A method for preparing ethacridine or a salt thereof

Abstract

The present invention discloses a method for preparing ethacridine as shown in formula (1) or a pharmaceutically acceptable salt thereof, comprising the following steps: (a) subjecting the compound shown in formula (2) to an amination reaction with an ammonia donor in the presence of a ligand, a catalyst, a base and a solvent to generate the compound shown in formula (1); and optionally, (b) salifying the compound shown in formula (1) with an acid in a solvent. The method of the present invention uses catalytic amination for the reaction, the materials are relatively common, the reaction conditions are mild, fewer impurities are generated, the reaction yield is high, and it is easy to obtain qualified products; the process route of the present invention has short steps, less waste pollution, and is easy to carry out industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical synthesis, and particularly relates to a method for preparing ethacridine or its salt. Background Art

[0002] Ethacridine, that is, 2-ethoxy-6,9-diaminoacridine, has a structure as shown in formula (1). Clinically, the commonly used one is the lactate of ethacridine, namely ethacridine lactate. The trade name of ethacridine lactate is rivanol or rivanolum, which is an acridine bactericidal preservative and has a strong killing effect on Gram-positive bacteria and a very small number of Gram-negative bacteria. It has a good antibacterial effect on cocci, especially streptococcus, and is mainly used for the treatment of various traumas and infectious skin diseases, wound cleaning and external disinfection. In addition, due to the special effect of this product on the uterine amnion, it can be used as a drug for inducing mid-term pregnancy.

[0003]

[0004] The synthesis route of ethacridine was first disclosed in German Patent DE364033C. React 2-chloro-4-nitrobenzoic acid (I) with 4-ethoxyaniline (II) to form 2-(p-ethoxyanilino)-4-nitrobenzoic acid (III); the intermediate III reacts with phosphorus oxychloride, and after ring closure, 2-ethoxy-6-nitro-9-chloroacridine (IV) is formed, and then it reacts with ethanolamine solution, and after amination, 2-ethoxy-6-nitro-9-aminoacridine (V) is obtained. Compound V is reduced with stannous chloride to obtain ethacridine, that is, 2-ethoxy-6,9-diaminoacridine (1):

[0005]

[0006] Patent CN102786471B discloses a synthesis method of the key intermediate 2-ethoxy-6-nitro-9-aminoacridine (V). The process route adopted is similar to that of German Patent DE364033C. After the intermediate 2-(p-ethoxyanilino)-4-nitrobenzoic acid (III) reacts with phosphorus oxychloride and ring closure, a polar aprotic solvent is directly added, and a polyhydric aliphatic alcohol is added as a catalyst, and ammonia water or ammonia gas is used as the ammonia source for amination to obtain the compound 2-ethoxy-6-nitro-9-aminoacridine (V), and the reaction is continuously carried out in one pot.

[0007] Patent Application CN101560185A also discloses a synthesis method of a key intermediate 2-ethoxy-6-nitro-9-aminoacridine (V). Using ammonium sulfate, ammonium chloride, ammonium bromide, ammonium carbonate, urea or ammonium acetate as the aminating agent, and potassium salts such as potassium chloride, potassium bromide, potassium sulfate or potassium carbonate as the activator, the intermediate 2-ethoxy-6-nitro-9-chloroacridine (IV) is aminated to obtain the key intermediate 2-ethoxy-6-nitro-9-aminoacridine (V).

[0008] U.S. Patent No. US3678054 discloses a method for obtaining the key intermediate 2-ethoxy-6-nitro-9-aminoacridine (V) by heating an amination reaction of 2-ethoxy-6-nitro-9-chloroacridine (IV) with urea in the presence of a polar organic solvent and a weak acid strong base salt.

[0009] In the above patent routes, the intermediate 2-ethoxy-6-nitro-9-chloroacridine (IV) is used, and amino substitution is carried out under different ammonia sources, different solvents, catalysts, pressures and temperature conditions to obtain the key intermediate 2-ethoxy-6-nitro-9-aminoacridine (V). However, in actual experiments, the above reactions will inevitably produce a relatively large impurity, namely 2-ethoxy-6-nitro-9-hydroxyacridine (VI), and it will be further derived into 2-ethoxy-6-amino-9-hydroxyacridine (VII) when reducing the nitro group in the next step. This impurity has a similar structure to the product and is difficult to remove, making it impossible to obtain a qualified product.

