CN115850171A - Method for preparing ethacridine or salt thereof - Google Patents

Method for preparing ethacridine or salt thereof Download PDF

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CN115850171A
CN115850171A CN202111118803.3A CN202111118803A CN115850171A CN 115850171 A CN115850171 A CN 115850171A CN 202111118803 A CN202111118803 A CN 202111118803A CN 115850171 A CN115850171 A CN 115850171A
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catalyst
acid
ethacridine
copper
formula
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刘振德
高河勇
邹长杰
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Shanghai Biobond Pharmaceutical Co ltd
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Abstract

The invention discloses a method for preparing ethacridine as shown in formula (1) or pharmaceutically acceptable salt thereof, which comprises the following steps: (a) Subjecting a compound represented by formula (2) and an ammonia donor to amination reaction in the presence of a ligand, a catalyst, a base and a solvent to produce a compound represented by formula (1); and optionally, (b) salifying the compound of formula (1) with an acid in a solvent. The method adopts a catalytic amination mode to react, so that the materials are common, the reaction condition is mild, the generated impurities are less, the reaction yield is high, and qualified products can be obtained easily; the method has the advantages of short process route steps, less pollution of generated wastes and easy industrial production.

Description

Method for preparing ethacridine or salt thereof
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing ethacridine or salts thereof.
Background
Ethacridine, namely 2-ethoxy-6, 9-diaminoacridine, has a structure shown as a formula (1). The lactate of ethacridine, namely ethacridine lactate, is commonly used clinically. Ethacridine lactate is sold as rivanol or rivanol, is an acridine bactericidal preservative and has strong killing effect on gram-positive bacteria and a very small number of gram-negative bacteria. Has good antibacterial effect on cocci, especially streptococcus, and is mainly used for treating various wounds and infectious skin diseases, cleaning wounds and externally disinfecting wounds. In addition, due to the special effect of the product on the amniotic membrane of uterus, the product can be used as a labor induction medicine for midgestation.
Figure BDA0003276337560000011
The synthetic route of ethacridine was first disclosed in german patent DE364033C. Reacting 2-chloro-4-nitrobenzoic acid (I) with 4-ethoxyaniline (II) to generate 2-p-ethoxyanilino-4-nitrobenzoic acid (III); and (3) reacting the intermediate III with phosphorus oxychloride, closing a ring to generate 2-ethoxy-6-nitro-9-chloroacridine (IV), reacting with an ethanol ammonia solution, aminating to obtain 2-ethoxy-6-nitro-9-aminoacridine (V), and reducing a nitro group of the compound V by stannous chloride to obtain ethacridine, namely 2-ethoxy-6, 9-aminoacridine (1):
Figure BDA0003276337560000012
patent CN102786471B discloses a synthesis method of a key intermediate 2-ethoxy-6-nitro-9-aminoacridine (V). The adopted process route is similar to that of German patent DE364033C, the intermediate 2-p-ethoxyanilino-4-nitrobenzoic acid (III) reacts with phosphorus oxychloride, after ring closure, a polar aprotic solvent is directly added, polyhydric aliphatic alcohol is added for catalysis, ammonia water or ammonia gas is used as an ammonia source, amination is carried out, and the compound 2-ethoxy-6-nitro-9-aminoacridine (V) is obtained.
Patent application CN101560185A also discloses a synthesis method of a key intermediate 2-ethoxy-6-nitro-9-aminoacridine (V). Aminating the intermediate 2-ethoxy-6-nitro-9-chloroacridine (IV) by using ammonium sulfate, ammonium chloride, ammonium bromide, ammonium carbonate, urea or ammonium acetate as aminating agents and potassium salts such as potassium chloride, potassium bromide, potassium sulfate or potassium carbonate as activating agents to obtain the key intermediate 2-ethoxy-6-nitro-9-aminoacridine (V).
U.S. Pat. No. 3,36, 054 discloses a method for obtaining 2-ethoxy-6-nitro-9-aminoacridine (V), a key intermediate, by heating and aminating 2-ethoxy-6-nitro-9-chloroacridine (IV) with urea in the presence of a polar organic solvent and a weak acid strong base salt.
