Claims:We claim:

1. A process for preparation of Trientine dihydrochloride compound represented by structural formula (I) comprising the steps of:

i. treating compound represented by structural formula (VIII) with benzaldehyde to obtain compound represented by structural formula (III).

ii. treating compound represented by structural formula (III) with hydrochloric acid to obtain Trientine tetrahydrochloride compound represented by structural formula (II) which is converted to Trientine dihydrochloride compound represented by structural formula (I).

Wherein R is alkyl, alkyl aryl, BOC, -COCH3, -COCF3, -COOX wherein X is C1-C6 alkyl or any other amino protecting group.

2. A process as claimed in claim 1, step i) wherein compound represented by structural formula (VIII) is reacted with benzaldehyde in organic solvent selected from the group consisting of alcohol solvent such as methanol, ethanol, propanol, isopropanol, butanol; hydrocarbon solvent such as toluene, xylene; ether solvent such as diethyl ether, di-isopropyl ether, methyl tertiary butyl ether, THF; ester solvent such as ethyl acetate, propyl acetate, butyl acetate & isopropyl acetate; nitrile solvent such as acetonitrile, propionitrile; ketone solvent such as acetone, methyl isobutyl ketone, cyclopentanone, butanone or combination thereof.

3. A process as claimed in claim 1, step i) wherein compound represented by structural formula (VIII) is reacted with benzaldehyde in presence of organic acid selected from the group consisting of acetic acid, formic acid and propionic acid.

4. A process as claimed in claim 1, step i) wherein compound represented by structural formula (VIII) is reacted with benzaldehyde at a temperature in the range of 30°C to 70°C.

5. A process as claimed in claim 1, step ii) wherein Compound represented by structural formula (III) is reacted with hydrochloric acid in organic solvent at a temperature in the range of 60°C to 65°C to obtain Trientine tetrahydrochloride compound represented by structural formula (II).

6. A process as claimed in claim 5 wherein organic solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol and butanol.

7. A process as claimed in claim 1, step ii) wherein Trientine tetrahydrochloride compound represented by structural formula (II) is treated with base in an organic solvent followed by treatment with hydrochloric acid to adjust pH to 7 to 7.5 to obtain Trientine dihydrochloride compound represented by structural formula (I).

8. Compound represented by structural formula (III).

Wherein R is alkyl, alkyl aryl, BOC, -COCH3, -COCF3, -COOX wherein X is C1-C6 alkyl or any other amino protecting group.

9. A process for preparing Compound represented by structural formula (III) comprising steps of:
i. reducing compound represented by structural formula (VII) by catalytic hydrogenation using Raney nickel, palladium on carbon or platinum on carbon in an organic solvent and in presence of ammonia solution in alcohol solvent to obtain compound represented by structural formula (VIII);

ii. treating compound represented by structural formula (VIII) with benzaldehyde at a temperature in the range of 30°C to 70°C to obtain compound represented by structural formula (III);

Wherein R is alkyl, alkyl aryl, BOC, -COCH3, -COCF3, -COOX wherein X is C1-C6 alkyl or any other amino protecting group.

iii. optionally converting compound represented by structural formula (III) in to Trientine dihydrochloride compound represented by structural formula (I).

10. The process as claimed in claim 9 wherein organic solvent can be selected from the group consisting of alcohol solvent such as methanol, ethanol, propanol, isopropanol, butanol; hydrocarbon solvent such as toluene, xylene; ether solvent such as diethyl ether, di-isopropyl ether, methyl tertiary butyl ether, THF; ester solvent such as ethyl acetate, propyl acetate, butyl acetate & isopropyl acetate; nitrile solvent such as acetonitrile, propionitrile; ketone solvent such as acetone, methyl isobutyl ketone, cyclopentanone, butanone or combination thereof.
, Description:
FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)

1. TITLE OF THE INVENTION:
A PROCESS FOR PREPARATION OF TRIENTINE DIHYDROCHLORIDE

2. APPLICANT:

(a) NAME: Pharmadesk Solutions Pvt Ltd
(b) NATIONALITY: An Indian Company incorporated under the Indian Companies ACT 1956.
(c) ADDRESS: Pharmadesk Solutions Pvt Ltd, Level 2/09, Electronic Sadan No. 01, Electronic Zone, MIDC, Mahape, Navi Mumbai – 400701.

