A process for the preparation of Trientine and its Pharmaceutically acceptable salts thereof.

Priority

This application claims the benefit to the provisional application No. 3708/CHE/2015. filed on Jury 20*,2015 entitled "A process for the preparation of Trientine and its Pharmaceutically acceptable salts thereof " the contents of which incorporated by reference herein.

Field of Invention
The present invention relates to a process for preparing pure Triethylenetetramines and Triethylenetetramine salts (N,N'-Bis(2-aminoethyl)ethane-l,2-diamine dihydrochloride) starting from ethylenediamine compound. Specifically the present invention relates to a process for preparing Triethylenetetramines from protected diamine derivative compound.

Background of the Invention
Triethylenetetramine dihydrochloride also known as Trientin 2HC1 and chemically known as (N,N,-Bis(2-aminoethyl)ethane-l,2-diamine dihydro chloride) and represented by formula (I). Hydrochloride salt of triethylenetetramine is a chelating agent and is used to bind up and remove copper in the body to treat Wilson's disease.
According to, Polyethylenepolyamine compounds such as diethylenetriamine, triethylenetetramine and the higher homologs have been produced by the reaction of an alkyl halide such as ethylene dichloride with an amine such as ammonia or ethylenediamine at elevated temperatures and pressures. Normally, relatively high yields of predominately nón-cyclic polyethylenepolyamine compounds are obtained with varying yields of heterocyclic cyclic polyethylenepolyamine compounds are obtained with varying yields of heterocyclic amines. The large amounts of energy required to produce the reactants as well as the difficult separation procedures required to recover the more valuable linear polyethylenepolyamines diminish the usefulness of the ethylene dichloride process. The hydrohalide salts of ammonia and the polyethylenepolyamine products must also undergo difficult and time consuming caustic neutralization to yield the frée polyethylenepolyamines.

Japanese Patent No. 06065161 to Hara.et al. is said to be directed to the synthesis of polyethylenepolyamines by reacting ethylenediamine with ethanolamine in the presence of silica-treated Nb205 supported on a carrier. Japanese Patent No. JP03047154 to Watanabe et al., is said to be directed to production of noncyclic polyethylenepolyamines by reaction of ammonia with monoethanolamine and ethylenediamine. Production of non-cyclic polyethylenepolyamines by reaction of ethylenediamine and monoethanolamine in the presence of hydrogen or a phosphorous-containing substance was said to be reported in Japanese Patent No. JP03048644. Regenerative preparation of linear polyethylenepolyamines using a phosphorous-bonded catalyst was proposed in European Patent No. EP 115,138, to Larkin et al.
U.S. Pat. Nos. 6,897,243, 6,610,693 and 6,348,465 describe the use of copper binding compounds in the treatment of various disorders, including treatment of diabetes mellitus and complications thereof, including, for example, diabetic cardiomyopathy.
Production of triethylenetetramine dihydrochloride was said to have been reported in Kuhr et al., Czech Patent No. 197,093, via conversion of triethylenetetramine to crystalline . tetrahydrochloride and subsequently to triethylenetetramine dihydrochloride. "A study of efficiënt preparation of triethylenetetramine dihydrochloride for the treatment of Wilson's disease and hygroscopicity of its capsule," Fujito, et al., Yakuzaigaku, 50:402-8 (1990), is also said to be directed to production of triethylenetetramine.

US Patent 4550209 discloses polyethylenepolyamines preparation process. The '209 patent discloses the preparation of essentially linear polyethylenepolyamines by reacting monoethanolamine with ethylenediamine in the presence of an intercalatively catalytically activê tetravalent zirconium polymeric reaction product of an organo phosphonic acid or an ester thereof with a compound of tetravalent zirconium reactive therewith. The process disclosed in the '209 patent is schematically represented by Scheme-l'.

Scheme-l
US Patent 5225599 (the '599 patent) discloses a process for the preparation of Triethylenetetramine having a high yield weight percent of Tetraethylenetetramine and Aminoethylethanolamine which comprises condensing an amino compound in the presence of a condensation catalyst selected from a Group IVB metal oxide, a Group VIB metal-containing substance and a promoted condensation catalyst. The amino compound used herein preferably comprises an alkyleneamine and an alkylene glycol, in particular, EDA and EG. The process disclosed in the '599 patent is schematically represented by Scheme-2.

