A PROCESS FOR THE PREPARATION OF MELITRACEN HYDROCHLORIDE (Formula-I) AND ITS INTERMEDIATE 10,10-DIMETHYL ANTHRONE (Formula-II)

Abstract

ABSTRACT A PROCESS FOR THE PREPARATION OF MELITRACEN HYDROCHLORIDE (Formula-I) AND ITS INTERMEDIATE 10,10-DIMETHYL ANTHRONE (Formula-II) The present invention provides a process for the preparation of the Active Pharmaceutical Ingredient (API), melitracen hydrochloride (Formula I), and its commercially important key intermediate, 10,10-dimethyl anthrone (Formula II). Specifically, the invention involves the use of recoverable, reusable, bio-renewable, and greener solvents in three consecutive Grignard reactions for the preparation of both Formula I and Formula II from phthalic anhydride, as well as for the preparation of Grignard reagents used in these reactions. The invention also includes the preparation of Formula II in a shorter reaction time with improved yields by replacing conventional sulfuric acid with anhydrous Lewis acid. Furthermore, the invention covers the synthesis of Formula I from Formula II with fewer reaction steps through a hydroxy intermediate, achieved by dehydrative salt formation using alcoholic HCl instead of aqueous HCl in chlorinated solvents. This process yields the API with the desired purity, eliminating the need for a separate recrystallization step.

Specification

Description:FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)



Title: A PROCESS FOR THE PREPARATION OF MELITRACEN HYDROCHLORIDE (Formula-I) AND ITS INTERMEDIATE 10,10-DIMETHYL ANTHRONE (Formula-II)


APPLICANT DETAILS:
(a) NAME: NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION
AND RESEARCH (NIPER), HYDERABAD
(b) NATIONALITY: Indian
(c) ADDRESS: Balanagar, Hyderabad, Telangana 500037, India







PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the nature of this invention and the manner in which it is to be performed.
A PROCESS FOR THE PREPARATION OF MELITRACEN HYDROCHLORIDE (Formula-I) AND ITS INTERMEDIATE 10,10-DIMETHYL ANTHRONE (Formula-II)
Field of Invention:
The present invention relates to a process for the preparation of active pharmaceutical ingredient (API) melitracen Hydrochloride (Formula I) and its commercially important key intermediate 10,10-dimethyl anthrone (Formula II). More precisely, the invention includes using greener solvents while reducing number of reaction steps for the preparation of Formula-I and Formula-II starting from phthalic anhydride as a starting material.