3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF INVENTION:

Present invention relates to a process for preparation of Trientine dihydrochloride compound represented by structural formula (I) through an intermediate compound represented by structural formula (II) and (III).

Wherein R is alkyl, alkyl aryl, BOC, -COCH3, -COCF3, -COOX wherein X is C1-C6 alkyl or any other amino protecting group.

BACKGROUND OF THE INVENTION:

Trientine dihydrochloride is chemically defined as N, N'-bis (2-aminoethyl)-l,2-ethanediamine dihydrochloride and is very old molecule known from the publication W. von Hoffmann, Ber. 23, 3711 (1890) and is represented by structural formula (I).

Trientine dihydrochloride is approved in the US and is indicated in the treatment of patients with Wilson's disease who are intolerant of penicillamine.

U.S. Patent No.7,582,796 discloses process for preparation of Trientine dihydrochloride compound represented by structural formula (I) which involves reduction of compound represented by structural formula (IV) to provide compound represented by structural formula (V) which is further deprotected to provide Trientine dihydrochloride compound represented by structural formula (I).

Deprotection of this intermediate compound represented by structural formula (V) resulted in a mixture of triethylenetetramine primary, secondary, tertiary or quaternary salt.

PCT Publication No. 2018/193482 discloses process for preparation of Trientine dihydrochloride compound represented by structural formula (I) which involves reduction of compound represented by structural formula (IV) to provide compound represented by structural formula (V) which is further treated with fumaric acid to provide difumarate salt compound represented by structural formula (VI) which is further treated with hydrochloric acid to provide Trientine Tetrahydrochloride(II). which is further treated with sodium hydroxide followed by hydrochloric acid to provide Trientine dihydrochloride compound represented by structural formula (I).

The process provides very low yield (i.e. 35%) of difumarate salt compound represented by structural formula VI and hence the process is not commercially feasible.

In view of the above the inventors of present invention have designed an efficient and economical process for the preparation of Trientine dihydrochloride compound represented by structural formula (I).

OBJECT OF THE INVENTION:

An object of the present invention is to provide an efficient and economical process for preparation of Trientine dihydrochloride compound represented by structural formula (I) through an intermediate compound represented by structural formula (II) and (III).

Wherein R is alkyl, alkyl aryl, BOC, -COCH3, -COCF3, -COOX wherein X is C1-C6 alkyl or any other amino protecting group.

Another object of present invention is to provide a novel intermediate compound represented by structural formula (III).

Wherein R is alkyl, alkyl aryl, BOC, -COCH3, -COCF3, -COOX wherein X is C1-C6 alkyl or any other amino protecting group.

SUMMARY OF THE INVENTION:

First aspect of this invention is to provide efficient and economical process for preparation of Trientine dihydrochloride compound represented by structural formula (I) comprising the steps of:

i. treating compound represented by structural formula (VIII) with benzaldehyde to obtain compound represented by structural formula (III).

ii. treating compound represented by structural formula (III) with hydrochloric acid to obtain Trientine tetrahydrochloride compound represented by structural formula (II) which is converted to Trientine dihydrochloride compound represented by structural formula (I).

Wherein R is alkyl, alkyl aryl, BOC, -COCH3, -COCF3, -COOX wherein X is C1-C6 alkyl or any other amino protecting group.

Second aspect of this invention is to provide an efficient, economical and safe an efficient, economical and safe a process for preparation of Trientine dihydrochloride compound represented by structural formula (I) comprising the steps of:

i. reducing compound represented by structural formula (VII) to obtain compound represented by structural formula (VIII);

ii. treating compound represented by structural formula (VIII) with benzaldehyde to obtain compound represented by structural formula (III).

iii. treating compound represented by structural formula (III) with hydrochloric acid to obtain Trientine tetrahydrochloride compound represented by structural formula (II) which is converted to Trientine dihydrochloride compound represented by structural formula (I).

