HU207324B - New process for producing amino-phtalid-izoquinolines and slats of pharmacological activity - Google Patents

Abstract

Anti-allergenic amino-phthalic-isoquinolines (V) and their salts are new, where R1 = Me or Et gps. R2 = H or methoxy gp., R3, R4, R5 always identical methoxy or ethoxy gps., (V) are prepd. from sodium-sulphonic acid salts of isoquinoline derivs. of glu formula (I) and tri:alkoxy-nitrophthalides in the presence of alkali-carbonates, in a medium of aliphatic alcohols to yield nitrophthalic isoquinoline type cpds. of glu formula (III). These are reduced in aliphatic alcohols by hydrazine-hydrate in the presence of a Raney-Ni:catalyst, or by ammonium formate in a mixt. of an aliphatic alcohol and a cyclic ether in the presence of charcoal supported palladium catalyst, to yield amino-phthalic-isoquinolines (IV). Cpds. (IV) are epimerised and opt. converted to salts.

Description

(57) EXTRAS

The present invention relates to a process for the preparation of aminophthalide isoquinolines and their salts having the formula (V), wherein R 1 methyl or ethyl group, R ₂ methoxy group, R ₃ R ₄ = R ₅ = methoxy group or ethoxy group and are always the same according to which a trialkoxy group of the isoquinoline sulfonic acid sodium salt of the formula I in an aliphatic alcohol Reaction with nitrophthalide (in the presence of an alkali carbonate) yields the nitrophthalide isoquinolines represented by the general formula (III) and then, in the presence of a Raney-Ni catalyst in aliphatic alcohols or palladium carbonate in the presence of an aliphatic alcohol and a cyclic ether. The resulting amino phthalide isoquinolines of formula (IV) are epimerized and optionally converted to a salt.

HU 207 324 B

Scope of the description: 6 pages (including page 1 figure)

HU 207 324 Β

The present invention relates to a novel process for the preparation of pharmacologically active aminophthalide isoquinolines and their salts.

The present invention relates to the preparation of amino-phthalide isoquinolines of formula (V) wherein R, methyl, ethyl, R ₂ = methoxy, R ₃ = R ₄ = R ₅ = methoxy or ethoxy and the three are always the same. . The process of the present invention relates to the preparation of the 1RS-3'RS epimers of the compounds of formula (V).

This invention relates to inorganic acids (such as HC1, HBr, HI, H ₂ SO _4, HMO _3, H ₃ PO ₄₎ salts of the compounds of formula (V) or organic acids (such as acetic acid, fumaric acid, citric acid, benzoic acid, tartaric acid , maleic acid, lactic acid). The amino-phthalide-isoquinoline derivatives of formula (V) and their salts are used in medicine as active ingredients in anti-allergic formulations. Their effect is based on inhibiting the enzyme histidine decarboxylase, which catalyzes the histidine-histamine conversion. [Arzneimittel-Forschung / Drug. Gap. 20, (10) 1490-1496 (1970); AmzneimittelForschung / Drug. Gap. 36, (5) 822-825 (1986).] Recent studies have shown the hepatoprotective activity of amino phthalide isoquinolines. [Yuasa, S.; et. al. Nichyakurishi 1985, 85: 249; Umezu, K .; et. al .: Folica Pharmacol Jap. 1985,85: 185-192.]

Preparation of nitrophthalide isoquinolines:

Preparation of nitro-phthalide isoquinolines of formula (III) from iralkoxy nitrophthalides (II) by reaction with compounds of formula (I) is typically Robinson condensation. This type of reaction was first accomplished by Robinson and Hope. [E. Hope and. R. Robinson, J. Chem. Soc. 105, 2085 (1914)], when condensation of cotarnine and nitromeconone yielded alpha-nitro gnoscopin in near quantitative yield.

During the condensation, both the 1RS-3'RS (A-mer) and 1RS-3'SR (B-mer) epimers of the compound of formula III are formed.

The reaction is usually carried out in aliphatic alcohols - methanol, ethanol, propanes butanol - at a temperature of 40-80 ° C for 1-3 hours. A mixture of A- and B-mer (EP 152090) can be obtained in good yield in methanol at 60 ° C for 2 hours, and the production can be increased by boiling the reaction mixture for 10 hours (EP 0201359) in NaOH using Na ₂ SO ₄ as a water scavenger. The preparation of nitro-phthalide isoquinolines (2B, 873, 935; Ger. Offen 1206909; Fr. 1, 295, 309 CA. 57, 16576b) was also solved under reflux for 3 days under ₂ atmospheres. The reaction is also effected by heating the trialkoxynitrophthalides and the quaternary methiodide of the compound of formula I in methanol in the presence of K ₂ CO ₃ (EP 0028279).

