benzene / hexane. T, pl, 148-153 ° C (without recrystallization, T. pl, 1300C).
Analogously to Example 1, the following compounds of the formula are obtained by cleaving water from the corresponding compound of formula II (see, Table 1),
Example 15 trans-1,2,3,4,40 10b-hexahydro-3-metshbenz (f) isoquinoline.
Analogously to example 1 of 10.0 g of trans, 2,3,4,4а, 5,6, Yu-octahydro-3-methylbenz (f) and eoquinolin-b-ol in 25 ml of isopropanol and 30 ml of 5N. Isopropanol solution of hydrogen chloride after boiling for 2 hours, the desired compound is obtained and is isolated in the form of hydrochloride. M.p. 285 ° C (decomposed), yield 80%.
The original connection can be obtained as follows.
A suspension of 12.0 g of lithium aluminum .hydride in 800 ml of anhydrous is added dropwise over 30 minutes with a solution of 15.0 g of trans-1,2,37 4,4a, 10o-hexahydro-3-methylbenz (f) - isoquinoline-6- (5H) -one in 300 ml of anhydrous ether. The resulting suspension
The mixture is stirred at room temperature for 1 hour, mixed with 100 ml of water and an insoluble part is filtered off with a drop of water and washed several times with methylene chloride. The organic phase is separated from the filtrate, dried with water, dried with sodium sulfate and evaporated. The solid residue is recrystallized from ether / petroleum ether. M.p. 118-128 C.
0
Analogously to Example 15, the compounds of Formula 1 listed in Table 2 are prepared.
The compounds of general formula 1 or their salts have anti-aggressive properties 5 and can be used in medicine.
Table 1
table 2
8-CHj,
Also
n n
H
n
SNY
240

权利要求:
Claims (1)
[1]
1. Buhler, K., Pearson, D. Organic Reactions, M., 1973, Vol. 1, p. 86

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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SE8302361D0|1983-04-27|1983-04-27|Astra Laekemedel Ab|NEW TRICYCLIC AMINES|

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US5294618A|1989-07-28|1994-03-15|Merck Sharp & Dohme Limited|Octahydrobenzisoquinoline derivatives as antipsychotic agents|

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GB8917333D0|1989-07-28|1989-09-13|Merck Sharp & Dohme|Therapeutic agents|

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JPH07500333A|1991-10-24|1995-01-12|

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EP0539209A1|1991-10-24|1993-04-28|The Upjohn Company|Benzo-isoquinoline derivatives and analogs and their use in therapeutics|

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AT407636B|1999-07-09|2001-05-25|Martin Dr Kratzel|Diels-Alder products of tetrahydropyridinedienes with naphthoquinones and their oxidation products, process for their preparation and their use for producing medicaments|

法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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CH82077A|CH630902A5|1977-01-24|1977-01-24|Process for preparing novel derivatives of 1,2,3,4,4a,10b-hexahydrobenzoisoquinoline.|

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