Description:Field of the invention:
The present invention relates to an improved process for the preparation of Melitracen of formula-1 or its salts.

Formula-1
The present invention also relates to an improved process for the preparation of 10,10-dimethyl-9(10H)-anthracenone of formula-4 which is a key intermediate for the synthesis of Melitracen of formula-1.

Formula-4
Background of the invention:
Melitracen is a tricyclic antidepressant (TCA) chemically known as 3-(10,10-Dimethyl-9(10H)-anthracenylidene)-N,N-dimethyl-1-propanamine.
Melitracen approved in the form of Melitracen hydrochloride indicated for the treatment of depression and anxiety. In addition to single drug preparations, it is also available as a combination product containing both Melitracen hydrochloride and Flupentixol dihydrochloride.
US3177209 patent discloses the process for the preparation of Melitracen by reacting 10,10-dimethylanthrone with dimethyl aminopropylmagnesium chloride in ether followed by dehydration and hydrochloride salt preparation by reacting with hydrochloric acid in chloroform and recrystallization from acetone to obtained the crystals of Melitracen hydrochloride with melting range of 245-248°C.

Process described in US’209 patent is shown in the following scheme

Chinese journal of modern applied pharmacy, 2009, 26(2), 125-126 discloses the process of preparation of Melitracen hydrochloride and also discloses the preparation of 10,10-dimethyl-9(10H)-anthracenone by reacting 9,10-dihydro-10,10-dimethyl anthracene with chromium trioxide (CrO3) in-presence of acetic acid. Further Melitracen hydrochloride was prepared by reacting 10,10-dimethyl-9(10H)-anthracenone with N,N-dimethyl aminopropylmagnesium chloride in tetrahydrofuran followed by reaction with concentrated hydrochloric acid in dichloromethane to obtained Melitracen hydrochloride with melting range of 246-248°C.
Process described in the above is shown in the following scheme.

The above said process has some disadvantages i.e. includes the usage of combustible reagent chromium trioxide (CrO3) and acetic acid in the reaction. Handling such combustible chemical is unsafe and not acceptable in large scale.
Thus, there remains a need to develop an improved process for the preparation 10,10-dimethyl-9(10H)-anthracenone which is simple, economic and industrially viable process with excellent yields and good quality.
The present inventors have developed an improved industrially viable process which does not involve the usage of any explosive and/or costly solvents or reagents and critical workup procedures. Accordingly, the present invention provides improved processes for the preparation of Melitracen or its salts and 10,10-dimethyl-9(10H)-anthracenone, which are simple, efficient, cost effective, environmentally friendly and commercially scalable for large scale operations with excellent yields and good quality.
Summary of the invention
The first embodiment of the present invention provides a process for the preparation of 10,10-dimethyl-9(10H)-anthracenone of formula-4.
The second embodiment of the present invention provides a process for the preparation of Melitracen of formula-1or its salts.
The third embodiment of the present invention provides a process for the preparation of Melitracen of formula-1or its salts.
Detailed description of the invention
The term "solvent" used in the present invention refers to "non polar solvents like "hydrocarbon solvent" selected from n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene or mixtures thereof; "ether
solvents" selected from dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane or mixtures thereof; "ester solvents" selected from methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate or mixtures thereof; "polar-aprotic solvents selected from dimethylacetamide, dimethylformamide, dimethyl
sulfoxide, N-methylpyrrolidone or mixtures thereof; "chloro solvents" selected from dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixtures thereof; "ketone solvents" selected from acetone, methyl ethyl ketone, methyl isobutyl ketone or mixtures thereof; "nitrile solvents" selected from acetonitrile, propionitrile, isobutyronitrile or mixtures thereof; "alcoholic
solvents" selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol or mixtures thereof; "polar solvents" selected from water or mixtures thereof.
The term “pharmaceutically acceptable salts” or ”salts” described hereinbefore are obtained by reacting organic compound with acid selected from but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; and organic acids such as oxalic acid, maleic acid, malonic acid, tartaric acid, fumaric acid, citric acid, malic acid, succinic acid, mandelic acid, lactic acid, acetic acid, propionic acid, salicylic acid, 2-chloromandelate, para toluene sulfonic acid, ethane-1,2-disulfonic acid, camphor sulfonic acid, ethane sulfonic acid, methane sulfonic acid, naphthalene-2-sulfonic acid, benzene sulfonic acid, adipic acid, glutaric acid, glutamic acid, palmitic acid or aspartic acid and thereof.
The term "room temperature" as used in the present invention herein refers to the temperature in the range from about 25-35°C.

The first embodiment of the present invention provides a process for the preparation of 10,10-dimethyl-9(10H)-anthracenone of formula-4, comprising: treating 2-(2-benzyl phenyl)propan-2-ol of formula-3 with sulphuric acid followed by reacting with chromium trioxide (CrO3) to provide 10,10-dimethyl-9(10H)-anthracenone of formula-4

In first aspect of first embodiment, wherein reaction temperature ranges from about 20°C to 70°C. Preferably from about 30°C to 60°C.
The second embodiment of the present invention provides a process for the preparation of Melitracen of formula-1or its salts, comprising:
a) treating 2-(2-benzyl phenyl)propan-2-ol of formula-3 with sulphuric acid
followed by reacting with chromium trioxide (CrO3) to provide 10,10-dimethyl-9(10H)-anthracenone of formula-4

b) converting 10,10-dimethyl-9(10H)-anthracenone of formula-4 to Melitracen of
formula-1or its salts

Formula-1.
In first aspect of second embodiment, 10,10-dimethyl-9(10H)-anthracenone of formula-4 can be converted to Melitracen of formula-1or its salts by different processes known in the art.

