DESC:Field of the Invention

The present invention relates to the preparation of substantially pure Mepacrine (Phenol free) of Formula (I) and its intermediate of Formula (V). The present invention also relates to the process for the preparation of Mepacrine and its intermediate of Formula (V) which is substantially free from 6-chloro-2-methoxy-10H-acridin-9-one of Formula (VII).

Formula (I)

Background of the Invention

Mepacrine (also called Quinacrine) is chemically designated as N4-(6-Chloro-2-methoxy-9-acridinyl)-N1,N1-diethyl-1,4-pentanediamine dihydrochloride dihydrate (herein after called Mepacrine). Mepacrine was initially approved in the 1930’s as an antimalarial drug.

Certain literatures state that Mepacrine is not the drug of choice because side effects are common, including toxic psychosis, and may cause permanent damage. It is hypothesized that the side effect or toxicity of Mepacrine is likely due to the presence of 6-chloro-2-methoxy-10H-acridin-9-one of Formula (VII) and/or in addition to the presence of phenol. Although the pharmacopeia specifies a limit of NMT 0.5% for 6-chloro-2-methoxy-10H-acridin-9-one of Formula (VII) for Mepacrine salts to the best of applicant’s knowledge no manufacturers produce the Mepacrine and its intermediate which is substantially free from 6-chloro-2-methoxy-10H-acridin-9-one of Formula (VII) and phenol

The reported process for the preparation of Mepacrine involves Modified Ullmann-Goldberg coupling reaction of 2,4-dichlorobenzoic acid with p-anisidine followed by cyclization, aromatization and chlorination of resulting chloromethoxy diphenylamine-2-carboxylic acid to 6,9-dichloro-2-methoxyacridine of Formula (V). The compound of Formula (V) reacted with 1-diethylamino-4-aminopentane affords Mepacrine. The reported process is schematically represented below:

During cyclization of Formula (VI) and subsequent chlorination proceeds, about 20 to 40% of 6-chloro-2-methoxy-10H-acridin-9-one of Formula (VII) also forms which is presumably due to hydrolysis of the compound of formula (V-A) in the presence acidic conditions. The 6,9-dichloro-2-methoxyacridine of Formula (V) prepared based on the reported process contains large amount of 6-chloro-2-methoxy-10H-acridin-9-one of Formula (VII), which affects the yield and quality. In addition a degree of degradation was observed in nearly all of the 6,9-dichloro-2-methoxyacridine synthesized, through hydrolysis to form 6-chloro-2-methoxy-10H-acridin-9-ones upon storage.

The preparation of Mepacrine as described in literatures like British Patent No. 363,392, US2,439,746A, Synthetic Communications; vol. 52; nb.7; (2022); p. 1004 – 1011and WO 2012/077136 A2 involves condensation of 2-methoxy- 6,9-dichloroacridine and 2-amino-5-diethylaminopentane together in phenol.
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Thus, there is a need to prepare Mepacrine and its intermediate of Formula (V) which is substantially free from 6-chloro-2-methoxy-10H-acridin-9-one of Formula (VII) and avoids the use of phenol during its synthesis. Like any synthetic compound, Mepacrine prepared according to the prior art process using phenol as solvent in the last step result with Mapacrine contain higher amount of phenol.

Objectives of the Invention

An objective of the present invention is to provide an environmentally improved scalable process for the preparation of Mepacrine and its intermediate of Formula (V) which is substantially free from 6-chloro-2-methoxy-10H-acridin-9-one of Formula (VII) with good purity and overall yield.
Another objective of the present invention is to provide an improved process for the preparation of Mepacrine and its intermediate of Formula (V) which is substantially free from 6-chloro-2-methoxy-10H-acridin-9-one of Formula (VII) and avoids use of phenol in the reaction and suitable for manufacturing point of view.
Summary of the Invention
Accordingly, an aspect of the present invention is directed to an improved process for the preparation of Mepacrine of Formula (I) said process comprising the steps of:
a) condensing 2, 4-dichloro benzoic acid of Formula (II) with p-anisidine of Formula (III) in water to provide chloromethoxy diphenyl amine-2-carboxylic acid of Formula (IV);
b) converting the chloromethoxy diphenyl amine-2-carboxylic acid of Formula (IV) in the presence of a cyclizing agent and in the presence of organic base to yield 6,9-dichloro-2-methoxyacridineof Formula (V); and
c) condensing 6,9-dichloro-2-methoxyacridine of Formula (V) with 1-diethylamino-4-aminopentane of Formula (VI) in the presence of alkali metal halide to yield Mepacrine of Formula (I).