During the condensation reaction, cotarnine and / or potassium hydroxide were added. the corresponding isoquinoline derivative is used in a molar ratio of 0.8 to 1.2 times, preferably 0.9 to 1.0 times, relative to the trialkoxynitrophthalides. Limitations of reaction: At high temperatures, cotarnine decomposes; at low temperatures, the reaction rate is low; with a longer reaction time, the A-mer ratio in the product increases but the yield is lower.

Preparation of aminophthalide isoquinolines:

The nitro-phthalide isoquinolines of formula (III) can be prepared by various reduction methods to form the amino-phthalide isoquinolines of formula (IV). The reduction may be accomplished by: SnCl ₂ x 2H ₂ O / cc HCl in acetic acid (British 873, 935; Ger. Offen 1 206909; Fr. 1,295, 309 CA. 57. 16576b); in acetone with Sn / HCl at 35 ° C (EP 152090; US4684732; EP 0201 359; JP 5944382); methanol with NaBH ₄ in the presence of CuSO ₄ (EP 0 161 499) in a mixture of methanol and 1 N NaOH in the presence of CuSO ₄ , NaBH ₄ (JP 61229880); with metal borohydrides in methanol to form Ib or VIII. column in the presence of their derivatives, (JP 61233685 CA. 106, 84933z; JP 61 186388 CA. 106, 18521η; JP 61, 152, 686 CA. 106, 18381s); NaBH ₂ S ₃ , 111. LiBH ₄ -el {JP 61 186388 CA. 106.

52In); by catalytic hydrogenation in ethanol with RaneyNi catalyst at 65 ° C and 10 bar.

epimerisation:

It is intended that the aminophthalide isoquinolines of formula (IV), which are a mixture of Amer and B-mer, obtained by reduction, provide the pharmacologically active A (V) useful to us. Epimerization takes place in 2 to 20 hours when treated with a mixture of A-mer and B-mer in aliphatic alcohols. Aliphatic alcohols are methanol, ethanol, propanes or butanol, and the epimerization is usually carried out with NaOH or KOH.

Alkali hydroxide is used in an amount of 2 to 5% by weight based on the amino-phthalide isoquinoline (EP 0 161 499; EP 152 090; EP 0201359, JP 61 233 685 CA 106, 84933z; JP 61 229880 CA 106; 84932y). The temperature of the reaction mixture is maintained at 50-80 ° C. It is not advisable to go beyond this, because at higher temperatures, decomposition reactions will become more prominent. The aliphatic alcohol is used in amounts of 3 to 20 times the weight of the amino-phthalide isoquinolines.

Disadvantages of the prior art methods: In order to increase the condensation rate, increasing the temperature also accelerates the decomposition of the starting material, thus reducing the yield, although higher temperatures favor the formation of the pharmacologically active epimer. As a result of the effect, the total weight of epimer A is reduced. The known reducing agents of the reduction step are expensive (boron compounds), the optimum temperature and solvent for the tin reduction are solved, though slow. A further disadvantage of the reducing agents described so far is that they also contaminate the product with a metal residue which requires cleaning to remove the product. Catalytic hydrogenation also entails metal contamination which requires cleaning of the product during use. Nascent hydrogen reduction is not selective, which impairs yields. Catalytic hydrogenation, although selective, occurs at 10 bar and 85 ° C.

The process of the present invention is based on one finding that the sulfonic acid sodium salt of the hydrocotarnine-1-sulfonic acid or the corresponding isoquinoline derivative is directly condensable with the trialkoxynitrophthalides; reaction. A Kotarnin

Purification of HU 207 324 B is carried out in commercial scale through hydrocotarnine-1-sulfonic acid sodium (Dénes Beke, Marietta Martosné Bárczai, 1956, Hungarian Journal of Chemistry 62 (5) 159-162). The storage of cotarnine is also solved in the form of this salt, thus avoiding the decomposition of the cotarnine base. The condensation reaction is carried out in aliphatic alcohols at a temperature of from 50 to 100 ° C, preferably from 70 to 80 ° C. Suitable aliphatic alcohols are: methanol, ethanol, propanes butanol. The reaction is carried out in the presence of an alkali metal carbonate, K ₂ CO ₃ or Na ₂ CO ₃ .