Background of the Invention:
The following background discussion includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication expressly or implicitly referenced is prior art.
Melitracen, chemically known as 3-(10,10-dimethylanthracen-9(10H)-ylidene)-N,N-dimethylpropan-1-amine hydrochloride is a tricyclic anti-depressant developed by Danish Lundbeck pharmaceutical company, that acts by inhibiting the reuptake of 5-HT and norepinephrine, which is available in the form of a tablet. It is available both individually and in combination with flupentixol for the treatment of depression and anxiety.
Various researchers have attempted to synthesize the melitracen hydrochloride and key intermediate 10,10-dimethyl anthrone in different routes. For example, Chinese Pat. No. CN 105061177 A discloses the synthesis of 10,10-dimethyl anthrone with 2-chlorobenzyl chloride as the starting material, and another Chinese Pat. No. CN 115417753 A discloses Cumene (isopropyl benzene) as the starting material to synthesize 10,10 dimethyl anthrone followed by Wittig reaction to get melitracen hydrochloride. Chinese Pat. No. CN 109824493 A discloses the synthesis of 10,10-dimethyl anthrone using phthalic anhydride as the starting material. Benzoyl benzoic acid as the starting material was used for the synthesis of 10,10-dimethyl anthrone as disclosed in Chinese Pat. No. CN 114685255 A.
The synthesis of 10,10-dimethyl anthrone from phthalic anhydride route was disclosed in Chinese Pat. No. CN 109824493 A wherein 10,10-dimethyl anthrone is prepared by a synthetic route, that employs a methyl magnesium bromide/methyl magnesium iodide in THF reacting with phthalic anhydride as the first step to synthesize 3,3-dimethylisobenzofuran-1(3H)-one, followed by treating with phenyl magnesium bromide in THF to attain 3,3-dimethyl-1-phenyl-1,3-dihydroisobenzofuran-1-ol as the second step, followed by the third step involving dehydrative cyclization using sulphuric acid at 150 ℃ for 5 h. to attain the crude 10,10-dimethyl anthrone further recrystallized by using petroleum ether to get pure 10,10-dimethyl anthrone.
Chinese Pat. No. CN 105418436 A, discloses a method for preparing melitracen hydrochloride from the key intermediate 10,10-dimethylanthrone by a synthetic route that employs a (3-(dimethylamino)propyl)magnesium chloride which is synthesized from 3-chloro-N,N-dimethylpropan-1-amine hydrochloride as the commercial starting material after de- saltification using NaOH solution and the free base is extracted into toluene. The Grignard reagent formation is done using THF and magnesium. The resultant (3-(dimethylamino)propyl)magnesium chloride is treated with 10,10-dimethyl anthrone to attain 9-(3-(dimethylamino)propyl)-10,10-dimethyl-9,10-dihydroanthracen-9-ol, which is further treated with aqueous HCl in DCM/Chloroform for dehydrative salt formation to get crude melitracen hydrochloride, which is thereafter recrystallized with alcoholic solvents to obtain pure melitracen hydrochloride.
It is clearly evident from the prior art that the product obtained by prior methods involve a greater number of steps, lower yields, longer duration of reaction, usage of unrecoverable/ less recoverable solvents and highly inflammable solvents in the large-scale production that needs high safety precautions while manufacturing. Moreover, the existing processes are not eco-friendly and do not facilitate the recovery and reuse of the solvents.
Therefore, to overcome the problems associated with the prior art, we need to develop
i) A simple, efficient process ruling out the additional steps involved in the synthesis and with less duration of reaction;
ii) A process which yields compound with the desired purity and higher yields and decreased economic burden; and
iii) A process which uses greener, cheaper, highly recoverable and reusable solvents.

Object(s) of the present invention:
The primary objective of the present invention is to overcome the drawback associated with prior art.
An object of the present invention is to provide a process for the preparation of the Active Pharmaceutical Ingredient (API), melitracen hydrochloride (Formula-I) and its commercially important key intermediate 10,10-dimethyl anthrone (Formula II) with improved yields and safety.

Summary of the Invention:
In an aspect, the present invention provides a process for the preparation of the Active Pharmaceutical Ingredient (API), melitracen hydrochloride (Formula-I) and its commercially important key intermediate 10,10-dimethyl anthrone (Formula II). More specifically the invention includes use of recoverable, reusable bio-renewable and greener ethereal solvents in three consecutive Grignard reactions for the preparation of Formula -I and Formula II from phthalic anhydride, and also for the preparation of Grignard reagents for these reactions. The invention also includes preparation of Formula II in shorter reaction time and lower temperatures by modifying the reagent from conventional Sulphuric acid to Anhydrous AlCl3. Further, the invention also covers synthesis of Formula-I from Formula-II with less number of reaction steps through a hydroxy intermediate by dehydrative salt formation using alcoholic HCl, instead of aqueous HCl in chlorinated solvents and the process offered the API with desired purity circumventing a separate recrystallization step.

Brief description of Drawings:
The accompanying drawings, which are incorporated in and constitute a part of this disclosure, illustrate exemplary embodiments and, together with the description, explain the disclosed principles. The reference numbers are used throughout the figures to describe the features and components. Some embodiments of system and/or methods in accordance with embodiments of the present subject matter are now described, by way of example only, and regarding the accompanying figures, in which
Figure 1: illustrates the structural formula of the compound of formula I, 3-(10,10-dimethylanthracen-9(10H)-ylidene)-N,N-dimethylpropan-1-amine hydrochloride.
Figure 2: illustrates the structural formula of the compound of formula II, 10,10-dimethyl anthracene-9 (10H)-one.
Figure 3: illustrates the scheme I, a synthetic process for the preparation of melitracen hydrochloride of formula I, starting from isobenzofuran-1,3-dione of formula III.