In the above patent routes, 2-ethoxy-6-nitro-9-chloroacridine (IV) as an intermediate is used, and amino substitution is carried out by using different ammonia sources under different conditions of solvents, catalysts, pressures and temperatures to obtain the key intermediate 2-ethoxy-6-nitro-9-aminoacridine (V). However, in practical experiments, the above reaction inevitably produces a larger impurity, namely 2-ethoxy-6-nitro-9-hydroxyacridine (VI), and further derivatizes the impurity to 2-ethoxy-6-amino-9-hydroxyacridine (VII) during the next reduction of the nitro group. The impurities have similar structure with the product, are difficult to remove, and can not obtain qualified products.
Figure BDA0003276337560000021
In the existing route for industrially producing ethacridine (national institute of medicine and administration, 1980, national Assembly of bulk drugs and technology, pages 254-256), an intermediate 2-ethoxy-6-nitro-9-hydroxyacridine (VI) is reacted with ammonia water in the presence of phenol to generate a key intermediate 2-ethoxy-6-nitro-9-aminoacridine (V), nitro is reduced by iron powder and hydrochloric acid to obtain ethacridine (1), and finally, the ethacridine (3) is salified with lactic acid in an ethanol solvent to obtain ethacridine lactate:
Figure BDA0003276337560000031
the route uses a large amount of phenol, and the phenol is difficult to recover and treat and seriously pollutes the environment. The iron powder hydrochloric acid method used in the nitro reduction produces a large amount of iron mud solid waste and also seriously pollutes the environment. The national development and improvement committee has already clearly pointed out that the iron powder reduction process belongs to the elimination class in the industrial structure adjustment catalogue, because a large amount of iron mud which is difficult to treat is generated after reduction, and the iron mud belongs to a high-pollution process. The reaction residues in the reaction process of chemicals specified in the national hazardous waste list are hazardous wastes. The iron mud obtained by the reduction reaction of the iron powder contains a large amount of aniline compounds, is toxic and belongs to dangerous solid wastes.
Therefore, the existing process route takes 2-ethoxy-6-nitro-9-aminoacridine (V) as a key intermediate, and the reduction method adopted by nitro reduction has large waste discharge and serious pollution. The route is long, the process conditions adopted in the other steps, the material quantity of the used solvent and the like are large, the discharge amount of the waste is large, the waste is difficult to treat, and the industrial production is not facilitated.
Therefore, there is a need for development of an improved method for producing ethacridine or a salt thereof, which has a short process, a high yield, less waste, good product quality, and is suitable for industrial scale-up production.
Disclosure of Invention
In view of the above-mentioned drawbacks of the prior art, the present invention aims to provide a method for preparing ethacridine or a salt thereof, which has the advantages of short steps, less waste and good product quality, and is suitable for industrial scale-up production with high yield.
The purpose of the invention is realized by the following technical scheme:
the invention provides a method for preparing ethacridine as shown in formula (1) or a pharmaceutically acceptable salt thereof, which comprises the following steps:
Figure BDA0003276337560000032
(a) Subjecting a compound represented by formula (2) and an ammonia donor to amination reaction in the presence of a ligand, a catalyst, a base and a solvent to produce a compound represented by formula (1); and
optionally, (b) salifying the compound of formula (1) with an acid in a solvent.
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, ammonium sulfate and the like.
Preferably, wherein in step (a), the catalyst is selected from one or more of a palladium catalyst, a copper catalyst, a nickel catalyst and a cobalt catalyst; preferably, the catalyst is a copper catalyst. The inventors have unexpectedly found that not only is the cost low, but the reaction yield is high when a copper catalyst is used.
Preferably, wherein in step (a), the palladium catalyst is selected from palladium chloride, palladium acetate, palladium nitrate, pd (PPh) 3 ) 4 、Pd(PPh 3 ) 2 Cl 2 、Pd 2 (dba) 3 、Pd(dba) 2 、Pd(dppf)Cl 2 One or more of allylpalladium chloride and bis (tricyclohexylphosphine) palladium chloride;
the copper catalyst is selected from one or more of copper powder, copper oxide, cuprous bromide, copper acetate, copper sulfate, cuprous iodide, cuprous chloride and copper acetylacetonate;
the nickel catalyst is bis (1-5-cyclooctadiene) nickel (Ni (COD) 2 ) (ii) a And/or
The cobalt catalyst is tri (triphenylphosphine) cobalt chloride ((Ph) 3 P) 3 CoCl)。
Preferably, in step (a), the ligand is selected from one or more compounds represented by the following formulas (4) to (24):
Figure BDA0003276337560000041
/>
Figure BDA0003276337560000051
preferably, wherein in step (a), the base is selected from one or more of potassium carbonate, potassium phosphate, potassium acetate and the like.