The molar ratio of trialkoxynitrophthalide to hydrocotarnine-1-sulfonic acid sodium is 1: 0.8 to 1.2, preferably 1: 0.91.00.

The aliphatic alcohol is generally used in an amount of from 15 to 30 times, preferably 2025 times, based on the weight of the hydrocotarnine-1-sulfonic acid sodium.

From the nitrophthalidisoquinolines of formula (III), the preparation of the amino phthalidisoquinolines of formula (IV) was accomplished in aliphatic alcohols in the presence of a Raney-Ni catalyst with hydrazine hydrate, respectively. in aliphatic alcohols in the presence of a Pd / C catalyst with ammonium phosphate. In the latter case, a cyclic ether was used to improve the solubility conditions. The advantage of these two reduction methods over the conventional methods is that the product is free of the metal contaminants that occur in most of the methods described above. A further advantage of the process according to the invention is that the reduction takes place in a very short time. For the Raney-Ni-hydrazine hydrate method, for 15-20 minutes, for the Pd / C-ammonium formate method, for 1 hour.

Epimerization can be accomplished by conventional alkaline treatment after both condensation and reduction.

The invention is further illustrated by the following non-limiting Examples.

Melting points were determined on a Koffler apparatus and data were not corrected. The purity of the compounds was assayed by thin layer chromatography. Merck 5554 silica gel 60 F ₂₅₄ films were used. Solvents: benzene methanol: 8-2; chloroform-methanol: 9-1; chloroform-acetone-diethylamine: 5-4-1 (v / v). PMR recordings were made on a BRUKER W200SY 200 MHz device. Chemical shifts are reported in ppm. Mass spectra were performed on a VG-7035 (GC-MS-DS) using electron impact ionization. Relative intensities are given in brackets after the mass numbers.

Examples:

1. 2-Medl-6,7-methylenedioxy-8-methoxy-1- [4,5,6-triethoxyl-7-nitrophthalidyl- (3)] - 1,2,3,4-tetrahydroisoquinoline g 7- nitro-4,5,6-triethoxyphthalide (16 mmol), 5.2 g of hydrocotarnine-1-sulfonic acid sodium (16 mmol) and 2.65 g of potassium carbonate in 160 ml of methanol in an oil bath at 80 ° C for 4 hours. We are stirred. The solution is allowed to cool and 96 ml of distilled water are added. The precipitate was filtered off and washed with a little cold methanol. Yield: 5.28 g (62%), m.p. 149-150 ° C.

1 H-NMR (CDCl 3): 1.29-1.67 m (C ₆ H ₁₂ CH ₂ O-4.5.6;

\ '

9H); 2.08 s (N-CH ₃ ; 3H); 2.32 to 3.08 m (3.4-position / needle _-CH2, 4H); 4.09 s _(OCH3, 3H); 4.02-4.47 m (CH ₃ C ₆ O ₂ O-; 6H at 4.5,6); 4.53 d (1-position II-needle -CH-; 1H); 5.67 d (3-position -CH-; 1H);

5.89 dd (-OCH ₂ O-; 2H); 6.47 s (5-position -CH-;

IH). II

MS (EI-70eV) m / e 530 (M ⁺ ; 6); 137 (100)

2. 2-Methyl-6,7-methylenedioxy-8-methoxy-1- [4,5,6-trimethoxy-7-nitrophthalidyl (3)] -], 2,3,4-tetrahydroisoquinoline 4.30 g of 7-nitro-4,5,6-trimethoxyphthalide (16 mmol),

5.2 g of hydrocotarnine-1-sulfonic acid sodium (16 mmol) and 2.65 g of potassium carbonate in 160 ml of methanol are stirred at 80 ° C for 4 hours.

The reaction mixture was worked up as described in Example 1. Yield: 4.45 g (57%); Mp 191 ° C.

