PL176081B1 - Method of obtaining 3-aminoisoquinoline and its n-mono- and n,n-disubstituted derivatives - Google Patents

Abstract

A method for the production of 3-aminoisoquinoline and its N-mono and N,N-disubstituted derivatives of the general formula L where R1 and R2 are hydrogen atoms, or Rr is a hydrogen atom and R2 is an alkyl group or an aryl group, or a hydroxyl group, or an amino group, or R1 and R2 are the same or different alkyl groups or aryl groups, or R1 together with R2 are a polymethylene chain separated by an oxygen atom or a nitrogen atom substituted with an alkyl group, and X is a hydrogen atom, or a halogen atom, or an alkyl group, characterized in that 2-(cyanomethylbenzaldehydes) of the general formula 2, where X has the meaning given above, are reacted with ammonia or its derivatives of the general formula 3, where R1 and R2 have the meaning given above, in the presence of lower carboxylic acids which act as a catalyst, and the reaction is carried out in lower alcohol, at a temperature of 40-90°C.

Description

The invention relates to a process for the preparation of 3-aminoisoquinoline and its N-mono and N, N-disubstituted derivatives.

3-aminoisoquinoline is used to obtain active biological compounds such as drugs and plant protection products. The unspecified N-mono and N, N-disubstituted 3-aminoisoquilines can also be used for the preparation of biologically active compounds or as intermediates in organic synthesis.

According to known methods, 3-aminoisoquinoline is obtained by reacting 3-chloroisoquinoline with ammonia water in the presence of copper sulphate in a pressure reactor at 140 ° C (AR Osborn, K. Schofield, LN Short, J. Chem. Soc., 4191 ( 1956)), or by reaction of 3-halo (chloro, bromo) isoquinolines with a potassium amide (GM Sanders, M. van Dijk, MJ den Hertog, Rec. Trav. Chim. Pays-Bas, 93, 198 (1974)).

Other methods are by reacting isoquinoline-3-carboxylic acid amide with sodium hypobromin (CE Teague, Jr., A. Roe, J. Am. Chem. Soc, 73, 688 (1951)), or the reduction of bromine to l-bromo-3 -aminoisoquinoline with hydrogen gas over a palladium catalyst (F. Johnson, WA Nasutavicus, J. Org. Chem., 27, 3953 (1962)).

The known methods have a number of disadvantages, difficulties or even threats, which consist in the use of hardly available substrates (e.g. isoquinoline-3-carboxylic acid amide), working with hazardous reagents (e.g. potassium amide, hydrogen gas), or in hazardous conditions (pressure reactors).

The process according to the invention overcomes these drawbacks and risks, and moreover, this process can produce both 3-aminoisoquinoline and its N-mono and N, N-disubstituted derivatives.

According to the invention, the 3-aminoisoquinolines of the general formula I, where Ri and R2 represent hydrogen atoms, or Ri represents a hydrogen atom, and R2 represents an alkyl group or an aryl group, or a hydroxyl group, or an amino group, or R1 and R2 represent the same or different alkyl groups or aryl groups, or R 'including R 2 is a polymethylene chain, or a polymethylene chain interrupted by an oxygen atom, or a nitrogen atom substituted with an alkyl group, and X is a hydrogen atom, or a halogen atom, or an alkyl group, obtained by the reaction of the aldehyde 2 - (cyanomethyl) benzoic acid of formula 2 where X is as defined above with ammonia, or its derivatives of formula 3, wherein Ri and ^R2 are as defined above.

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This reaction is carried out by heating both components in a lower alcohol at 40-90 ° C in the presence of a carboxylic acid that acts as a catalyst. This role is preferably played by lower carboxylic acids such as acetic acid or trifluoroacetic acid. The products obtained are isolated by crystallization or by distillation under reduced pressure. The starting aldehydes of formula II are simply prepared in a known manner (A. Jończyk, D. Lipiak, J. Org. Chem. 56, 6933 (1991)).

The following examples illustrate the use of the invention without limiting its scope.

Example 1. 2- (Cyanomethyl) benzaldehyde (0.87 g, 6 mmol) was dissolved in methanol (30 ml), 5 drops of trifluoroacetic acid were added, the mixture was heated to reflux for 5 hours and ammonia gas was bubbled through during this time. The solvent was then evaporated, the dry residue dissolved in benzene (30 ml), washed with water, dried (MgSO4) and concentrated. The residue was crystallized from benzene to give 3-aminoisoquinoline 0.60 g, 70% of theory, m.p. 178-180 ° C. Literature, m. 178-180 ° C (G. M. Sanders, M. van Dijk, H. J. den Hertog, Rec. Trav. Chim. Pays-Bas, 93, 198 (1974)).