Wherein R is alkyl, alkyl aryl, BOC, -COCH3, -COCF3, -COOX wherein X is C1-C6 alkyl or any other amino protecting group.

Third aspect of present invention is a novel intermediate compound represented by structural formula (III).

Wherein R is alkyl, alkyl aryl, BOC, -COCH3, -COCF3, -COOX wherein X is C1-C6 alkyl or any other amino protecting group.

DETAIL DESCRIPTION OF THE INVENTION:

According first aspect present invention provides an efficient, economical and safe a process for preparation of Trientine dihydrochloride compound represented by structural formula (I) comprising the steps of:

i. treating compound represented by structural formula (VIII) with benzaldehyde to obtain compound represented by structural formula (III).

ii. treating compound represented by structural formula (III) with hydrochloric acid to obtain Trientine tetrahydrochloride compound represented by structural formula (II) which is converted to Trientine dihydrochloride compound represented by structural formula (I).

Wherein R is alkyl, alkyl aryl, BOC, -COCH3, -COCF3, -COOX wherein X is C1-C6 alkyl or any other amino protecting group.

Compound represented by structural formula (VIII) can be prepared by methods known in the art such as disclosed in U.S. Patent No.7,582,796.

Compound represented by structural formula (VIII) can be reacted with benzaldehyde in organic solvent in presence of organic acid to obtain compound represented by structural formula (III).

Organic solvent can be selected from the group consisting of alcohol solvent such as methanol, ethanol, propanol, isopropanol, butanol; hydrocarbon solvent such as toluene, xylene; ether solvent such as diethyl ether, di-isopropyl ether, methyl tertiary butyl ether, THF; ester solvent such as ethyl acetate, propyl acetate, butyl acetate & isopropyl acetate; nitrile solvent such as acetonitrile, propionitrile; ketone solvent such as acetone, methyl isobutyl ketone, cyclopentanone, butanone or combination thereof.

Organic acid can be selected from the group consisting of acetic acid, formic acid and propionic acid.

Compound represented by structural formula (VIII) can be reacted with benzaldehyde at a temperature in the range of 30°C to 70°C for a period of 2 to 6 hours.

Compound represented by structural formula (III) can be isolated by method of filtration, centrifugation, drying or combination thereof.

Compound represented by structural formula (III) can be reacted with hydrochloric acid in organic solvent to obtain Trientine tetrahydrochloride compound represented by structural formula (II).

Organic solvent can be selected from the group consisting of methanol, ethanol, propanol, isopropanol and butanol.

Hydrochloric acid can be in used as solution in solvents selected from the group consisting of methanol, ethanol, propanol, isopropanol and butanol.

Compound represented by structural formula (III) can be reacted with hydrochloric acid at a temperature in the range of 60°C to 65°C for a period of 3 hours to 6 hours.

Trientine tetrahydrochloride compound represented by structural formula (II) can be isolated by method of filtration, centrifugation, drying or combination thereof.

Trientine tetrahydrochloride compound represented by structural formula (II) can be treated with base in an organic solvent to obtain Trientine base which can be further treated with hydrochloric acid solution in organic solvent to adjust pH of reaction mixture to 7 to 7.5 to obtain Trientine dihydrochloride compound represented by structural formula (I).

Organic solvent can be selected from the group consisting of methanol, ethanol, propanol, isopropanol and butanol.

Base can be selected from but not limited to the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate.

Hydrochloric acid solution in organic solvent can be selected from but not limited to methanolic hydrochloric acid, isopropyl acohol hydrochloric acid, etc.

Trientine dihydrochloride compound represented by structural formula (I) can be isolated by method of filtration, centrifugation, drying or combination thereof.

According to second aspect present invention provides an efficient, economical and safe a process for preparation of Trientine dihydrochloride compound represented by structural formula (I) comprising the steps of:

iii. reducing compound represented by structural formula (VII) to obtain compound represented by structural formula (VIII);

iv. treating compound represented by structural formula (VIII) with benzaldehyde to obtain compound represented by structural formula (III).

iv. treating compound represented by structural formula (III) with hydrochloric acid to obtain Trientine tetrahydrochloride compound represented by structural formula (II) which is converted to Trientine dihydrochloride compound represented by structural formula (I).