Another aspect of the present invention is directed to green process for the preparation of chloromethoxy diphenyl amine-2-carboxylic acid of Formula (IV) said process comprising the steps of reacting 2, 4-dichloro benzoic acid of Formula (II) with p-anisidine of Formula (III) in water at a temperature in the range of 50 to 150 °C.
Still another aspect of the present invention directed to process for the preparation of Mepacrine comprising preparation of chloromethoxy diphenyl amine-2-carboxylic acid of Formula (IV) by reacting 2, 4-dichloro benzoic acid of Formula (II) with p-anisidine of Formula (III) in water at a temperature in the range of 50 to 150 °C followed by cyclising chloromethoxy diphenyl amine-2-carboxylic acid of Formula (IV) in presence of POCl3 and an organic base.
One more aspect of the present invention provides 6,9-dichloro-2-methoxyacridine of Formula (V) which is substantially free from 6-chloro-2-methoxy-10H-acridin-9-one of Formula (VII).
Yet another aspect of the present invention provides a process for the preparation of Mepacrine of Formula (I) which is substantially free from 6-chloro-2-methoxy-10H-acridin-9-one of Formula (VII) and phenol.

Detailed Description of the Invention

In an embodiment of the present invention, the term Mepacrine substantially free from 6-chloro-2-methoxy-10H-acridin-9-one of Formula (VII) or substantially pure Mepacrine or its intermediate is meant that Mepacrine or its intermediate of Formula (V) prepared in accordance with the present invention contains less than about 0.5%, more preferably less than about 0.3 %, of 6-chloro-2-methoxy-10H-acridin-9-one of Formula (VII) as characterized by HPLC and/or NMR.

In an embodiment of the present invention, the term Mepacrine substantially free from 6-chloro-2-methoxy-10H-acridin-9-one of Formula (VII) or substantially pure Mepacrine is meant that Mepacrine having less than about 0.5%, more preferably less than about 0.3 %, of 6-chloro-2-methoxy-10H-acridin-9-one of Formula (VII) as characterized by HPLC and/or NMR and avoids the use of phenol for the manufacturing. Accordingly, the present invention provides Mepacrine obtained is substantially free from phenol.

The term Mepacrine as described herein includes Mepacrine and its pharmaceutically acceptable salts such as but not limited to dihydrochloride dihydrate.

In another embodiment of the present invention condensation of 2,4-dichloro benzoic acid of Formula (II) with p-anisidine of Formula (III) is carried out under Modified Ullmann-Goldberg reaction condition or any equivalent condition. The Modified Ullmann-Goldberg reaction is carried out in the presence of copper compounds which can be used as catalysts. The following compounds are exemplary: Cu powder, CuCl, CuBr, CuI, CuOCOCH3, Cu2O and its mixtures. The said reaction also involves optional use of base like K2CO3, Na2CO3, NaOH, KOH and the like.

In another embodiment of the present invention condensation of 2,4-dichloro benzoic acid of Formula (II) with p-anisidine of Formula (III) is carried in water as a solvent which is environmentally viable. To the best of applicant knowledge, the prior reported process involves the use of organic solvents.

In yet another embodiment of the present invention the cyclizing agent used for cyclizing chloromethoxy diphenyl amine-2-carboxylic acid of Formula (IV) is selected from, but not limited to, phosphorousoxy chloride (POCl3). Applicant found that the cyclization reaction as reported as per literature process results with 6,9-dichloro-2-methoxyacridine of Formula (V) with higher amount of 6-chloro-2-methoxy-10H-acridin-9-one of Formula (VII). Further 6,9-dichloro-2-methoxyacridineof Formula (V) having higher amount of 6-chloro-2-methoxy-10H-acridin-9-one of Formula (VII) is prone to further hydrolysis. Applicant found that the use of organic base during the cyclization reaction produces substantially pure 6,9-dichloro-2-methoxyacridine of Formula (V). The 6,9-dichloro-2-methoxyacridine of Formula (V) prepared according to the present invention contain less than 0.2% of 6-chloro-2-methoxy-10H-acridin-9-one of Formula (VII). The said conversion can be effected at a temperature in the range of 60 to 150 °C.