Scheme-2
WO2013030249 discloses a process for the Catalytic production of amines from nitriles. The process disclosed in the '249 patent is schematically represented by Scheme-3 US Patent 7582796 (the '796 patent) discloses a process for the preparation of triethylenetetramine salts based generally on the Strecker-synthesis of a dinitrile, wherein dinitrile is derivatized with B0C2O (di-tert-butyl dicarbonate) to form a Boc-protected dinitrile, the Boc-protected dinitrile is reduced in an aqueous solution of ethanol and ammonia in the presence of Raney-nickel and dihydrogen to form a protected diamine, and the protected diamine is purified by precipitation in isopropanol. The resulting compound is deprotected and hydrolyzed with an acid to form a triethylenetetramine salt, which may include a triethylenetetramine primary salt, a triethylenetetramine secondary salt, a triethylenetetramine tertiary salt, or a triethylenetetramine quaternary salt. The process disclosed in the '796 patent is . schematically represented by Scheme-4.

Scheme-4
Mainly the prior art process for the preparation of Trientin involves in the formation of trientin salts from diamine as starting material.
This process of preparation of Trientin as described in the prior art references have few disadvantages which is difficult to be used on an industrial level because of the rather critical stability conditions, such as the deprotection of the protected derivative and preparation of a triethylenetetramine salt.
The main disadvantage of the known processes of Trientin is carry ing out the reactions at more Unstable conditions thereby obtaining the required product with low purity and low yields. Moreover maintaining reaction at higher temperatures is not preferable at commercial scale.

The entire prior art procedures results a mixture of products and related impurities which require a tedious and uneconomical purification procedure which results Trientin in low yield.
In addition to the above disadvantages the prior art routes also have disadvantage of use of highly toxic reagents or catalyst in excess quantity which results the prior art processes are uneconomical and not süitable at commercial scale.
Hence there is a need to develop an improved and commercially viable process for the preparation of Trientin di hydro halide salts.
It is therefore obj eet of the present invention to pro vide a process for the preparation of Trientin di hydro halide salts on an industrial scale, under particularly stable conditions and with high. yields.

Objective of the invention
It is the main object of the present invention is to pro vide a stable process for the preparation of triethylenetetramine di hydro halide salt in yield, stability and scalable process for the commercial production.

Summary of the invention
The main aspect of the present invention is to provide process for the preparation of triethylenetetramine di hydro halide salt by alkylation reaction of formula (II) with halo acetonitrile and then protected with a protecting group. The protected dinitrile is reduced to form a protected diamine, and the protected diamine derivatized with sulfonic acid to form a corresponding sulfonic acid salt of compound of formula (VI). The acid salt is converted to Trientin free base and then foliowed by reaction with an acid to form a Triethylenetetramine di acid salt of Formula (I).HoN
Wherein,
R is selected from methane, trifluoromethane, para toluene, ortho toluene, benzene, 4-nitro benzene or halobenzene, X is halogen group.
Wherein the sulfonic acid also include camphorsulfonic acid.