1 H-NMR (CDCl 3): 2.12 s (N-CH ₃ ; 3H); 2.38-3.10 m / (-CH ₂ - in the 3,4-position; 4H); 4.00 s (~ OCH ₃ ; 3H); 4.03 s _(OCH3, 3H); 4.10 s _(OCH3, 3H); 4.14 s _(OCH3, 3H); 4.48 d (1-CH; 1H); 5.72 d (3-CH;

II II

IH); 5.92 dd (OC ₂ O-; 2H); 6.47 s (5-CH; 1H);

II

MS (EI-70eV) m / e 488 (M ⁺ ; 12); 269 (100)

3. 2-Methyl-6,7-methylenedioxy-8-methoxy-1- [4,5,6-trimethoxy-7-aminophialidyl (3)] - 1,2,3,4-tetrahydroisoquinoline

4.24 g of 2-methyl-6,7-methylenedioxy-8-methoxy-1- [4,5,6-triethoxy-7-nitrophthalidyl- (3)] - 1,2,3,4-tetrahydroisoquinoline (8 mmol) ) was added to 95 ml of methanol containing 0.424 g of Raney-Ni. A solution of 1.95 ml of hydrazine hydrate (40 mmol) in 95 ml of methanol is added dropwise with ice-water cooling. After the addition is complete, the reaction mixture is refluxed for 15-20 minutes. The catalyst is filtered off hot from the system and washed with a little methanol. The solution was kept in the freezer for 2-3 hours. The precipitated crystalline material is filtered off. Yield: 3.16 g (79%); Mp 182-183 ° C.

1 H-NMR (CDCl 3): 1.33-1.52 m (4.5.6 position \

CH, CH ₂ O; 9H); 2.14 s (N-CH ₃ ; 3H); 2.34-3.13 m / (-CH ₂ - in the 3,4-position; 4H); 4.08 s _(OCH3, 3H);

3.96 to 4.36 m _(4,5,6-CH3 at position C7 / ₂ O-; 6H);

4.54 d (1-CH; 1H); 5.04 s (-NH ₂ ; 2H); 5.60 d (3II

CH; IH); 5.90 dd (-OCtf ₂ O-; 2H); 6.37 s (5-CH;

II II

IH);

MS (EI-70eV) m / e 500 (M ⁺ ; 2); 220 (100)

4. 2-Methyl-6,7-methylenedioxy-8-methoxy-1- [4,5,6-trimethoxy-7-aminophthalidyl- (3)] - 1,2,3,4-tetrahydroisoquinoline.

3.90 g of 2-methyl-6,7-methylenedioxy-8-methoxy-1- [4,5,63].

324 Β Trimethoxy-7-nitrophthalidyl (3)] -1,2,3,4-tetrahydroisoquinoline (8 mmol) was added to 95 mL methanol containing 0.39 g Raney Ni. A solution of 1.95 ml of hydrazine hydrate (40 mmol) in 95 ml of methanol is added dropwise with ice-water cooling. After the addition is complete, the reaction mixture is refluxed for 15-20 minutes. The processing is the same as in Example 3.

Yield: 3.07 g (84%); 192-193 ° C.

\

1 H-NMR (CDCl ₃ ): 2.18 s (N-CH ₃ ; 3H); 2.41-3.18 m /

(3,4-position -CH, -; 4H); 3.86 s (-OCH3; 3H); 3.94 s (-OCH3; 3H); 4.00 s (-OCH ₃ ; 3H); 4.10 s (-OCH3; 3H); 4.54 d (1-CH; 1H); 5.07 s (-NH ₂ ;

II

2 H); 5.66 d (3-CH; 1H); 5.92 dd (-OC / AO-; 2H);

II

6.36 s (5-CH; 1H);

II

MS (EI-70eV) m / e 458 (M ⁺ ; 15); 238 (100)

5. 2-Melyl-6,7-methylenedioxy-8-methoxy-1- [4,5,6-methoxy-7-aminophthalidyl- (3)] - [2,3,4-tetrahydroisoquinoline]

2.65 g of 2-methyl-6,7-methylenedioxy-8-methoxy-1- [4,5,6-triethoxy-7-nitrophthalidyl- (3)] - 1,2,3,4-tetrahydroisoquinoline (5 mmol) ) A solution of dry tetrahydrofuran (20 mL) was added with Pd / C (0.265 g) and abs. suspension of methanol. 1.57 g of fine powdered anhydrous ammonium formate (25 mmol) were added in portions under an inert atmosphere (N ₂ ). The reaction mixture was stirred at 35 ° C for one hour. The catalyst is filtered off and the filtrate is evaporated to dryness under reduced pressure. To the residue was added distilled water (25 ml), the product was extracted with chloroform (3 x 10 ml), and the chloroform solution was dried over Na ₂ CO ₄ and concentrated under reduced pressure. The resulting light yellow oil was triturated with methanol (5 mL). The product was filtered. Yield: 1.5 g (60%); Mp 183 ° C.