[0010]

[0011] The existing industrial production route of ethacridine (National Pharmaceutical Administration, 1980, "Compilation of National API Processes", pages 254 - 256) is to react the intermediate 2-ethoxy-6-nitro-9-hydroxyacridine (VI) with ammonia water in the presence of phenol to generate the key intermediate 2-ethoxy-6-nitro-9-aminoacridine (V), then reduce the nitro group with iron powder and hydrochloric acid to obtain ethacridine (1), and finally form a salt with lactic acid in an ethanol solvent to obtain ethacridine lactate (3):

[0012]

[0013] This route uses a large amount of phenol, which is difficult to recycle and treat, seriously polluting the environment. The iron powder-hydrochloric acid method used for nitro reduction generates a large amount of iron mud solid waste, also seriously polluting the environment. The National Development and Reform Commission clearly pointed out in the industrial structure adjustment catalog that the iron powder reduction process belongs to the phased-out category because a large amount of difficult-to-treat iron mud is generated after reduction, which is a highly polluting process. The National Hazardous Waste List stipulates that the reaction residues in the chemical reaction process are hazardous wastes. The iron mud after the reduction reaction of iron powder contains a large amount of aniline compounds, which are toxic and belong to hazardous solid waste.

[0014] It can be seen that the existing process routes all use 2-ethoxy-6-nitro-9-aminoacridine (V) as the key intermediate, and the reduction methods used for nitro reduction have a large amount of waste emissions and serious pollution. The route is long, and the process conditions and the amount of other materials such as solvents used in the remaining steps are also very large, with a large amount of waste emissions and the waste is difficult to treat, which is not conducive to industrial production.

[0015] Therefore, there is a need to develop an improved method for preparing ethacridine or its salts, which has short steps, high yield, less waste, good product quality and is suitable for industrial scale-up production. Summary of the Invention

[0016] Aiming at the above-mentioned defects of the prior art, the object of the present invention is to provide a method for preparing ethacridine or its salts with short steps, less waste and good product quality. The method of the present invention has a high yield and is suitable for industrial scale-up production.

[0017] The object of the present invention is achieved by the following technical solutions:

[0018] The present invention provides a method for preparing ethacridine or its pharmaceutically acceptable salts as shown in formula (1), comprising the following steps:

[0019]

[0020] (a) Subjecting the compound shown in formula (2) to an amination reaction with an ammonia donor in the presence of a ligand, a catalyst, a base and a solvent to form the compound shown in formula (1); and

[0021] Optionally, (b) subjecting the compound shown in formula (1) to salt formation with an acid in a solvent.

[0022] Preferably, in step (a), the ammonia donor is selected from one or more of liquid ammonia, aqueous ammonia, ammonium carbonate, ammonium bicarbonate, ammonium chloride, ammonium acetate and ammonium sulfate, etc.

[0023] Preferably, in step (a), the catalyst is selected from one or more of palladium catalysts, copper catalysts, nickel catalysts and cobalt catalysts; preferably, the catalyst is a copper catalyst. The inventors unexpectedly found that when a copper catalyst is used, not only the cost is low, but also the reaction yield is high.

[0024] Preferably, in step (a), the palladium catalyst is selected from one or more of palladium chloride, palladium acetate, palladium nitrate, Pd(PPh3)4, Pd(PPh3)2Cl2, Pd2(dba)3, Pd(dba)2, Pd(dppf)Cl2, allyl palladium chloride and bis(tricyclohexylphosphine) palladium chloride;

[0025] The copper catalyst is selected from one or more of copper powder, copper oxide, cuprous oxide, cuprous bromide, copper acetate, copper sulfate, cuprous iodide, cuprous chloride and copper acetylacetonate;

[0026] The nickel catalyst is bis(1,5-cyclooctadiene) nickel (Ni(COD)2); and / or

[0027] The cobalt catalyst described above is tris(triphenylphosphine)cobalt chloride ((Ph3P)3CoCl).

[0028] Preferably, in step (a), the ligand is selected from one or more of the compounds shown in the following formulas (4) to (24):

[0029]

[0030]

[0031] Preferably, in step (a), the base is selected from one or more of potassium carbonate, potassium phosphate, potassium acetate, etc.

[0032] Preferably, in step (a), the solvent is selected from one or more of toluene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, DMF, DMSO, DMI, NMP, sulfolane, etc.

[0033] Preferably, the pharmaceutically acceptable salt of ethacridine is the lactate, citrate, malate, tartrate, sorbate, maleate, hydrochloride, sulfate or acetate of ethacridine.

[0034] Preferably, the pharmaceutically acceptable salt of ethacridine is shown in the following formula (3):

[0035]

[0036] Preferably, in step (b), the solvent is selected from water, ethanol, isopropanol, tetrahydrofuran or any combination thereof; and / or the acid is selected from lactic acid, citric acid, malic acid, tartaric acid, sorbic acid, maleic acid, hydrochloric acid, sulfuric acid or acetic acid, and preferably, the acid is lactic acid.