Wherein R is alkyl, alkyl aryl, BOC, -COCH3, -COCF3, -COOX wherein X is C1-C6 alkyl or any other amino protecting group.

Compound represented by structural formula (VIII) can be prepared by methods known in the art such as disclosed in U.S. Patent No.7,582,796.

Reduction of compound represented by structural formula (VII) can be carried out by catalytic hydrogenation using Raney nickel, palladium on carbon and platinum on carbon in an organic solvent and in presence of ammonia solution in alcohol solvent.

Organic solvent can be selected from the group consisting of methanol, ethanol, propanol, isopropanol and butanol.

Alcohol solvent for ammonia solution can be selected from the group consisting of methanol, ethanol, propanol, isopropanol and butanol.

Reduction of compound represented by structural formula (VII) can be carried out at a temperature in the range of 15°C to 25°C for a period of 1 hour to 3 hours.

Compound represented by structural formula (VIII) can be isolated by methods of filtration, concentration, drying or combination thereof.

Compound represented by structural formula (VIII) can be reacted with benzaldehyde in organic solvent in presence of organic acid to obtain compound represented by structural formula (III).

Organic solvent can be selected from the group consisting of alcohol solvent such as methanol, ethanol, propanol, isopropanol, butanol; hydrocarbon solvent such as toluene, xylene; ether solvent such as diethyl ether, di-isopropyl ether, methyl tertiary butyl ether, THF; ester solvent such as ethyl acetate, propyl acetate, butyl acetate & isopropyl acetate; nitrile solvent such as acetonitrile, propionitrile; ketone solvent such as acetone, methyl isobutyl ketone, cyclopentanone, butanone or combination thereof.

Organic acid can be selected from the group consisting of acetic acid, formic acid and propionic acid.

Compound represented by structural formula (VIII) can be reacted with benzaldehyde at a temperature in the range of 30°C to 70°C for a period of 2 to 6 hours.

Compound represented by structural formula (III) can be isolated by method of filtration, centrifugation, drying or combination thereof.

Compound represented by structural formula (III) can be reacted with hydrochloric acid in organic solvent to obtain Trientine tetrahydrochloride compound represented by structural formula (II).

Organic solvent can be selected from the group consisting of methanol, ethanol, propanol, isopropanol and butanol.

Hydrochloric acid can be in used as solution in solvents selected from the group consisting of methanol, ethanol, propanol, isopropanol and butanol.

Compound represented by structural formula (III) can be reacted with hydrochloric acid at a temperature in the range of 60°C to 65°C for a period of 3 hours to 6 hours.

Trientine tetrahydrochloride compound represented by structural formula (II) can be isolated by method of filtration, centrifugation, drying or combination thereof.

Trientine tetrahydrochloride compound represented by structural formula (II) can be treated with base in an organic solvent to obtain Trientine base which can be further treated with hydrochloric acid solution in organic solvent to adjust pH of reaction mixture to 7 to 7.5 to obtain Trientine dihydrochloride compound represented by structural formula (I).

Organic solvent can be selected from the group consisting of methanol, ethanol, propanol, isopropanol and butanol.

Base can be selected from but not limited to the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate.

Hydrochloric acid solution in organic solvent can be selected from but not limited to methanolic hydrochloric acid, isopropyl acohol hydrochloric acid, etc.

Trientine dihydrochloride compound represented by structural formula (I) can be isolated by method of filtration, centrifugation, drying or combination thereof.

EXAMPLES:

In the following examples, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.