Preferably, wherein in step (a), the solvent is selected from one or more of toluene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, DMF, DMSO, DMI, NMP, sulfolane, and the like.
Preferably, wherein the pharmaceutically acceptable salt of ethacridine is lactate, citrate, malate, tartrate, sorbate, maleate, hydrochloride, sulfate or acetate salt of ethacridine.
Preferably, the pharmaceutically acceptable salt of ethacridine is represented by the following formula (3):
Figure BDA0003276337560000052
preferably, 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, preferably the acid is lactic acid.
Compared with the synthetic route disclosed by the literature, the method disclosed by the invention adopts a catalytic amination mode for reaction, so that the materials are common, the reaction condition is mild, the reaction can be carried out more thoroughly, the generated impurities are less, the impurities are easy to remove cleanly in post-treatment, the reaction yield is high, and qualified products are easy to obtain; the process route of the invention has short steps, the produced waste has less pollution, the pressure of environmental pollution is greatly reduced, and the industrial production is easy to carry out.
Detailed Description
The present invention will be further described with reference to the following examples. This example is merely to illustrate the present invention and is not meant to limit the content of the present invention in any way.
Example 1: synthesis of 2-ethoxy-6, 9-diaminoacridine (1)
Figure BDA0003276337560000061
A500 ml stainless steel pressure resistant reaction vessel was charged with a solvent (150 ml), the reactant 2-ethoxy-6, 9-dichloroacridine (2, 20g, 68.46mmol), a base (136.92 mmol), a ligand (6.85 mmol), a catalyst (3.42 mmol) and an ammonia donor (342.3 mmol), and after stirring to uniformity, the reaction vessel was closed. Heating the reaction kettle to 80-120 ℃, and stirring for reaction. After the reaction is finished, cooling the reaction kettle to room temperature, and opening the reaction kettle. The reaction solution in the kettle is dripped into water (500 ml), and the suspension continues to be stirredStirring for 30 min, stirring, filtering, and washing with appropriate amount of water. And drying the filter cake to obtain a yellow-green solid product. 1 HNNR(400MHz,DMSO-d6)δ:8.07(d,1H,J＝8.8Hz),7.61-7.58(m,2H),7.24(dd,2H,J＝9.2Hz,2.4Hz),6.80(dd,1H,J＝9.2Hz,1.2Hz),6.73(s,1H),5.62(bs,2H),4.16(q,2H,J＝6.8Hz),1.42(t,3H,J＝6.8Hz).MS(ESI):m/z＝254.1[(M+H) + ]。
The solvent used in the reaction is selected from toluene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, DMF, DMSO, DMI, NMP, sulfolane, etc.; the ammonia donor is selected from liquid ammonia, ammonia water, ammonium carbonate, ammonium bicarbonate, ammonium chloride, ammonium acetate, ammonium sulfate, etc.; the alkali is selected from potassium carbonate, potassium phosphate, potassium acetate, etc.; the ligand is selected from the following:
Figure BDA0003276337560000062
Figure BDA0003276337560000071
the catalyst is selected from palladium catalyst, copper catalyst, nickel catalyst and cobalt catalyst; wherein the palladium catalyst is selected from palladium chloride, palladium acetate, palladium nitrate, pd (PPh) 3 ) 4 、Pd(PPh 3 ) 2 Cl 2 、Pd 2 (dba) 3 、Pd(dba) 2 、Pd(dppf)Cl 2 Allyl palladium chloride, bis (tricyclohexylphosphine) palladium chloride; wherein the copper catalyst is selected from copper powder, cupric oxide, cuprous bromide, cupric acetate, cupric sulfate, cuprous iodide, cuprous chloride, and copper acetylacetonate; wherein the nickel catalyst is bis (1-5-cyclooctadiene) nickel (Ni (COD) 2 ) (ii) a Wherein the cobalt catalyst is tris (triphenylphosphine) cobalt chloride ((Ph) 3 P) 3 CoCl)。
The results of the experiments with different solvents, ammonia donors, ligands and catalysts at different temperature conditions are shown in the following table:
Figure BDA0003276337560000072
/>
Figure BDA0003276337560000081
/>
Figure BDA0003276337560000091
/>
Figure BDA0003276337560000101
Figure BDA0003276337560000111
note: 1. when liquid ammonia is used as an ammonia donor, an air pipe is used for connecting a liquid ammonia gas cylinder and the reaction kettle and is used as an amine source, and certain pressure is kept in the reaction process.