[0037] Compared with the synthesis routes disclosed in the literature, the method of the present invention uses catalytic amination for the reaction. The materials are relatively common, the reaction conditions are mild, the reaction can proceed more thoroughly, fewer impurities are generated, and they are easily removed completely during post-treatment. The reaction yield is high, and it is easy to obtain qualified products; the process route of the present invention has short steps, less waste pollution, greatly reduces the pressure of environmental pollution, and is easy to carry out industrial production. Detailed Embodiments

[0038] The following further illustrates the present invention with specific examples. These examples are only for explaining the present invention and do not mean to limit the content of the present invention in any way.

[0039] Example 1 : Synthesis of 2-ethoxy-6,9-diaminoacridine (1)

[0040]

[0041] Add the solvent (150 ml), reactant 2-ethoxy-6,9-dichloroacridine (2.20 g, 68.46 mmol), base (136.92 mmol), ligand (6.85 mmol), catalyst (3.42 mmol), and ammonia donor (342.3 mmol) to a 500 ml stainless steel pressure reactor. After stirring evenly, seal the reactor. Heat the reactor to 80 - 120 °C and stir for the reaction. After the reaction is completed, cool the reactor to room temperature and open the reactor. Dropwise add the reaction solution in the reactor into water (500 ml). Continue to stir the suspension for 30 minutes. After stirring evenly, filter and wash with an appropriate amount of water. Dry the filter cake to obtain a yellow-green solid product. 1 HNNR (400 MHz, DMSO-d6) δ: 8.07 (d, 1H, J = 8.8 Hz), 7.61 - 7.58 (m, 2H), 7.24 (dd, 2H, J = 9.2 Hz, 2.4 Hz), 6.80 (dd, 1H, J = 9.2 Hz, 1.2 Hz), 6.73 (s, 1H), 5.62 (bs, 2H), 4.16 (q, 2H, J = 6.8 Hz), 1.42 (t, 3H, J = 6.8 Hz). MS (ESI): m / z = 254.1 [(M + H) + .

[0042] The solvents used in the reaction are selected from toluene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, DMF, DMSO, DMI, NMP, sulfolane, etc.; the ammonia donors are selected from liquid ammonia, ammonia water, ammonium carbonate, ammonium bicarbonate, ammonium chloride, ammonium acetate, ammonium sulfate, etc.; the bases are selected from potassium carbonate, potassium phosphate, potassium acetate, etc.; the ligands are selected from the following several types:

[0043]

[0044]

[0045] The catalysts are selected from palladium catalysts, copper catalysts, nickel catalysts, and cobalt catalysts; among them, the palladium catalysts are selected from palladium chloride, palladium acetate, palladium nitrate, Pd(PPh3)4, Pd(PPh3)2Cl2, Pd2(dba)3, Pd(dba)2, Pd(dppf)Cl2, allyl palladium chloride, bis(tricyclohexylphosphine)palladium chloride; among them, the copper catalysts are selected from copper powder, copper oxide, cuprous oxide, copper bromide, copper acetate, copper sulfate, copper iodide, cuprous chloride, copper acetylacetonate; the nickel catalyst is bis(1,5-cyclooctadiene)nickel (Ni(COD)2); the cobalt catalyst is tris(triphenylphosphine)cobalt chloride ((Ph3P)3CoCl).

[0046] The experimental results of different solvents, ammonia donors, ligands and catalysts under different temperature conditions are shown in the following table:

[0047]

[0048]

[0049]

[0050]

[0051]

[0052] Note: 1. When liquid ammonia is used as the ammonia donor, a gas pipe is used to connect the liquid ammonia gas cylinder to the reaction kettle. As the amine source, a certain pressure is maintained during the reaction.

[0053] Example 2: Synthesis of Ethacridine Lactate (3)

[0054]

[0055] Add crude ethacridine (10.0 g), 85% aqueous lactic acid solution (5.0 g) and purified water (50 ml) to the reaction flask. The reaction solution is heated to reflux. After it becomes clear, it is slowly cooled to 0 °C. Keep stirring at this temperature for 1 hour, then filter and wash with an appropriate amount of cold water. The wet solid is dried by blowing air heating to obtain 12.40 g of yellow powder, with a yield of 87%. 1 HNNR(400MHz,DMSO-d6)δ:8.88(bs,1H),8.26(d,1H,J=9.2Hz),7.87(s,2H),7.79-7.73(m,1H),7.51(d,1H,J=9.2Hz),6.88(d,1H,J=9.2Hz),6.71(m,3H),4.19(q,2H,J=6.8Hz),3.65-3.58(m,1H),1.43(t,3H,J=6.8Hz),1.16(t,3H,J=6.8Hz).MS(ESI):m / z=254.1[(M+H) + .