Detailed description of the invention:
In the present document, the word "exemplary" is used herein to mean "serving as an example, instance, or illustration." Any embodiment or implementation of the present subject matter described herein as "exemplary" is not necessarily to be construed as preferred or advantageous over other embodiments.
While the disclosure is susceptible to various modifications and alternative forms, specific embodiment thereof has been shown by way of example, in the drawings and will be described in detail below. It should be understood, however, that it is not intended to limit the disclosure to the specific forms disclosed, but on the contrary, the disclosure is to cover all modifications, equivalents, and alternative falling within the spirit and the scope of the disclosure.
The terms "comprises", "comprising", "includes", or any other variations thereof, are intended to cover a non-exclusive inclusion, such that a setup, device or method that comprises a list of components or steps does not include only those components or steps but may include other components or steps not expressly listed or inherent to such setup or device or method. In other words, one or more elements in a system or apparatus proceeded by "comprises... a" does not, without more constraints, preclude the existence of other elements or additional elements in the system or method.
In an embodiment, the present invention provides a process for the preparation of the Active Pharmaceutical Ingredient (API), melitracen hydrochloride (Formula-I) and its commercially important key intermediate 10,10-dimethyl anthrone (Formula II). More specifically the invention includes use of recoverable, reusable bio-renewable and greener solvents in three consecutive Grignard reactions for the preparation of Formula -I and Formula II from phthalic anhydride, and also for the preparation of Grignard reagents for these reactions. The invention also includes preparation of Formula II in shorter reaction time by modifying the reagent from conventional Sulphuric acid to Anhydrous AlCl3. Further, the invention also covers synthesis of Formula-I from Formula-II with less number of reaction steps through a hydroxy intermediate by dehydrative salt formation using alcoholic HCl, instead of aqueous HCl in chlorinated solvents and the process offered the API with desired purity circumventing a separate recrystallization step.
In an embodiment, in the present invention methyl magnesium chloride in the greener solvent, 2-methyl THF is used as in Step 1 of Scheme I instead of methyl magnesium bromide in THF in conventional procedure. This also confers an additional advantage of solvent recovery along with a higher yield of 91% of 3,3-dimethylisobenzofuran-1(3H)-one(IV), compared to 63 % of the reported procedure.
Even in Step 2, another Grignard reaction of 3,3-dimethylisobenzofuran-1(3H)-one(IV) was done with phenyl magnesium bromide in the greener solvent, 2-methyl THF to result in an improved yield of 80% of 3,3-dimethyl-1-phenyl-1,3-dihydroisobenzofuran-1-ol(V) than the reported procedure in which the yield was only 55% and since it is a recoverable solvent, the solvent could be recovered in good quantities.
In Step 3, dehydrative cyclization of 3,3-dimethyl-1-phenyl-1,3-dihydroisobenzofuran-1-ol (V) was carried out using commercially available Anhydrous AlCl3 used as an alternative reagent to yield crude 10,10-dimethyl anthrone. The usage of Anhydrous AlCl3 could bring about a significant reduction in the acid waste generation after workup, improved yield of 84% of 10,10-dimethylanthrone (II) than the reported procedure in which the yield was only 64% and reduction in the reaction duration from 5 hours to 1.5 hours compared to the reported procedure. To purify the crude 10,10-dimethyl anthrone, an alcohol has been used. The alcohol may be a C1-C5 alcohol and can be methanol, ethanol, isopropanol, butanol, pentanol or mixture thereof to yield pure 10,10-dimethylanthrone (II).
In step 4, the Grignard reaction of 10,10-dimethyl anthrone (II) was carried out with (3-(dimethylamino)propyl)magnesium chloride (XIII) in the greener solvent, 2-Methyl THF to result in an improved yield of 85% of 9-(3-(dimethylamino)propyl)-10,10-dimethyl-9,10-dihydroanthracen-9-ol (VI), than the reported procedure in which the yield was only 80% And since it is a recoverable solvent, the solvent could be recovered in good quantities
In step 5, the dehydrative salt formation reaction of 9-(3-(dimethylamino)propyl)-10,10-dimethyl-9,10-dihydroanthracen-9-ol (VI) with alcoholic HCl in alcohol was carried out, yielding 89% of melitracen hydrochloride (I) with the desired purity. The alcoholic HCl may be a C1-C5 alcoholic HCl in C1-C5 alcohol solvent.