Description of the Invention
In one aspect of the present invention, Triethylenetetramines, and triethylenetetramine di hydro chloride salts and polymorphs and crystals thereof in high yields and purity are obtained.
In one embodiment at least one intermediate is synthesized that may be crystallized. Intermediates which may, but need not be, crystallized include protected dinitrile intermediates.
Another aspect of the inventio,, it has been found that the protected dinitrile reduced to form a protected triethylenetetraamine in the presence of a reducing agent. The protected triethylenetetraamine reacted with sulfonic acid to obtain sulfonic acid salt of triethylenetetraamine formula (VI). The obtained sulfonic acid salt of compound of formula (VI) include, mono sulfonic acid salt, secondary sulfonic acid salt, tertiary sulfonic ac.d salt and quaternary sulfonic acid salt. This compound was crystalüzed wuh alcoholic solvent to prov.de pure form of crystalline sulfonic acid salt of triethylenetetraamine formula (VI).This su.fomc acid salt further reacted with a base to afford Trienün free base. The Trientin free base treated with acid in an alcohol solvent to form the compound of formula (I).
Another aspect of the invention, it has been found that, the XRD dffiacüon values of crystalline tri-Benzene sulfonic acid salt of triethylenetetraamine formula (VI a).
Another aspect of the invention, it has been found that, the XRD dtffraction values of crystalline Camphor sulfonic acid salt of triethylenetetraamine formula (VI b).
The present invention for the preparation of Tnentin di hydro halide salt can be dep.cted by the following Synthetic Scheme-5.
di hydro halide salt of formula (I) can be obtained by known processes in the prior be briefly explained by the following procedure which comprising,
The present invention can
Stage I- Compound (II) is reacted with Compound (III) in the presence of base and haloacetonitrile at 25-30°C for 6-14 hrs. To this mixture added a protected group slowly and maintained at 25-30°C for another 5-6 hrs.

Stage II: To a solution of stage -I compound in an organic solvent a reducing agent was added foliowed by methanolic ammonia at 25-30°C and pressurised with hydrogen to 7-8 Kg/cm2. The reaction mixture was maintained at 25-30°C for 22-24 hrs.
Stage III: To a solution of Stage-II compound in an organic solvent sulphonic acid was added slowly and resulting mixture was maintained at the same temperature for 3 hr. The resulting product was crystallized by conventional methods.

Stage IV: To the obtained Stage -III compound in an organic solvent, a base was added at 10-15°C and maintained the resulting mixture at 25-30°C for 3-4 hrs.