Example 2. A mixture of 2- (cyanomethyl) benzaldehyde (0.29 g, 2 mmol), ethanol (5 ml), t-butylamine (0.7 g, 1 ml, 9.5 mmol) and trifluoroacetic acid (2-3 drops) was heated to boiling for 10 days. The mixture was evaporated, benzene (20 ml) was added and the basic products were extracted with 10% hydrochloric acid (2 x 10 ml). The combined aqueous extracts were basified with solid NaHCO3, extracted with hexane (3 x 10 ml), dried (Na2SO4), the solvent evaporated and the residue distilled. 0.20 g (50% yield) of 3- (t-butylamino) isoquinoline were obtained, boiling at 95 ° C / 1.333 Pa, identified by the * HNMR spectrum. 'HNMR (CDCl),: 1.47 (s, 9H), 4.72 (brs, 1H), 6.66 (s, 1H), 7.13-7.22 (m, 1H), 7.40 -7.55 (m, 2H), 7.71 (dd, J = 0.82 Hz, J = 0.82 Hz, J = 8.2 Hz, 1H), 8.83 (s, 1H).

Example 3 To a solution of 2- (cyanomethyl) benzaldehyde (7.25 g, 50 mmol) in methanol (200 ml) was added dimethylamine (4.51 g, 100 mmol) and acetic acid (0.5 ml) successively, The mixture was heated at 50-60 ° C for 12 days. The mixture was concentrated, diluted with water, extracted with benzene (2 x 40 ml), the organic extracts washed with brine, dried (MgSO 4) and the solvent was evaporated. The residue was distilled to give

4.75 g (55%) of 3- (N, N-dimethylamino) isoquinoline, b.p. 85 ° C / 1.333 Pa.

For Formula C "H13N2 (172.23): obi. N 16.27% equivalent N 16.23%

Example 4. A mixture consisting of 2- (cyanomethyl) benzaldehyde (1.45 g, 10 mmol), ethanol (25 ml), morpholine (2.60 g, 30 mmol) and propionic acid (ca 0.1 ml) was heated at 80 ° C for 10 days and then volatile compounds were evaporated. Water was added to the residue, extracted with toluene (3 x 20 mL), the organic extracts washed with brine, dried over Na2SO4, and concentrated. The tarry residue was applied to silica gel and eluted with ethyl acetate / hexane (1: 2). The effluents were concentrated, the solid residue was crystallized from ethanol to give 1.1 g (51%) of 3- (N-morpholino) isoquinoline, mp 126-127.5 ° C (yellow crystals).

For the formula C13H14N2O (214.17): cal. C 72.87%; H 6.59%; N 13.07% Equivalent C 72.99%; H 6.51%; N 13.12%

C NMR (CDC11,: 46.66, 66.83, 99.02, 123.54, 123.90, 125,: ^ (^, 127.60, 130.34, 138.90, 151.22, 156.77 .

Example 5. A mixture of 5-chloro-2- (cyanomethyl) benzaldehyde (0.23 g, 1.3 mmol), ethanol (4 ml) aniline (0.15 g, 1.6 mmol) and trifluoroacetic acid (2-3 drops) was heated to reflux for 15 hours. The mixture was cooled to room temperature, concentrated, the solid was filtered off, washed with a little methanol and dried. 0.25 g (77% yield) of 7-chloro-3- (phenylamino) -isoquinoline was obtained, mp 132-4 ° C.

For the formula C15H11CIN2 (254.72): obi. C 70.73%; H 4.355%; N 11.00% Equivalent C 70.66%; H 4.39%; N 11.12%

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Example 6 To a solution made from hydroxylamine hydrochloride (0.7 g, 10 mmol) and potassium acetate (1.0 g, 10 mmol) in methanol (5 ml) was added 2- (cyanomethyl) benzaldehyde (0.29 g, 2 mmol) and heated at a temperature of about 40 ° C for 5 hours, with occasional shaking. The mixture was concentrated, water (10 ml) was added, extracted with chloroform (3 x 10 ml), the combined organic extracts were washed with water, dried (NagSOi) and the solvent was evaporated. 3- (hydroxylamino) isoquinoline was obtained in the form of a viscous oil in the amount of 0.3 g (94%), which was 98% pure when analyzed by gas chromatography.

¹ HNMR (CDCl-),: 6.55 (H-4), 13.75 (HU).

¹ CNMR (CDCls),: 101.56 (C-)), 147.72 (C-3. ^ - ^^ 7 ^ 4 (Cl).

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Claims (2)

Patent claims 1. A method for the preparation of 3-aminoisoquinoline and its N-mono and N, N-disubstituted derivatives of the general formula 1, where R ¹ and R ² are hydrogen atoms, or R ¹ is a hydrogen atom and R ² is an alkyl group or an aryl group, or a hydroxyl group or an amino group, or R 1 and R ² are the same or different alkyl groups or aryl groups, or R ¹ together with R ² represent a polymethylene chain separated by an oxygen atom or an alkyl-substituted nitrogen atom, and X is a hydrogen atom, or a halogen atom or an alkyl group, characterized in that 2- (cyanomethylbenzaldehydes) of the general formula 2, where X is as defined above, are reacted with ammonia or with its derivatives of general formula 3, where Ri and R2 are as defined above , in the presence of lower carboxylic acids as a catalyst, the reaction being carried out in the lower alcohol at 40-90 ° C. 2. The method according to p. The process of claim 1, wherein the lower carboxylic acids are acetic acid or trifluoroacetic acid.