EXAMPLES
Example 1
Preparation of 3,3-dimethylisobenzofuran-1(3H)-one (Compound of Formula IV)
For the preparation of methyl magnesium chloride (VIII), a set-up was made in which magnesium turnings (102 gm) were taken along with THF in an RBF connected to a cold trap condenser having an inlet for methyl chloride gas. The RBF was connected to a bubbler which serves as an outlet. The RBF was maintained at 0 ℃ using ice and the cold trap condenser was maintained at -30 ℃ using dry ice/acetone solution to condense the methyl chloride gas (210 gm). Iodine (2.5 gm) was added to initiate the Grignard reagent formation and the reaction continued till the complete consumption of magnesium. The methyl magnesium chloride (1350 mL) in 2-Methyl THF thus formed is slowly added to Phthalic anhydride (III) (200 gm) in 2- Methyl THF (400 mL), at 0-15 ℃ for 3 hours and then the temperature is gradually raised to room temperature, and maintained for 2 hours. After completion of the reaction, quenched using 15% acetic acid in crushed ice (300 gm in 1850 gm) and extracted with 2-Methyl THF (300 mL*2). The organic layer was washed with soda ash solution (50 gm in 200 mL) followed by water (200 mL) and then evaporated to Preparation of 3,3-dimethylisobenzofuran-1(3H)-one (1V) (202 grams).
Example 2
Preparation of 3,3-dimethyl-1-phenyl-1,3-dihydroisobenzofuran-1-ol (Compound of Formula V)
Magnesium turnings (40 g) in 2-methyl THF (25 mL) were taken in a three-neck RBF to which 10 mL of bromobenzene in 2-methyl THF (257 gm in 550 mL) was added slowly using iodine (2.5 gm) as a catalyst for initiation of the reaction, followed by complete addition of bromobenzene 2-methyl THF solution and then it is refluxed for 1.5 hours for the formation of Formula X, which is cooled down to 0-5 ℃ followed by addition of Formula IV(200 grams ) obtained in Example 1, in 2-methyl THF (300 mL). Then, the reaction mixture is refluxed for 2 hours and it was decomposed using 10 % acetic acid in crushed ice (118 gm in 1200 gm crushed ice) and is extracted using 2-methyl THF (200 mL*2). The formed organic layer is washed with soda ash solution (50 g in 200 mL) followed by water (200 mL) and further evaporated to obtain 3,3-dimethyl-1-phenyl-1,3-dihydroisobenzofuran-1-ol (V) (238 grams) and the solvent, 2-methyl THF is recovered (80-85%).
Example 3
Preparation of 10,10-dimethyl anthrone (Compound of Formula II)
The Compound 3,3-dimethyl-1-phenyl-1,3-dihydroisobenzofuran-1-ol (V) (170 grams) was placed in a round bottom flask containing Benzene (850 mL) as the solvent. The reaction mixture was cooled to 0-5 °C, and anhydrous AlCl3 (150 grams) was added slowly with continuous stirring. After the addition was complete, the reaction temperature was gradually increased to 60 °C and maintained for 1.5 hours. Upon confirming the completion of the reaction by TLC, the mixture was cooled back to 0-5 °C. Ice-cold water (350 mL) was then slowly added to quench the reaction mass. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (1 × 150 mL, 1 × 100 mL). The combined organic layers were washed with a 20% soda ash solution (20 g in 100 mL) and then with water (100 mL). The organic layer was dried over sodium sulfate, and the solvent was evaporated. The workup yielded crude of 10,10-dimethyl anthrone (II) (132 g).
Crude 10,10-dimethyl anthrone (132 grams) was taken in methanol (400 mL) and was heated to 60 ℃ which yields a clear solution that is further treated with activated charcoal and maintained for 15 minutes at 60 ℃ then hot filtration is performed through a hyflow bed. The filtrate was cooled down to 0-5 ℃ and the crystals thus formed are filtered and washed with chilled methanol (60 ml) and dried to get a pure compound 10,10-dimethyl anthrone II (120 grams).
