WO2020075024A1

WO2020075024A1 - Process for preparation of memantine

Info

Publication number: WO2020075024A1
Application number: PCT/IB2019/058453
Authority: WO
Inventors: Sandeep Mohanty; Pavan Kumar Bathini; Pavithran Vinay Kumar KUCHIPUDI; Sathibabu GOLLAPALLI; Jaganmohan CHIKKANTI
Original assignee: Dr. Reddy’S Laboratories Limited
Priority date: 2018-10-12
Filing date: 2019-10-04
Publication date: 2020-04-16

Abstract

The present invention provides an improved process of manufacturing 1-Bromo-3,5-dimethyladamantane compound of formula-IV starting from 1,3-dimethyladamantane that avoids use of liquid bromine and minimizes the use of hazardous chemicals. The present invention also provides use of 1-Bromo-3,5-dimethyladamantane prepared by the process of present invention in the process of producing Memantine hydrochloride and pharmaceutical compositions thereof.

Description

PROCESS FOR PREPARATION OF MEMANTINE

FIELD OF THE INVENTION

The present invention relates to a process for preparing l-Bromo-3,5- dimethyladamantane, an intermediate product in the process of producing 1 -Amino- 3, 5 -dime thyladamantane hydrochloride (Memantine hydrochloride).

BACKGROUND OF THE INVENTION

Memantine is an orally active NMDA (N-methyl-D-aspartate) receptor antagonist which works by blocking the NMDA receptors in the brain. Memantine hydrochloride is used as a medicament in the treatment of moderate to severe Alzheimer’s disease, and is commercially available in the market in products sold under the trademark NAMENDA. Memantine hydrochloride is represented by the stmctural formula I.

US Patent No. 3,391,142 (US ‘142) discloses memantine and analogues compounds, and their pharmaceutically acceptable salts. US ‘142 also describes a process for the preparation of memantine as depicted in scheme 1.

PCT Publication No. W02005/062724 A2 describes a modified process for the preparation of memantine as depicted in scheme 2, and US Patent No.5,06l,703 (US ‘703) discloses a process for the preparation of derivatives of memantine. The synthetic process described in the US ‘703 comprises three steps: halogenation of alkyladamantanes with elemental chlorine or bromine; formylation of the halogenated alkyladamantanes with formamide. The final acid hydrolysis gives a range of aminioalkyladamantanes.

1,3-dimethyl l-bromo-3, 5-dimethyl /V-(3,5-dimcthyladamantan-l-yl) adamantane adamantane acetamide

Memantine

Scheme 1

1,3-dimethyl 1 -hydroxy-3, 5-dimethyl /V-(3,5-dimethyladamantan-l-yl) adamantane adamantane acetamide

NaOH/ Diethyleneglycol

- ►

Memantine

Scheme 2

A PCT Publication No. WO 2006/122238 Al describes a process for preparing memantine by reacting l-bromo-3, 5 -dime thyladamantane with formamide to form 1- N-formyl-3,5-dimethyladamantane, and reacting the l-N-formyl-3,5- dimethyladamantane with hydrochloric acid to form memantine. The prior art methods employs hazardous and toxic reagents (in particular chlorine or bromine) and the synthesis typically requires a large excess of the key reagents. This generates a considerable amount of waste, which is not desirable, among others, from an environmental and an economic point of view.

The use of liquid bromine in the prior art method causes generation of toxic hydrogen bromide and causes harm to human body and environment, and therefore the prior art methods require special equipment of high ventilation to perform the reaction.

Another method for the direct preparation of N-formyl-l -amino-3, 5- dimethyladamantane from 1,3 -dime thyladamantane using strong acids and formamide was described by L. Wanka et al in Eur. J. Org. Chem. 2007, 1474-1490.