[0056] Example 3: Synthesis of Ethacridine Lactate (3)

[0057]

[0058] Add crude ethacridine (10.0 g), 85% aqueous lactic acid solution (5.0 g) and absolute ethanol (30 ml) to the reaction flask. Heat the reaction solution under reflux. After it becomes clear, slowly cool it down to 0 °C. Add tetrahydrofuran (15 ml) dropwise to the reaction solution, continue to stir at a constant temperature for 1 hour, filter, and wash with an appropriate amount of cold absolute ethanol. Dry the wet solid by heating with forced air to obtain 12.21 g of yellow powder, with a yield of 85.6%. 1 HNNR(400MHz,DMSO-d6)δ:8.88(bs,1H),8.26(d,1H,J=9.2Hz),7.87(s,2H),7.79-7.73(m,1H),7.51(d,1H,J=9.2Hz),6.88(d,1H,J=9.2Hz),6.71(m,3H),4.19(q,2H,J=6.8Hz),3.65-3.58(m,1H),1.43(t,3H,J=6.8Hz),1.16(t,3H,J=6.8Hz).MS(ESI):m / z=254.1[(M+H) + .

[0059] Example 4: Synthesis of ethacridine lactate (3)

[0060]

[0061] Add crude ethacridine (10.0 g), 85% aqueous lactic acid solution (5.0 g) and isopropanol (50 ml) to the reaction flask. Heat the reaction solution under reflux. After it becomes clear, slowly cool it down to 0 °C. Continue to stir at a constant temperature for 1 hour, filter, and wash with an appropriate amount of cold isopropanol. Dry the wet solid by heating with forced air to obtain 12.58 g of yellow powder, with a yield of 88.2%. 1 HNNR(400MHz,DMSO-d6)δ:8.88(bs,1H),8.26(d,1H,J=9.2Hz),7.87(s,2H),7.79-7.73(m,1H),7.51(d,1H,J=9.2Hz),6.88(d,1H,J=9.2Hz),6.71(m,3H),4.19(q,2H,J=6.8Hz),3.65-3.58(m,1H),1.43(t,3H,J=6.8Hz),1.16(t,3H,J=6.8Hz).MS(ESI):m / z=254.1[(M+H) + .

Claims

1. A method for preparing ethacridine as shown in formula (1) or a pharmaceutically acceptable salt thereof, comprising the following steps: (a) Subjecting the compound shown in formula (2) to an amination reaction with an ammonia donor in the presence of a ligand, a catalyst, a base, and a solvent to produce the compound shown in formula (1), wherein the catalyst is selected from one or more of a copper catalyst, a nickel catalyst, and a cobalt catalyst; and Optionally, (b) reacting the compound shown in formula (1) with an acid to form a salt in a solvent; Wherein in step (a), the ammonia donor is selected from one or more of liquid ammonia, aqueous ammonia, ammonium carbonate, ammonium bicarbonate, ammonium chloride, ammonium acetate, and ammonium sulfate; Wherein in step (a), the copper catalyst is selected from one or more of copper powder, copper oxide, cuprous oxide, cuprous bromide, copper acetate, copper sulfate, cuprous iodide, cuprous chloride, and copper acetylacetonate; and the ligand used in combination with the copper catalyst is selected from one or more of the compounds shown in the following formula (12) to formula (20), and formula (23) and formula (24): The nickel catalyst is bis(1,5-cyclooctadiene)nickel (Ni(COD)2); and the ligand used in combination with the nickel catalyst is selected from one or more of the compounds shown in the following formula (12) and formula (21): The cobalt catalyst is tris(triphenylphosphine)cobalt chloride ((Ph3P)3CoCl); and the ligand used in combination with the cobalt catalyst is selected from one or more of the compounds shown in the following formula (13) and formula (22):

2. The method according to claim 1, wherein in step (a), the base is selected from one or more of potassium carbonate, potassium phosphate, and potassium acetate.

3. The method according to claim 1 or 2, wherein in step (a), the solvent is selected from one or more of toluene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, DMF, DMSO, DMI, NMP, and sulfolane.

4. The method according to claim 1, wherein the pharmaceutically acceptable salt of ethacridine is the lactate, citrate, malate, tartrate, sorbate, maleate, hydrochloride, sulfate, or acetate of ethacridine.

5. The method according to claim 1, wherein the pharmaceutically acceptable salt of ethacridine is as shown in the following formula (3):

6. The method according to claim 1 or 2, wherein in step (b), The solvent is selected from water, ethanol, isopropanol, tetrahydrofuran, or any combination thereof; and / or The acid is selected from lactic acid, citric acid, malic acid, tartaric acid, sorbic acid, maleic acid, hydrochloric acid, sulfuric acid, or acetic acid.

7. The method according to claim 6, wherein the acid is lactic acid.

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