Example 2:synthesis of ethacridine lactate (3)
Figure BDA0003276337560000112
To a reaction flask were added crude ethacridine (10.0 g), 85% aqueous lactic acid (5.0 g) and purified water (50 ml). Heating and refluxing the reaction solution, and slowly cooling to 0 ℃ after the reaction solution is dissolved and clear. Stirring for 1 hr, filtering, and washing with cold water. The solid wet product is blown by air and heated to be dried, so that 12.40g of yellow powder is obtained, and the yield is 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) + ]。
Example 3:synthesis of ethacridine lactate (3)
Figure BDA0003276337560000113
To a reaction flask were added crude ethacridine (10.0 g), 85% aqueous lactic acid (5.0 g) and absolute ethanol (30 ml). Heating and refluxing the reaction solution, and slowly cooling to 0 ℃ after the reaction solution is dissolved and clear. Tetrahydrofuran (15 ml) was added dropwise to the reaction solution, stirring was continued for 1 hour with heat preservation, filtration was carried out, and washing was carried out with an appropriate amount of cold absolute ethanol. The wet solid product is dried by air blast heating to obtain 12.21g of yellow powder, and the yield is 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) + ]。
Example 4:synthesis of ethacridine (3) lactate
Figure BDA0003276337560000121
To a reaction flask were added crude ethacridine (10.0 g), 85% aqueous lactic acid (5.0 g) and isopropanol (50 ml). Heating and refluxing the reaction solution, and slowly cooling to 0 ℃ after the reaction solution is dissolved and clear. Stirring for 1 hr, filtering, and washing with cold isopropanol. The solid wet product is blown, heated and dried to obtain 12.58g of yellow powder, and the yield is 88.2 percent. 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 (10)

1. A method for preparing ethacridine of formula (1) or a pharmaceutically acceptable salt thereof, comprising the steps of:
Figure FDA0003276337550000011
(a) Subjecting a compound represented by formula (2) and an ammonia donor to an amination reaction in the presence of a ligand, a catalyst, a base and a solvent to produce a compound represented by formula (1); and
optionally, (b) salifying the compound of formula (1) with an acid in a solvent.
2. The method of claim 1, 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.
3. The process of claim 1 or 2, wherein in step (a) the catalyst is selected from one or more of a palladium catalyst, a copper catalyst, a nickel catalyst and a cobalt catalyst; preferably, the catalyst is a copper catalyst.
4. The process of claim 3 wherein in step (a) the palladium catalyst is selected from the group consisting of palladium chloride, palladium acetate, palladium nitrate, pd (PPh) 3 ) 4 、Pd(PPh 3 ) 2 Cl 2 、Pd 2 (dba) 3 、Pd(dba) 2 、Pd(dppf)Cl 2 One or more of allylpalladium chloride and bis (tricyclohexylphosphine) palladium chloride;
the copper catalyst is selected from one or more of copper powder, copper oxide, cuprous bromide, copper acetate, copper sulfate, cuprous iodide, cuprous chloride and copper acetylacetonate;
the nickel catalyst is bis (1-5-cyclooctadiene) nickel (Ni (COD) 2 ) (ii) a And/or
The cobalt catalyst is tri (triphenylphosphine) cobalt chloride ((Ph) 3 P) 3 CoCl)。
5. The method according to claim 1 or 2, wherein in step (a), the ligand is selected from one or more compounds represented by the following formulae (4) to (24):
Figure FDA0003276337550000021
6. the process of claim 1 or 2, wherein in step (a) the base is selected from one or more of potassium carbonate, potassium phosphate and potassium acetate.
7. The process of 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.
8. The method of claim 1, wherein the pharmaceutically acceptable salt of ethacridine is lactate, citrate, malate, tartrate, sorbate, maleate, hydrochloride, sulfate, or acetate salt of ethacridine.
9. The method of claim 1, wherein the pharmaceutically acceptable salt of ethacridine is represented by the following formula (3):
Figure FDA0003276337550000031
10. the method of 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, and preferably the acid is lactic acid.
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