Example-1: Synthesis of Trientine dihydrochloride compound represented by structural formula (I):

i. Preparation of [2-(benzylidene-amino)-ethyl]-(2-{[2-(benzylidene-amino)-ethyl]-tert-butoxy carbonyl-amino}-ethyl)-carbamicacid tert-butyl ester compound represented by structural formula (III):

A solution of Raney nickel (123 g) in isopropanol (100 ml) was added with 2-([2-[cyanomethyl)-t-butyloxycarbonylamino]ethyl-t-butyloxycarbonylamino)acetonitrile compound represented by structural formula (VII) (200 g) in isopropanol (400 ml) in pressure reactor. Resultant reaction mixture was added with ammonia solution in isopropanol (1400 ml) (equivalent to 125 g ammonia) and applied hydrogen gas pressure of 3 to 5 Kg/cm2 at a temperature in the range of 15°C to 25°C for a period of 2 hours. Reaction mixture was filtered, concentrated under vacuum to obtain compound represented by structural formula (VIII). A solution of compound represented by structural formula (VIII) in methanol (400 ml) was added acetic acid (2.2 g). The resultant reaction mixture was added benzaldehyde (124 g) at a temperature in the range of 25°C to 30°C. Reaction mixture was stirred at a temperature in the range of 45°C to 50°C for a period of 3 to 4 hours and then was cooled to a temperature in the range of 10°C to 15°C. The product [2-(benzylidene-amino)-ethyl]-(2-{[2-(benzylidene-amino)-ethyl]-tert-butoxy carbonyl-amino}-ethyl)-carbamicacid tert-butyl ester compound represented by structural formula (III) is isolated by filtration. Wet cake was washed with methanol and dried under vacuum at a temperature in the range of 40°C to 45°C.

Yield: 265 g Purity: 98%

ii. Trientine tetrahydrochloride compound represented by structural formula (II):
A solution of [2-(benzylidene-amino)-ethyl]-(2-{[2-(benzylidene-amino)-ethyl]-tert-butoxy carbonyl-amino}-ethyl)-carbamicacid tert-butyl ester compound represented by structural formula (III) (75 g) in methanol (240 ml) was added with methanolic HCl solution (8%) (494 gm). Resultant reaction mixture was stirred at a temperature in the range of 60°C to 65°C for a period of 4 to 5 hours. Reaction mixture was cooled to a temperature in the range of 25°C to 30°C. Product Trientine tetrahydrochloride compound represented by structural formula (II) was isolated by filtration. Solid was washed with methanol and dried under vacuum at a temperature in the range of 30°C to 37°C.
Yield: 38 g Purity: 99.5%

iii. Trientine dihydrochloride compound represented by structural formula (I):
A solution of Trientine tetrahydrochloride compound represented by structural formula (II) (35 g) in methanol was treated with sodium hydroxide (24 g). The reaction mixture was stirred for 15-16 hours at 25-30°C and then filtered through hyflow bed and filtrate was distilled under vacuum. Residue was dissolved in dichloromethane and resultant solution was treated with charcoal and was filtered. Filtrate was distilled under vacuum then ethanol (120 ml) was added to the residue. Resultant solution was cooled to 0-5°C further IPA.HCl 20% (43 g) was added dropwise to adjusted pH 7-7.5. The reaction mixture was stirred for at 0-5°C for 2 hours. Solid was filtered & Washed with chilled ethanol(30 ml).The wet solid was dried under vacuum below 40°C to obtain Product Trientine dihydrochloride compound represented by structural formula (I)
Yield: 25 g Purity: 99.9%

Example: 2: Preparation of [2-(benzylidene-amino)-ethyl]-(2-{[2-(benzylidene-amino)-ethyl]-tert-butoxy carbonyl-amino}-ethyl)-carbamicacid tert-butyl ester compound represented by structural formula (III):

A solution of compound represented by structural formula (VIII) (wherein R is BOC) (125 g) in methanol (500 ml) was added acetic acid (2.2 g). The resultant reaction mixture was added benzaldehyde (124 g) at a temperature in the range of 25°C to 30°C. Reaction mixture was stirred at a temperature in the range of 45°C to 50°C for a period of 3 to 4 hours and then was cooled to a temperature in the range of 10°C to 15°C. The product [2-(benzylidene-amino)-ethyl]-(2-{[2-(benzylidene-amino)-ethyl]-tert-butoxy carbonyl-amino}-ethyl)-carbamicacid tert-butyl ester compound represented by structural formula (III) is isolated by filtration. Wet cake was washed with methanol and dried under vacuum at a temperature in the range of 40°C to 45°C.
Yield: 168 g Purity: 98%