Stage V: To Stage-IV compound in an organic solvent an acid in an organic solvent preferably an acid in an alcohol solvent was added dropwise at 25-30°C and the resulting mixture is maintained at 25-30°C for 30 mins. The temperature of the reaction mixture is raised to 60-65°C and maintained for 30 mins. After reaction completed, the resulting compound was isolated and the solid is dried under vacuüm at 50 -55°C for 2hrs to afford compound-I.
In one aspect of the invention, the base used in stage (I) is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bi carbonate, ammonia, potassium tertiary butoxide, triethylamine, pyridine etc.
Preferably potassium carbonate is used as base in stage I reaction.
In another aspect of the invention, the protecting agent used in stage (I) is selected from, Carbobenzyloxy (Cbz), p-Methoxybenzyl carbonyl (Moz or MeOZ), tert-Butyloxycarbonyl (BOC), 9-Fluorenylmethyloxycarbonyl (FMOC), Tosyl (Ts) group, Benzoyl (Bz), Benzyl (Bn), Carbamate group thereof.
In another aspect of the invention, Reducing agent used in stage (II) is selected from Raney niekel, Lithium aluminium hydride, sodium borohydride, tin (II) chloride etc. Preferably Raney nickel used as reducing agent in stage II process.
In one aspect of the invention, the organic solvent used in stage (II) is selected from ethanolic ammonia or methanolic ammonia.
In another aspect of the invention, the sulphonic acid used in stage (III) is selected from methane sulphonic acid, trifluoro methane sulphonic acid, benzene sulphonic acid, 4- nitró benzene sulphonic acid, 4-methyl benzene sulphonic acid, 2-methyl benzene sulphonic acid and Camphor sulphonic acid thereof.
In another aspect of the invention, the organic solvent used in stage (III) is selected from methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, acetic acid, formic acid and or mixtures thereof.
The Triethylenetetramine acid salt as obtained by the present invention optionally further proceeds for purification by suitable procedure. The stage (III) compound optionally isolated by conventional methods.
In another embodiment of the invention, the base used in stage (IV) is selected from sodium methoxide, sodium ethoxide etc.
In stage (IV) the alcoholic solvent is selected from ethanol, methanol and or mixtures thereof.
In another aspect of the invention, the alcoholic HC1 used in stage (V) is selected from ethanolic HC1, Methanolic HC1. More preferably the alcoholic HC1 is ethanolic HC1.
In another embodiment the sulfonic acid salt of compound of formula (VI) is tri-Benzene sulfonic acid salt of triethylenetetraamine, which is isolated and crystallized in organic solvent.
The tri-Benzene sulfonic acid salt of triethylenetetraamine of Formula (VI a) represented in the following structure.
Another aspect of the invention, it has been found that, the XRD diffraction values of crystalline tri-Benzene sulfonic acid salt of triethylenetetraamine formula (Vla).
In another embodiment the acid salt of compound of formula (Vla).is characterized by the IR va.ues at wavenumbers comprising 3402, 2982, 2061, 2009, 1628, 1450, 1335, 1126, 1074 and 996.
In another embodiment the acid salt (Vla) is characterized by a DSC extrapolated onset/ peak melting temperature of from between about 95.61°C to about 103.34°C.
In another embodiment the acid salt (Vla) the x-ray diffraction 29 values comprise here 7.785, 13.934,15.434, 18.474, 19.168,21.819,24.607,25.041 and 27.200
In another embodiment, Triethylenetetramine di hydrochloride salt formula (I) obtained by the present invention is in crystalline form.
Another embodiment of the invention is novel process for the preparation of trientine and its pharmaceutically acceptable salts thereof as disclosed in schematic process in scheme 6.9bz
Scheme-6
One more embodiment of the invention is novel process for the preparation of trientinê and its pharmaceutically acceptable salts thereof as disclosed in schematic process in scheme 7.
Ethylene diamine (100 g , leq) was reacted with 2-chloroacetonitrile ( 263.8 g , 2.1 eq) in presenceofpotassiumcarbonate(459g, 2 eq) in Acetonitrile (10 vols) at 25-30°C for 12-14 hrs. Progress of the reacüon was monitored by TLC. After the reaction was completed the reaction mass was filtered under vacuüm and the filtrate was cooled to 0-10°C then Boe anhydride ( 762.5 g , 2.1 eq) was added slowly to the solution and maintained at 25-30°C for 5-6 hrs. The reaction mixture was washed water and concentrated under vacuüm to afford crude
product which was recrystallized from Ethylacetate ( 2vols) and hexane ( 5 vols) mixture to afford stage -I product. Yield: 350 g (65%)
To a solution of stage-I (500 g , leq) in methanol ( 5 vols) in autoclave Raney Ni catalyst wet ( 250 g , 50% w/w ) added foliowed by methanolic ammonia ( 3.5 L) at 25-30 C and pressurised with hydrogen to 7-8 Kg/cm2. The reaction mixture was maintained at 25-30 °C for 22-24 hrs. Progress of the reaction monitored by TLC. The reaction mixture is filtered over celite and the filtrate concentrated under vacuüm below 40 °C. The residue ( 470 g) was düuted with water ( 2 L) and washed with toluene ( 470 ml). The organic and aqueous layer separated, aqueous layer was filtered over hy-flow , concentrated under vacuüm at 60-70 °C to afford off white colored solid. Yield: 398 g (78%)
To a solution of Stage-II (25 g) in IPA (10 vols) at 55-60°C , benzene sulphonic acid (34.2 g , 3 eq) or camphor sulphonic acid was added slowly and resulting mixture was maintained at the same temperature for3 hr. The precipitate was cooled to 25-30 °C and maintained for 1 hr at the same temperarture. The precipitate was filtered under vacuüm, solid washed with pre-cooled IPA ( 5 vols) and dried to afford stage-III. Yield: 17g (40 %).
The IR values of BSA salt comprising: 3402, 2982, 2061, 2009, 1628, 1450, 1335, 1126, 1074 and 996.
The acid salt is characterized by a DSC extrapolated onset/ peak melting temperature of from between about 95.61°C to about 103.34°C.
The x-ray diffraction 29 values comprise here 7.785, 13.934, 15.434, 18.474, 19.168, 21.819,24.607, 25.041 and 27.200.