In still another embodiment of the present invention the organic base used in step (b) includes but not limited to diisopropyl ethylamine (DIPEA), DBU, diethylamine, N,N dimethyl aniline, triethyl amine (TEA), and the like. The cyclization step is carried out in any solvent that does not affect the course of the reaction which includes but not limited to toluene, monochlorobenzene, di chlorobenzene, xylene and its mixtures and the like.

In still another embodiment of the present invention the alkali metal salt used in step (c) is selected from KI, NaCl, NaBr and its mixtures and the like. Applicant found the use of the alkali metal halide greatly reduces the reaction times and also allows the reaction to proceed without any major side product formation. The said conversion can be effected at a temperature in the range of 80 to 150 °C.

In still another embodiment of the present invention the reaction in step (c) is carried out in a solvent selected from group consisting of DMF, NMP, DMSO, DMAc sulfolane or mixtures thereof. Preferably the step (c) reaction is not carried out in the presence of phenol.

In one more embodiment of the present invention the Mepacrine or its intermediates obtained according to the present invention is optionally purified using a method known in the art, for example by re-crystallization.

In yet another embodiment of the present invention, wherever possible the clear solution is subjected to carbon treatment.

Mepacrine obtained as per the present invention can be further micronized, milled or sieved to get the particle size (d90 less than 200 micron or 100 micron, preferably less than 50 micron or below 10 micron) required for pharmaceutical composition to achieve the desired dissolution profile. Mepacrine prepared according to the present invention is a free flow solid and suitable for pharmaceutical composition. The HPLC / TLC condition described herein can be easily arrived by the person skilled in the art.

Many other beneficial results can be obtained by applying disclosed invention in a different manner or by modifying the invention with the scope of disclosure. The present invention is provided by the examples below, which are provided by way of illustration only and should not be considered to limit the scope of the invention.

Example 1: Preparation of chloromethoxy diphenylamine-2-carboxylic acid [Formula (IV)]

In water, 2,4-dichloro benzoic acid (100 gm), p-anisidine (75 gm), potassium carbonate (75 gm), and Cu/Cu2O were added and heated till completion of reaction and the course of reaction is monitored using TLC or HPLC. After completion of reaction additional water was added to the reaction mass at room temperature and pH of the reaction mass adjusted to acidic using aq. HCl. The solid obtained was filtered, washed/ slurry washed at reflux condition with methanol (alternatively with water, IPA, ethanol, acetone), and dried at 105° C to yield chloromethoxy diphenyIamine-2-carboxylic acid.
Yield 120 gm; Purity by HPLC: 99.4%.

Example – 2: Preparation of 6,9-dichloro-2-methoxyacridine [Formula (V)]

To a solution of chloromethoxy diphenyl amine-2-carboxylic acid (100 gm) in monochlorobenzene, POCl3 (181 gm) and N,N dimethyl aniline (186 gm) were added. The reaction mass heated till completion of reaction and the course of reaction is monitored using TLC or HPLC. Once the reaction completed, the reaction mass was quenched with ice cooled aqueous ammonia solution. The solid obtained was filtered, washed with IPA/water, and dried under vacuum at 60° C to yield 6,9-dichloro-2-methoxyacridine.
Yield 90 gm; Purity by HPLC – 99.6%; content of 6-chloro-2-methoxy-10H-acridin-9-one (VII) –0.1%

Example – 2A: Preparation of 6,9-dichloro-2-methoxyacridine [Formula (V)]

To a solution of chloromethoxy diphenyl amine-2-carboxylic acid (100 gm) in toluene, POCl3 (181 gm) and DIPEA (199 gm) were added. The reaction mass heated till completion of reaction and the course of reaction is monitored using TLC or HPLC. Once the reaction completed, the reaction mass was quenched with ice cooled aqueous ammonia solution. The solid obtained was filtered, washed with IPA/water, and dried to yield 6,9-dichloro-2-methoxyacridine.
Yield 90 gm; Purity by HPLC – 99.5; content of 6-chloro-2-methoxy-10H-acridin-9-one (VII) – 0.1%

Example 3 Preparation of Mepacrine dihydrochloride dihydrate [Formula (I)]