Example 4
Preparation of 9-(3-(dimethylamino)propyl)-10,10-dimethyl-9,10-dihydroanthracen-9-ol (Compound of Formula VI)
60% aqueous solution of 3-chloro-N,N-dimethylpropan-1-amine hydrochloride (XI )(500 gm) was cooled down to 0-5 ℃ and 2-Methyl THF (200 mL) was added to it. Dropwise addition of 50% NaOH solution (125 gm in 125 mL water) to obtain a free base, 3-chloro-N,N-dimethylpropan-1-amine (XII). The organic layer was separated and then extracted with 2-Methyl THF (150 mL*1, 50 mL*1), and the moisture was nullified using potassium hydroxide flakes since the moisture should not be more than 0.2% to obtain the Grignard reagent.
Further, magnesium turnings (35 g) in 2- Methyl THF (20 mL) were taken in a three-neck RBF to which a solution of 10 mL of 3-chloro-N,N-dimethylpropan-1-amine (XII) in 2- Methyl THF (400 g in 400 mL) and 2- Methyl THF (430 mL) was added slowly using iodine (1 gm) as a catalyst for initiation of the reaction, followed by complete addition of a solution of 3-chloro-N,N-dimethylpropan-1-amine (XII) in 2- Methyl THF and then it is refluxed for 3 hours for the formation of Grignard reagent, (3-(dimethylamino)propyl)magnesium chloride(XIII) which is cooled down to 0-5 and then added the solution of 10,10-dimethyl anthrone (II) in 2- Methyl THF (100 g in 450 mL) is added to it at a temperature below 15 ℃ and refluxed for 1.5 h. After completion of the reaction, the reaction mass was quenched in 10% acetic acid in crushed ice (20 gm in 1000 g) and the organic layer was separated and the aqueous layer is extracted using 2- Methyl THF (100 mL*2). The organic layer is washed with soda ash solution (20 g in 80 mL) followed by water (200 mL*2) and then evaporated and cooled down to 0-5 ℃ for crystallization and then filtered and washed with chilled Toluene (20 mL) to yield 9-(3-(dimethylamino)propyl)-10,10-dimethyl-9,10-dihydroanthracen-9-ol (VI) (117 grams).
Example 5
Preparation of 3-(10,10-dimethylanthracen-9(10H)-ylidene)-N,N-dimethylpropan-1-amine hydrochloride (Compound of Formula I)
9-(3-(dimethylamino)propyl)-10,10-dimethyl-9,10-dihydroanthracen-9-ol (VI) (110 grams) obtained in Example 4 was taken in isopropyl alcohol (440 mL) and was heated to 82 ℃ which yields a clear solution that is further treated with activated charcoal (5 grams) and maintained for 15 minutes at 82 ℃, and then hot filtration is performed through a hyflow bed. The filtrate was taken in another RBF to which IPA HCl (20-26%)- (100 grams) was added at room temperature and refluxed for 4 h and cooled down to 0-5 ℃. The crystals thus formed are filtered and washed with chilled IPA (55 mL) to afford pure melitracen hydrochloride (I).
Yield:115 grams
HPLC Purity: >99.5%
, Claims:We Claim:
1. A process for the preparation of 3-(10,10-dimethylanthracen-9(10H)-ylidene)-N,N-dimethylpropan-1-amine hydrochloride (I) from phthalic anhydride (III) through 10,10-dimethyl anthrone (II) as the key intermediate, comprising:
(i) synthesis of 10,10-dimethylanthrone as the key intermediate from phthalic anhydride in three steps:
a) addition of the Grignard reagent in 2-Methyl THF to Phthalic anhydride (III) in organic ethereal solvent to form 3,3-dimethylisobenzofuran-1(3H)-one (IV), and maintained at a temperature of about 0 ℃ to about 30 ℃,
b) addition of 3,3-dimethylisobenzofuran-1(3H)-one in ethereal solvent to the Phenyl magnesium bromide (X) in ethereal organic solvent and maintained at about 0 ℃. to about 80 ℃,