A similar process is disclosed in WO 2007/101536 Al. However, the process described in these publications have several drawbacks. Although the process avoids the use of liquid bromine, the overall process still results in considerable waste as it employs a large excess of sulphuric acid (22 molar equivalents), and nitric acid (1.8 molar equivalents), all of which need to be disposed and/or carried through the work up procedure. Besides, a large amount of halogenated organic solvents must be used in said process in order to extract the product from the mixture. Furthermore an additional purification step by chromatography is reported, which may not be economically viable on the industrial scale.

SUMMARY OF THE INVENTION

In light of the prior art, it is one objective of the present invention to provide an improved process for manufacturing l-Bromo-3,5-dimethyladamantane starting from 1 ,3 -dime thyladamantane that avoids use of liquid bromine and minimizes any of the above mentioned problems, in particular the use of hazardous chemicals.

It is in another object to minimize the amount of waste and/or unused chemicals produced during the manufacture of memantine or its intermediate products. According to another object, the improved yield/ selectivity/ quality of product should particularly be visible in the process for manufacturing Memantine as scaled - up to a commercial/industrial use, i.e. involving on the kilogram scale.

In another aspect, the present application provides a process for preparation of l-Bromo-3,5-dimethyladamantane of formula IV, the process comprising reacting 1,3- dimethyladamantane with tertiary butyl bromide to obtain l-Bromo-3,5- dimethyladamantane.

In another aspect, the present application provides a process for preparation of memantine or an acid addition salt thereof, comprising

(a) reacting l,3-dimethyladamantane with tertiary butyl bromide to obtain 1- Bromo-3,5-dimethyladamantane of formula IV,

(b) reacting l-Bromo-3,5-dimethyladamantane with formamide to form N- formyl-3,5-dimethyladamantane-l-amine of formula III,

(c) hydrolysing the N-formyl-3,5-dimethyladamantane-l-amine using an organic acid or an inorganic acid to form memantine or an acid addition salt thereof.

In another aspect, the present application provides a pharmaceutical composition comprising memantine or an acid addition salt thereof prepared by the process of the present invention and pharmaceutically acceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for preparing l-Bromo-3,5- dimethyladamantane, an intermediate product in the process of producing memantine or an acid addition salt thereof.

In one aspect, the present invention provides a process for preparation of 1- bromo-3,5-dimethyladamantane, the process comprises reaction of 1,3- dimethyladamantane with tertiary butyl bromide to obtain l-bromo-3,5- dimethyladamantane of formula IV. Br

1,3-dimethyl IV

adamantane

The process involves reaction of 1,3 -dime thyladamantane with tertiary butyl bromide in the presence of a suitable Lewis acid catalyst such as AlCL, AlBr¾, FeCh, BF₃.OEt2, SnCl₄. The reaction is suitably carried out at a temperature of about 0 °C to about 80 °C and for a period of about 10 minutes to about 10 hours.

The reaction is monitored by TLC. After completion of the reaction the reaction mass may be filtered and concentrated.

In view of the nature of the bromo intermediate of formula IV, it is difficult to handle, hence an in-situ process which proceeds without isolating the bromo intermediate is advantageous.

(a) reacting l,3-dimethyladamantane with tertiary butyl bromide to obtain 1-

Bromo-3,5-dimethyladamantane of formula IV,

Br

1,3-dimethyl 1 -Bromo-3, 5-dimethyl adamantane adamantane

(b) reacting l-Bromo-3,5-dimethyladamantane with formamide to form N- formyl-3,5-dimethyladamantane-l-amine of formula III

(c) hydrolysing the N-formyl-3,5-dimethyladamantane-l-amine using an organic acid or an inorganic acid to form memantine or an acid addition salt thereof

The step (a) of the process is carried out as described above. The step (b) is an in-situ process to prepare the l-N-formyl-3,5-dimethyladamantane of formula III.

The step (b) involves converting the l-Bro mo-3, 5 -dime thyladamantane of formula IV to l-N-formyl-3,5-dimethyladamantane of formula III using formamide. The reaction is carried out using formamide itself acting as the solvent medium or the reaction can also be conducted using a suitable solvent such as methanol, ethanol, propanol, acetone, ethylacetate and the like.