To DMF, 6,9-dichloro-2-methoxyacridine (100 gm), KI (28 gm), 1-diethylamino-4-aminopentane (63 gm) were added and heated till completion of the reaction. After completion of reaction, the solvent (DMF) was completely distilled under vacuum at 80° C and the residue was dissolved in toluene. To the toluene layer, aqueous HCl was added and heated to 80° C. The aqueous layers were separated and cooled to 10°C, the precipitated product was filtered and slurred with acetone.
Yield -140gm; Purity by HPLC – 99.4%; content of compound of Formula (VII) –0.19%

Example 4 : Preparation of Mepacrine dihydrochloride dihydrate [Formula (I)]

To DMF, 6,9-dichloro-2-methoxyacridine (100 gm), NaI (70 gm), 1-diethylamino-4-aminopentane (63 gm) were added and heated till completion of the reaction, after completion of reaction the solvent (DMF) was completely distilled and the residue was dissolved in toluene. To the toluene layer, aqueous HCl was added and heated to 80° C. The aqueous layers were separated and cooled to 10°C, the precipitated product was filtered and slurred with acetone.
Yield -140 gm; Purity by HPLC – >99.3%; content of compound of Formula (VII) –0.23%. (C18 HPLC Column; gradient mobile phase consists of 50 mM phosphate buffer and acetonitrile; Detector: UV 254 nm).
The process described herein before, was carried out with size of 60 kg and obtained the similar results.

,CLAIMS:
1) A process for the preparation of Mepacrine of Formula (I) comprising the steps of:

a) condensing 2, 4-dichloro benzoic acid of Formula (II) with p-anisidine of Formula (III) in water at a temperature in the range of 50 to 150 °C to provide chloromethoxy diphenyl amine-2-carboxylic acid of Formula (IV);

b) converting the chloromethoxy diphenyl amine-2-carboxylic acid of Formula (IV) in the presence of a cyclizing agent and in the presence of an organic base to yield 6,9-dichloro-2-methoxyacridine of Formula (V); and

c) condensing 6,9-dichloro-2-methoxyacridine of Formula (V) with 1-diethylamino-4-aminopentane of Formula (VI) in the presence of alkali metal halide to yield Mepacrine of Formula (I).

2) The process as claimed in claim 1, wherein the step (a) condensing 2, 4-dichloro benzoic acid of Formula (II) with p-anisidine is carried out in the presence of a catalyst selected from Cu powder, CuCl, CuBr, CuI, CuOCOCH3, Cu2O and its mixtures thereof.

3) The process as claimed in claim 1, wherein the cyclizing agent used in step (b) is phosphorousoxy chloride (POCl3) and base used in step (b) is selected from diisopropyl ethylamine (DIPEA), DBU, diethylamine, N,N dimethyl aniline, or triethyl amine (TEA).

4) The process as claimed in claim 1, wherein the in step (b) is carried out in presence of solvent selected from toluene, monochlorobenzene, di chlorobenzene, or xylene.

5) The process as claimed in claim 1, wherein the alkali metal salt used in step (c) is selected from KI, NaCl, or NaBr.

6) The process as claimed in claim 1, wherein the step (c) reaction is carried out in the presence of solvent selected from DMF, NMP, DMSO, DMAc or sulfolane.

7) The process as claimed in claim 1, wherein Mepacrine obtained according to the process of claim 1 is substantially free from 6-chloro-2-methoxy-10H-acridin-9-one of Formula (VII).

8) The process as claimed in claim 1, wherein the Mepacrine obtained according to the process of claim 1 is substantially free from phenol.

9) Mepacrine substantially free from 6-chloro-2-methoxy-10H-acridin-9-one of Formula (VII).

10) A process for the preparation of Mepacrine substantially free from 6-chloro-2-methoxy-10H-acridin-9-one of Formula (VII) comprising preparation of chloromethoxy diphenyl amine-2-carboxylic acid of Formula (IV) by reacting 2, 4-dichloro benzoic acid of Formula (II) with p-anisidine of Formula (III) in water at a temperature in the range of 50 to 150 °C followed by cyclising chloromethoxy diphenyl amine-2-carboxylic acid of Formula (IV) in presence of POCl3 and an organic base.

Dated this twenty-eight (28th) day of August 2023

Dr. Arivozhi Mohan
Director
BIOPIN-AMBAL LIFE SCIENCE PRIVATE LIMITED