c) addition of Anhydrous Lewis acid to 3,3-dimethyl-1-phenyl-1,3-dihydroisobenzofuran-1-ol (V) and Benzene solution holding in the flask setup connected to scrubber and blower, and maintained at about 60 ℃ to 70 ℃. After quenching with ice cold water extracted with organic solvent,
(ii) synthesis and isolation of melitracen hydrochloride (I) with desired purity from 10,10-dimethyl anthrone (II) in two steps:
a) addition of 10,10-dimetyl anthrone (II) in organic ethereal solvent to (3-(dimethylamino)propyl)magnesium chloride (XIII) in organic ethereal solvent and maintained reflux at about 10 ℃ to about 80 ℃,
b) wherein the addition of alcoholic hydrochloric acid to the solution of 9-(3-(dimethylamino)propyl)-10,10-dimethyl-9,10-dihydroanthracen-9-ol (VI), in alcohol solvent to form 3-(10,10-dimethylanthracen-9(10H)-ylidene)-N,N-dimethylpropan-1-amine hydrochloride (I), and maintained reflux at about 82 ℃ to about 83 ℃. and cooled down to attain the crystalline compound with desired purity.
2. The process as claimed in claim 1, wherein the addition of Grignard reagent temperature is about 0 ℃. to about 15 ℃, wherein the maintenance temperature is about 25 ℃. to about 30 ℃, wherein the maintenance duration is about 2 h; wherein the Grignard reagent is Methyl magnesium chloride (VIII) in organic ethereal solvent. wherein the organic ethereal solvent is 2-Methyl THF/cyclopentyl methyl ether/THF. Preferably 2-Methyl THF.
3. The process as claimed in claim 1, wherein the organic solvent is an ethereal organic solvent, wherein the ethereal organic solvent is 2-Methy THF/ Cyclopentyl methyl ether/THF, Preferably 2-Methyl THF. wherein the organic ethereal solvent used to have moisture content limit is below 0.2%.
4. The process as claimed in claim 1, wherein ethereal solvent is 2-Methyl THF/cyclo pentyl methyl ether/THF, preferably 2-Methyl THF, wherein the ethereal organic solvent used to have moisture content below 0.2%, wherein addition of Phenyl magnesium bromide (X) to 3,3-dimethylisobenzofuran-1(3H)-one (IV) at about 0 ℃ to 30 ℃.
5. The process as claimed in claim 1, wherein reflux maintenance temperature is about 80 ℃., wherein reflux maintenance duration is about 1.5 h.
6. The process as claimed in claim 1, wherein the addition of bromobenzene in organic ethereal solvent to Magnesium in catalytic amount of iodine for the initiation of the Grignard reagent formation and maintained at about 25 ℃. to about 80 ℃.
7. The process as claimed in claim 1, wherein the addition of 3,3-dimethyl-1-phenyl-1,3-dihydroisobenzofuran-1-ol (V), to anhydrous AlCl3 in Benzene at the temperature about 60 ℃ to about 70 ℃, wherein maintenance duration is about 1.5 hours to about 2 hours.
8. The process as claimed in claim 1, wherein after completion of step-3, recrystallise the crude material of step-3 by an alcohol solvent.
9. The process as claimed in claim 1, wherein the addition of base to 3-chloro-N,N-dimethylpropan-1-amine hydrochloride(XI) in aqueous solution to de-saltification and extracting the free amine into organic ethereal solvent at about 0 ℃ to about 15 ℃. and dried the organic ethereal solvent layer using KOH.
10. The process as claimed in claim 1, wherein the addition of 3-chloro-N,N-dimethylpropan-1-amine(XII) in ethereal solvent to Magnesium in catalytic amount of iodine for the initiation of the Grignard reagent formation (XIII) and react with 10,10-dimethyl anthrone (II) and maintained reflux to form 9-(3-(dimethylamino)propyl)-10,10-dimethyl-9,10-dihydroanthracen-9-ol (VI), at about 25 ℃. to about 80 ℃.

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