The third embodiment of the present invention provides a process for the preparation of Melitracen of formula-1or its salts, comprising:
a) treating 1-benzyl-2-chlorobenzene of formula-2 with magnesium turnings in a solvent to provide corresponding grignard reagent which is in-situ reaction with acetone to provide 2-(2-benzyl phenyl)propan-2-ol of formula-3

b) treating 2-(2-benzyl phenyl)propan-2-ol of formula-3 with sulphuric acid
followed by reacting with chromium trioxide (CrO3) to provide 10,10-dimethyl-9(10H)-anthracenone of formula-4

c) treating 3-dimethylaminopropylchloride with magnesium turnings in a solvent to provide corresponding grignard reagent which is in-situ reaction with 10,10-dimethyl-9(10H)-anthracenone of formula-4 further in-situ reaction with acid to provide Melitracen acid addition salt.

In first aspect of third embodiment, solvent in step-a and step-c selected from but not limited to mixture of ether solvents and hydrocarbon solvents, preferably tetrahydrofuran and toluene mixture.
In second aspect of third embodiment of the present invention provides a process for the preparation of Melitracen hydrochloride of formula-1a, comprising:
a) treating 1-benzyl-2-chlorobenzene of formula-2 with magnesium turnings in a tetrahydrofuran and toluene mixture to provide corresponding grignard reagent which is in-situ reaction with acetone to provide 2-(2-benzyl phenyl)propan-2-ol of formula-3
b) treating 2-(2-benzyl phenyl)propan-2-ol of formula-3 with sulphuric acid
followed by reacting with chromium trioxide (CrO3) to provide 10,10-dimethyl-9(10H)-anthracenone of formula-4
c) treating 3-dimethylaminopropylchloride with magnesium turnings in tetrahydrofuran and toluene mixture to provide corresponding grignard reagent which is in-situ reaction with 10,10-dimethyl-9(10H)-anthracenone of formula-4 further in-situ reaction with hydrochloric acid to provide Melitracen hydrochloride of formula-1a

Formula-1a.
The inventors of present invention have also carried out the
preparation of 10,10-dimethyl-9(10H)-anthracenone of formula-4 in R&D scale using chromium trioxide in-presence of several acid includes hydrochloric acid, nitric acid and acetic acid. But these reactions have some disadvantages. The reactions carried out in-presence of hydrochloric acid or nitric acid independently has no product formation. Whereas the reactions carried out in-presence acetic acid is found to be an explosive reaction and not acceptable in large scale.
Advantages of the present invention:
• The process described in the present invention is simple, safe, economic, eco-friendly and suitable for the production of Melitracen of formula-1or its salts on commercial scale with a high reproducibility.
• In-situ preparation of Melitracen of formula-1or its salts provides environment friendly and cost-effective process which avoids the usage of combustible reagent, excess solvent, and also avoids the extra filtration and drying process. This makes the process suitable on commercial scale.
• Present invention process for preparation of 10,10-dimethyl-9(10H)-anthracenone of formula-4 from 2-(2-benzyl phenyl)propan-2-ol of formula-3 avoids the usage of combustible reagent this makes the process technically advanced over prior are literature.
• Over all yield of the reaction in in-situ manner is more compared with reactions wherein the intermediates are isolated.
• Usage of commercially available reagents and solvent provides cost-effective process.
• Solvents used in the present invention are recycled and reused in the process.