The reaction is carried out at about 50 °C to about 200 °C. After the completion of the reaction the reaction mass is quenched with a protic solvent such as water, methanol, propanol, n-butanol, acetic acid, formic acid and the like. The addition of protic solvent is suitably carried out at lower temperatures such as below 30 °C. The protic solvent used can be cooled to below 10 °C to allow the solvent addition below 30 °C.

The reaction mass is extracted using a suitable solvent such as ethylacetate, dichlorome thane, toluene and the like, and the organic layer is concentrated to obtain the compound of formula III.

The step (c) involves hydrolysing the compound of formula III using an organic acid or an inorganic acid to form memantine or an acid addition salt thereof.

The hydrolysis of the compound of formula III can be carried out using a suitable acid or a suitable base. The acid used may be an organic acid or an inorganic acid. The reaction may be carried at a temperature of about 30 °C to about 150 °C. The quantity of the acid used can range from about 5-50 fold molar excess of the acid per molar equivalent of the compound of formula III.

After completion of the reaction the memantine or a salt thereof can be isolated by filtering the reaction mixture. The memantine or a salt thereof may be purified using a suitable solvent to obtain pure memantine or salt thereof.

In another aspect, the compound of formula IV, produced by the process of the present invention may be reacted with acetonitrile in the presence of a concentrated acid such as sulphuric acid or nitric acid or a mixture thereof to obtain a compound N- acetyl-3,5-dimethyladamantane-l-amine of formula II. The compound of formula II is hydrolyzed using a suitable acid to obtain memantine or an acid addition salt thereof.

Br

Acetonitrile Cone. HC1

H₂SO₄ Water

1,3-dimethyl IV

adamantane

In another aspect the present invention provides a pharmaceutical composition comprising memantine or an acid addition salt thereof prepared by the process of the present invention and a pharmaceutically acceptable carrier.

The invention is further defined by reference to the following examples describing in detail the processes of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

EXAMPLES

Example-1: Preparation of l-Bromo-3,5-dimethyladamantane of formula IV

1,3-dimethyl _jy

adamantane l ,3-Dimethyladamantane (45 g) and tertiary butyl bromide (39.4 g) were charged into a round bottom flask and the mixture was cooled to 18 °C. AlCL (450 mg) was charged into the flask at 18 °C and stirred to mixture for 1 hour. The reaction was monitored by TLC. After completion of the reaction the reaction mass was filtered and concentrated to produce pale yellow colored oil. Purity: 90.55% (by GC).

¾NMR (500 MHz, CDC13): d 0.76 (s, 3H), 0.84 (s, 6H), 1.18 (m, 3H), 1.36 (m, 9H), 1.52 (d, 1H, Jl = 3.4 Hz)), 1.79 (s, 3H), 1.99 (dd, 6H, (Jl = 26.9 Hz, J2 = 11.7 Hz)), 2.14 (m, 3H).

Example-2: Preparation of lN-formyl-3,5-dimethyladamantaneamine of formula III

1

adamantane

l ,3-Dimethyladamantane (45 g) and tertiary butyl bromide (39.4 g) were charged into a round bottom flask and the mixture was cooled to 18 °C. AlCb (450 mg) was charged into the flask at 18 °C and stirred to mixture for 1 hour. The reaction was monitored by TLC. Formamide (1125 mL) was added to the flask and the reaction mixture was heated to 150 °C and stirred for 8 hours. The reaction was monitored by TLC. After completion of the reaction mass was gradually cooled to 0 °C. Precooled water (675 mL) was added to the reaction mass and stirred for 10 minutes. Temperature was raised to 25 °C and the mass was stirred for 15 minutes. The reaction mas was filtered through hyflow and the hyflow bed was washed with dichloromethane (450 mL). The resultant biphasic mixture was stirred for 10 minutes at 25 °C and layers separated. The aqueous layer was extracted with dichloromethane (2 x 225 mL). The combined organic layer was washed with 10% aqueous NaHCCh solution (2 x 450 mL), and with water (900 mL). The organic layer was concentrated under vacuum at 50 °C to yield 47.3 grams of brown colored oil of crude lN-formyl-3,5- dimethyladamantane of formula III. Purity: 83.45% (by GC).