To a mixture of Stage -III (trientine tri benzenesulphonic acid salt) ( 100 g ) and MeOH ( 10 vols) at 10-15 °C , 30% NaOMe in MeOH ( 4.1 eq., 240 ml ) is added slowly at same temperature and maintained the resulüng mixture ate 25-30 °C for 3- 4 hrs. The reaction mixture is filtered and the filtrate is concentrated under vacuüm. The residue is diluted with MTBE ( 2 vols) and maintained for 2-3 hrs for2 hrs. The precipitated salts are filtered off and the filtrate is concentrated under vacuüm to afford trien free base (stage-IV). Yield: 28.7 g ( 60%)
Stage - V Trientine dihydrochloride
To St-IV ( 45 g ) solution in EtOH ( 5 vols) at 25-30 "C, Ethanolic HCI ( 19%) ( 1.1 eq , 63.7 ml) was added dropwise at 25-30 °C and the resulting mixture is maintained at 25-30 0C for 30 mins. The temperature of the reaction mixture is raised to 60-65 » C and maintained for 30 mins.
The reaction mass is cooled to 25-30 °C and maintained for 12- 14 hrs The resulting precipitate is filtered under vacuüm , solid washed with ethanol ( 1 vol) and dried under nitrogen for 30 mins. The wet solid is diluted with ethanol ( 5 vols), the resulting mixture is heated to 70-75 °C and maintained for 30- 60 mins. The mixture is cooled to 25-30 °C, maintained for 5- 6 hrs and the precipitate is filtered under vacuüm with nitrogen blanket. The wet solid is dried under vacuüm at 50 -55 °C for 2hrs to afford stage -V as white colored, hygroscopic powder.
Yield: 33 g (48 %)
Claims

1. An improved process for the preparation of Trientine free base or its dihydrochloride salt from the corresponding sulfonic acid salt of Trientine.

2. The process according to claim 1, wherein the sulfonic acid salt comprising Trientine primary sulfonic acid salt, Trientine secondary sulfonic acid salt, Trientine tertiary sulfonic acid salt, Trientine quaternary sulfonic acid salt or mixture théreof.
3. The process according to claim 1, wherein the sulfonic acid is selected from para toluene sulfonic acid, ortho toluene sulfonic acid, benzene sulfonic acid, halo benzene sulfonic acid or camphor sulfonic acid.

4. The process according to claim 3, wherein the sulfonic acid is benzene sulfonic acid.

5. The crystalline Trientine tribenzene sulfonate salt having XRPD 29 values at about 7.785, 13.934 15.434, 18.474, 19.168, 21.819, 24.607,25.041 and 27.20°±0.2°.

6. An improved process for the preparation of Trientine dihydrochloride comprising,
a) reacting the protected diamine with benzene sulfonic acid in alcohol solvent at about 45-65°C for about 2-4 hours, stirring the reaction mass at 0-10°C and filtering to get the benzene sulfonic acid salt of Tientine;
b) reacting the sulfonic acid salt of Tientine of stage-a) with a base in an alcoholic solvent and isolating trientine free base by conventional methods;
c) mixing the obtained Trientine free base of stage b) with a source of hydrochloric acid at 20-30°C, stirring the contents at about 50-65°C for about 30 minutes foliowed by stirring at 20-3 5°C for about 10-14 hours and isolating the obtained Trientine dihydróchloride
salt, and
d) recrystallizing the obtained Trientine dihydróchloride salt of step c) in organic solvent.

7. The process of claim 6, wherêin the alcohol solvent of step a) is selected from methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tertiary butanol or mixtures thereof.

8. The process of claim 6, wherein the base of step b) is selected from sodium hydroxide, sodium carbonate, sodium methoxide, potassium hydroxide or potassium tertiary butoxide and the alcohol solvent is selected from methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tertiary butanol or mixtures thereof.

9. The process of claim 6, wherein the source of hydrochloric acid of step c) is selected from aqueous hydrochloric acid, methanolic hydrochloric acid or etahnolic hydrochloric acid.

10. The process of claim 6, wherein the organic solvent of step d) is selected from ethanol, methanol, isopropyl alcohol, toluene, ethyl acetate or heptane.