The other embodiment of the present invention provides a method of treating a patients suffering from depression and anxiety comprising administering to the patients with a therapeutically effective amount of Melitracen hydrochloride obtained by the process of the present invention.
Starting materials utilized in the present invention are commercially available in the market (or) they can be prepared according to the any of the processes known in the prior art.
The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are for illustrative purposes only and in no way limit the scope of the present invention.
Examples:
Example-1: Preparation of 2-(2-benzyl phenyl)propan-2-ol
1-benzyl-2-chlorobenzene of formula-2 (1000 g, 1.0 mole equivalent) in toluene (3000 ml) was added to the mixture of tetrahydrofuran (1000 ml), magnesium turnings (200 g, 1.66 mole equivalent), iodine (10 g, 0.008 mole equivalent) and dibromoethane (132.4 g, 0.14 mole equivalent) at 55-60°C temperature. Heated the reaction mixture to 100-105°C and stirred at same temperature for 12 hours. Reaction mixture was cooled to 50-55°C temperature. Toluene (1400 ml) and acetone (1400 ml) were added to the above reaction mixture at 50-55°C and stirred for 1 hour at same temperature. Quenched reaction mixture with aqueous acetic acid solution. Layers separated. Aqueous layer was extracted with toluene. Combined the organic layers and washed with sodium bicarbonate solution. Solvent was completely distilled off from the organic layer to get the title compound.
Yield: 1070 g (96.49%).
Example-2: Preparation of 10,10-dimethyl-9(10H)-anthracenone
2-(2-benzyl phenyl)propan-2-ol (1070 g, 1.0 mole equivalent) was added to pre-cooled aqueous solution of sulphuric acid (1550 ml) at room temperature and stirred for 4 hours at same temperature. Pre-cooled water was added to above reaction mixture and stirred for 10 minutes at same temperature. Chromium trioxide (1000 g, 2.11 mole equivalent) and sulphuric acid (1000 g, 2.15 mole equivalent) were added to the above reaction mixture at 50-55°C and stirred for 1 hour at same temperature. Reaction mixture was cooled to room temperature. Toluene was added to the above reaction mixture at room temperature and stirred for 10 minutes at same temperature. Layers separated. Aqueous layer was extracted with toluene. Combined the organic layers and washed with sodium bicarbonate solution. n-Heptane was added to the organic layer at 0-5°C and stirred for 10 minutes. Solid was filtered and dried to get the title compound.
Yield: 1004.59 g (95.59%).
Example-3: Melitracen hydrochloride of formula-1a
10,10-dimethyl-9(10H)-anthracenone (1000 g, 1.0 mole equivalent) in toluene (6000 ml) was added to the mixture of 3-dimethylaminopropylchloride (2800 g, 5.12 mole equivalent), tetrahydrofuran (1000 ml), toluene (2000 ml) magnesium turnings (240 g, 2.19 mole equivalent), iodine (10 g, 0.009 mole equivalent) and dibromo ethane (132.4 g, 0.17 mole equivalent) at 60-65°C temperature. Heated the reaction mixture to 100-105°C and stirred at same temperature for 1.5 hour.
Reaction mixture was cooled to room temperature. Quenched reaction mixture with aqueous acetic acid solution. Layers separated. Aqueous layer was extracted with toluene. Combined the organic layers and washed with sodium bicarbonate solution. Concentrated hydrochloric acid (804 g, 4.90 mole equivalent) was added above obtained organic layer at room temperature. Heated the reaction mixture to 55-60°C and stirred at same temperature for 1 hour. Reaction mixture was cooled to room temperature. Obtained solid was filtered, washed with toluene and acetone and dried to get the title compound.
Yield: 1438.24 kg (97.49%). , C , Claims:1. A process for the preparation of 10,10-dimethyl-9(10H)-anthracenone of
formula-4, comprising: treating 2-(2-benzyl phenyl)propan-2-ol of formula-3 with sulphuric acid followed by reacting with chromium trioxide (CrO3) to provide 10,10-dimethyl-9(10H)-anthracenone of formula-4

2. A process for the preparation of Melitracen of formula-1or its salts, comprising:
a) treating 2-(2-benzyl phenyl)propan-2-ol of formula-3 with sulphuric acid
followed by reacting with chromium trioxide (CrO3) to provide 10,10-dimethyl-9(10H)-anthracenone of formula-4

b) converting 10,10-dimethyl-9(10H)-anthracenone of formula-4 to Melitracen of formula-1or its salts

Formula-1.

3. A process for the preparation of Melitracen of formula-1or its salts, comprising:
a) treating 1-benzyl-2-chlorobenzene of formula-2 with magnesium turnings in a solvent to provide corresponding grignard reagent which is in-situ reaction with acetone to provide 2-(2-benzyl phenyl)propan-2-ol of formula-3

b) treating 2-(2-benzyl phenyl)propan-2-ol of formula-3 with sulphuric acid
followed by reacting with chromium trioxide (CrO3) to provide 10,10-dimethyl-9(10H)-anthracenone of formula-4

c) treating 3-dimethylaminopropylchloride with magnesium turnings in a solvent to provide corresponding grignard reagent which is in-situ reaction with 10,10-dimethyl-9(10H)-anthracenone of formula-4 further in-situ reaction with acid to provide Melitracen acid addition salt

4. The process as claimed in claim 2, solvent in step-a and step-c selected from
tetrahydrofuran and toluene mixture.

5. A process for the preparation of Melitracen hydrochloride of formula-1a, comprising:
a) treating 1-benzyl-2-chlorobenzene of formula-2 with magnesium turnings in a tetrahydrofuran and toluene mixture to provide corresponding grignard reagent which is in-situ reaction with acetone to provide 2-(2-benzyl phenyl)propan-2-ol of formula-3

b) treating 2-(2-benzyl phenyl)propan-2-ol of formula-3 with sulphuric acid
followed by reacting with chromium trioxide (CrO3) to provide 10,10-dimethyl-9(10H)-anthracenone of formula-4

c) treating 3-dimethylaminopropylchloride with magnesium turnings in tetrahydrofuran and toluene mixture to provide corresponding grignard reagent which is in-situ reaction with 10,10-dimethyl-9(10H)-anthracenone of formula-4 further in-situ reaction with hydrochloric acid to provide Melitracen hydrochloride of formula-1a

Formula-1a.