Example-3: Preparation of memantine hydrochloride

X O

The compound of formula III prepared in example 2 (46.3 g) and Cone. HC1 (500 mL) were charged into a round bottom flask and stirred for 10 minutes. The mixture was heated to 85 °C and stirred for 15 hours. Then the mixture was gradually cooled to 5 °C and stirred for 30 minutes. The reaction mixture was filtered and the wet solid was washed with chilled water (45 mL) and suck dried for 2 hours. The wet solid was dried at 75 °C for 5 hours to yield 34.5 g of crude memantine HC1.

15 g of the cmde memantine HC1 and methanol (37.5 mL) were charged into a 250 mL round bottom flask and the mixture was heated to 55 °C and stirred for 30 minutes. The clear solution obtained was filtered through a micron filter and the filtrate was heated to 55 °C. Acetone (112.5 mL) was slowly added to the mass and stirred for 30 minutes. The mixture was gradually cooled to 5 °C and stirred for 2 hours. The mixture was filtered and the wet solid was washed with chilled acetone (30 mL). The wet material was dried at 75 °C for 4 hours to yield 12.2 g of pure memantine HC1. Purity: 99.70% (by GC).

Claims

1. A process for preparation of l-bromo-3,5-dimethyladamantane, the process comprises reaction of l,3-dimethyladamantane with tertiary butyl bromide to obtain 1- bromo-3,5-dimethyladamantane of formula IV.

Br

1,3-dimethyl

adamantane

2. The process according to claim 1 , wherein the reaction is carried out in the presence of a suitable Lewis acid catalyst.

3. The process according to claim 2, the Lewis acid catalyst is selected from the group comprising AlCL, AlBr₃, FeCL, BF₃.OEt2, and SnCl₄.

4. The process according to claim 2, the Lewis acid catalyst is AlCl₃.

5. A process for preparation of memantine or an acid addition salt thereof, comprising

Br

1,3-dimethyl l-Bromo-3,5-dimethyl adamantane adamantane

6. The process according to claim 5, wherein the step (a) is carried out in the presence of a suitable Lewis acid catalyst.

7. The process according to claim 6, the Lewis acid catalyst is selected from the group comprising AlCb, AlBr₃, FeCb, BF₃.OEt2, and SnCl₄.

8. The process according to claim 6, the Lewis acid catalyst is AlCl₃.

9. The process according to claim 5, wherein the product in step (a), l-Bromo-3, 5- dimethyladamantane of formula IV, is not isolated.

10. The process according to claim 5, wherein the hydrolysis in step (c) is carried out using hydrochloric acid, and the product formed is memantine hydrochloride.

11. A process for preparation of memantine or an acid addition salt thereof, comprising

Br

1,3-dimethyl l-Bromo-3, 5-dimethyl adamantane adamantane

(b) reacting l-Bromo-3 ,5 -dimethyladamantane with acetonitrile to form N- acetyl-3,5-dimethyladamantane-l-amine of formula II,

(c) hydrolysing the N-acetyl-3,5-dimethyladamantane-l -amine using an organic acid or an inorganic acid to form memantine or an acid addition salt thereof

12. The process according to claim 11, wherein the product in step (a), l-Bromo-3,5- dimethyladamantane of formula IV, is not isolated.

13. The process according to claim 11, wherein the hydrolysis in step (c) is carried out using hydrochloric acid, and the product formed is memantine hydrochloride.

14. A pharmaceutical composition comprising memantine or an acid addition salt thereof prepared by the process of the present invention and a pharmaceutically acceptable carrier.

15. A pharmaceutical composition comprising memantine hydrochloride prepared by the process of the present invention and a pharmaceutically acceptable carrier.