6. 2-Ethyl-6,7-methylenedioxy-8-methoxy] - [4,5,6-triethoxy-7-nylphthalidyl- (3)] - [2,3,4-tetrahydroquinoline] 5.0 7 g of 7-nitrotrieloxyphthalide (16 mmol), 5.4 g of 2-ethyl-6,7-methylenedioxy-8-methoxy-1-sulfonic acid sodium (16 mmol) and 2.65 g of potassium carbonate in 160 ml of methanol 80 Stir in an oil bath at 4 ° C for 4 hours. The solution was evaporated, suspended in 100 ml of distilled water and extracted with chloroform. The chloroform was distilled under reduced pressure. The residue was 7.2 g of a yellow oil. Yield: 7.2 g (82%).

1 H-NMR (CDCl 3): 1.10-1.20 m (C 7 / CH ₂ N; 311);

~ \

1.32 to 1.60 m (4,5,6-position C / 7 _{(CH 2} O; 9H), 2.28 to 3.15 m (3.4-position _-CH2; '4 H); 4.12 s (-OCH3; 3H); 4.00-4.38 m (4.5.6-position CH, C / Y, O; 6H); 4.50 d (1-CH; 1H); , 69 d (3-CH;

II II

IH); 5.87 dd (-OCH ₂ O-; 2H); 6.49 s (5-CH; 1H)% II

MS (EI-70eV) m / e 544 (M ⁺ ; 3); 137 (100)

7. 2-Ethyl-6,7-methylenedioxy-8-methoxy-1- [4,5,6-triethoxy-7-aminophthalidyl- (3)) - 1,2,3,4-tetrahydroisoquinoline

4.35 g of 2-ethyl-6,7-methylenedioxy-8-methoxy-1- [4,5,6-triethoxy-7-nitrophthalidyl- (3)] - 1,2,3,4-tetrahydroisoquinoline (8 mmol) ) was added to 95 ml of methanol containing 0.424 g of Raney-Ni.

A solution of 1.95 mL of hydrazine hydrate (40 mmol) in 95 mL of methanol was added dropwise with ice-water cooling. The processing is the same as in Example 3. Yield: 3.5 g (85%); 157-159 ° C.

/

1 H-NMR (CDCl 3): 1.15-1.22 m (C / 7; CH ₂ N; 3H);

\

From 1.35 to 1.48 in (4,5,6-position -CH ₃ CH ₂ O-; 9H);

2.28-3.05 m (-CH ₂ -; 4H in the 3,4-position); 4.10 s _(OCH3, 3H); 3.80-4.15 m (4,5,6-position

-CH ₃ CH ₂ O; 6H); 4.50 d (1-CH; 1H); 5.0 s (-NH ₂ ; II

2 H); 5.60 d (3-CH; 1H); 5.94 dd (OCH _2; 2H);

6.45 s (5-CH; 1H).

II

MS (EI-70eV) m / e 514 (M ⁺ ; 4); 200 (100)

8. 2-Methyl-6,7-methylenedioxy-8-methoxy-1- [4,5,6-triethoxy-7-nitro-phthalide 1- (3)] - 1,2,3,4-tetrahydro-isoquinoline (1RS-3). 'SR) epinerization

3.9 g of 2-methyl-6,7-methylenedioxy-8-methoxy-1- [4,5,6-triethoxy-7-nitrophthalidyl- (3)] - 1,2,3,4-tetrahydroisoquinoline [1RS- 3'SR; m.p .; 147-150 ° C; Rf = 0.29 benzene / methanol 8: 2 (v / v)], 0.90 g of NaOH and 40 ml of methanol are stirred at 60 ° C for 6 hours. After cooling, filtration, 3.7 g (94%) of product 1RS-3'RS epimer were obtained. 146-149 ° C, Rf = 0.66 [benzene / methanol 8: 2 (v / v)]

1 H-NMR (CDCl 3): 1.3-1.5 m (CH, CH ₂ O-; 9H);

\

2.08 s (N-CH ₃ ; 3H); 2.3-3.1m (3,4-position /

-CH ₂ -; 4H); 4.10 s (-OCH, 3H); 4.1-4.4 m (CH, C // ₂ O-; 6H); 4.53 d (1-CH-; 1H); 5.66 d (3CH-; 1H); 5.66 dd (-OCH ₂ O-; 2H); 6.32 s (5CH-; 1H).

II

MS (EI-70eV) m / e 530 (M ⁺ ; 3); 220 (100)

9. 2-Methyl-6,7-methylenedioxy-8-methoxy-1- [4,5,6-triethoxy-7-aminophthalidine (3)] - 1,2,3,4-tetrahydroisoquinoline (IRS-3 '). SR) epimerization

1.86 g of 2-methyl-6,7-methylenedioxy-8-methoxy-1- [4,5,6-triethoxy-7-aminophthalidyl- (3)] - 1,2,3,4-tetrahydroisoquinoline [1RS- 3'SR; 96-97 ° C; CRf = 0.35 benzene / methanol 8: 2 (v / v)], 0.45 g of NaOH and 20 ml of methanol are stirred at 60 ° C for 8 hours. Cool, filter.

HU 207 324 Β

Mp 184-185 ° C, Rf. = 0.62 (benzene-methanol 8: 2 v / v). The product obtained was 1.69 g (90%) of the epimer 1RS-3'RS. 1 H-NMR (CDCl 3): 1.30-1.50 m (CH, CH ₂ O-; 9H);

\

2.3-3.1 m _{(3,4-position-CH2,} 4H); 2.15 s (NCH ₃ ;

/

3H); 3.9-4.3 m (CH ₃ CH ₂ O-; 6H); 4.05 s _(OCH3, 3H); 4.54 d (1-CH; 1H); 5.58 d (3-CH; 1H);

II II

5.82 dd (-OCtf ₂ O-; 2H); 5.05 s (-NH ₂ ; 2H)

MS (EI-70eV) m / e 500 (M ⁺ ; 2); 220 (100)

Claims (8)

PATENT CLAIMS A process for the preparation of amino-phthalide isoquinolines of the formula V wherein R _t is methyl or ethyl, R ₂ is methoxy, R ₃ , R ₄ , R ₅ are methoxy or ethoxy and all three are always the same. Reduction of compounds of formula (III) by reacting an isoquinoline derivative of formula (I), wherein R 1 and R ₂ are as defined above, for the preparation of a compound of formula (III) in an aliphatic alcohol is reacted with a trialkoxynitrophthalene followed by the nitrophthalide isoquinoline of the formula (III) (a) in an aliphatic alcohol boiled with hydrazine hydrate in the presence of a Raney-Ni catalyst, or b) reduction with ammonium formate in the presence of a palladium-carbon catalyst in the presence of a palladium-carbon catalyst in the presence of an aliphatic alcohol and a cyclic ether, and epimerizing the resulting aminophthalide isoquinolines of formula (IV) and optionally converting them to a salt. 2. Method according to claim 1, characterized in that the trialkoxy nitroftalidokat general formula (II) wherein R _3, R ₄ and R ₅ are as defined above - of formula (I) - wherein R and _R2 are as defined above - isokinoline derivatives in a 1: 0.8-1.2 molar ratio are suitably 1: 0.9-1.00 in aliphatic alcohols in the presence of alkaline carbonates. The process according to claim 1, wherein the condensation reaction is carried out at 50-100 ° C, preferably at 70-80 ° C. Reduction process according to claim 1, characterized in that the Raney-Ni catalyst is present in an amount of 6 to 14, preferably 8 to 12%, by weight of the nitrophthalide isoquinolines of the formula (III), in a molar ratio of nitro-phthalide isoquinolines of the formula (III) of from 1: 3.0 to 8.0, preferably from 1: 4.0 to 6.0, Reduction process according to claim 1, characterized in that the reduction is carried out at a temperature of 40-80 ° C, preferably 50-70 ° C. Reduction process b) according to claim 1, characterized in that the reduction is carried out with ammonium formate in the presence of a palladium-on-carbon catalyst and cyclic ethers are used to improve the solubility conditions in a ratio of 1: 0.7 to 1.3 per volume of aliphatic alcohol. preferably in a ratio of 1: 0.91.1. Reduction process b) according to claim 1, characterized in that the palladium carbon catalyst is present in an amount of 6 to 14, preferably 8 to 12% by weight, based on the weight of the nitrophthalide isoquinoline derivative of the formula (III). ammonium formate, 3- to 10-fold relative to the nitrophthalide isoquinoline derivative of formula (III), preferably 5 to 6 times molar excess. Reduction process b) according to claim 1, characterized in that the reduction is carried out at a temperature of 20-50 ° C, preferably 30-40 ° C. HU 207 324 Β Int.Cl. ⁵ : C 07 D 401/056