WO2024018394A1 - A process for the preparation of crystalline form a of n, n'-bis(2-aminoethyl)-1,2-ethanediamine tetrahydrochloride - Google Patents
A process for the preparation of crystalline form a of n, n'-bis(2-aminoethyl)-1,2-ethanediamine tetrahydrochloride Download PDFInfo
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- WO2024018394A1 WO2024018394A1 PCT/IB2023/057358 IB2023057358W WO2024018394A1 WO 2024018394 A1 WO2024018394 A1 WO 2024018394A1 IB 2023057358 W IB2023057358 W IB 2023057358W WO 2024018394 A1 WO2024018394 A1 WO 2024018394A1
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- tetrahydrochloride
- trientine
- crystalline form
- ethane
- boc
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- OKHMDSCYUWAQPT-UHFFFAOYSA-N n'-[2-(2-aminoethylamino)ethyl]ethane-1,2-diamine;tetrahydrochloride Chemical compound Cl.Cl.Cl.Cl.NCCNCCNCCN OKHMDSCYUWAQPT-UHFFFAOYSA-N 0.000 title claims abstract description 54
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 238000000034 method Methods 0.000 title claims abstract description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 57
- 238000006243 chemical reaction Methods 0.000 claims description 49
- 229950010580 trientine tetrahydrochloride Drugs 0.000 claims description 46
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 45
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- CSIFGMFVGDBOQC-UHFFFAOYSA-N 3-iminobutanenitrile Chemical compound CC(=N)CC#N CSIFGMFVGDBOQC-UHFFFAOYSA-N 0.000 claims description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- -1 Di-tert-butyl ethane- 1 ,2-diylbis(2-aminoethylcarbamate) difumarate Chemical compound 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 9
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 9
- 239000003586 protic polar solvent Substances 0.000 claims description 9
- IUDUQYZKURPHGL-UHFFFAOYSA-N cyanomethyl carbamate Chemical compound NC(=O)OCC#N IUDUQYZKURPHGL-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 239000000010 aprotic solvent Substances 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 claims description 6
- 125000001821 azanediyl group Chemical group [H]N(*)* 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 5
- 239000012296 anti-solvent Substances 0.000 claims description 5
- 125000006239 protecting group Chemical group 0.000 claims description 5
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- 239000007868 Raney catalyst Substances 0.000 claims description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 4
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000001530 fumaric acid Substances 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 claims description 2
- 238000005984 hydrogenation reaction Methods 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000007787 solid Substances 0.000 description 19
- 150000001875 compounds Chemical class 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- ZFOZEAYEEUISFP-UHFFFAOYSA-N tert-butyl n-(cyanomethyl)-n-[2-[cyanomethyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethyl]carbamate Chemical compound CC(C)(C)OC(=O)N(CC#N)CCN(CC#N)C(=O)OC(C)(C)C ZFOZEAYEEUISFP-UHFFFAOYSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- VILCJCGEZXAXTO-UHFFFAOYSA-N 2,2,2-tetramine Chemical compound NCCNCCNCCN VILCJCGEZXAXTO-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000002972 Hepatolenticular Degeneration Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 208000018839 Wilson disease Diseases 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000000113 differential scanning calorimetry Methods 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229960001124 trientine Drugs 0.000 description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- LJRDOKAZOAKLDU-UDXJMMFXSA-N (2s,3s,4r,5r,6r)-5-amino-2-(aminomethyl)-6-[(2r,3s,4r,5s)-5-[(1r,2r,3s,5r,6s)-3,5-diamino-2-[(2s,3r,4r,5s,6r)-3-amino-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-hydroxycyclohexyl]oxy-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl]oxyoxane-3,4-diol;sulfuric ac Chemical compound OS(O)(=O)=O.N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)N)O[C@@H]1CO LJRDOKAZOAKLDU-UDXJMMFXSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- HNRMPXKDFBEGFZ-UHFFFAOYSA-N 2,2-dimethylbutane Chemical compound CCC(C)(C)C HNRMPXKDFBEGFZ-UHFFFAOYSA-N 0.000 description 1
- FFRVQTGCNAGNJO-UHFFFAOYSA-N 2-(4-fluorophenyl)-2-pyrrolidin-1-ylethanamine Chemical compound C=1C=C(F)C=CC=1C(CN)N1CCCC1 FFRVQTGCNAGNJO-UHFFFAOYSA-N 0.000 description 1
- ZYFTZMADDQMCNB-UHFFFAOYSA-N 2-aminoethyl carbamate Chemical compound NCCOC(N)=O ZYFTZMADDQMCNB-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000001237 Raman spectrum Methods 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- FOOVFOZLDLQUDG-UHFFFAOYSA-N cyanomethyl-[2-[cyanomethyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethyl]carbamic acid Chemical compound C(C)(C)(C)OC(=O)N(CCN(C(O)=O)CC#N)CC#N FOOVFOZLDLQUDG-UHFFFAOYSA-N 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 125000005519 fluorenylmethyloxycarbonyl group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229960001639 penicillamine Drugs 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 1
- SYXYWTXQFUUWLP-UHFFFAOYSA-N sodium;butan-1-olate Chemical compound [Na+].CCCC[O-] SYXYWTXQFUUWLP-UHFFFAOYSA-N 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/82—Purification; Separation; Stabilisation; Use of additives
- C07C209/84—Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the present invention provides a process for the preparation of crystalline form A of N, N'-bis(2-aminoethyl)-l,2-ethanediamine tetrahydrochloride (I).
- Trientine tetrahydrochloride (I) is N, N'-bis (2-aminoethyl)-l,2-ethanediamine tetrahydrochloride. It is marketed in US as Cuvrior® (300 mg) tablet for oral administration. Cuvrior® is a copper chelator indicated for the treatment of adult patients with stable Wilson’s disease who are de-coppered and tolerant to penicillamine.
- Trientine tetrahydrochloride was reported in many patents and nonpatent literature. The contents of which are hereby incorporated as reference in their entirety.
- EP 1 778 618 describes synthetic techniques for producing triethylenetetramine and its salts including the 0.2 HC1 salt and the 0.4 HC1 salt. Only the 2 HC1 salt is said to be useful in the treatment of Wilson's disease.
- WO 2006/027705 describes the synthesis of triethylene tetr amines, including Form I and Form II triethylenetetramine dihydrochloride. This document does not mention the crystalline forms of triethylenetetramine tetrahydrochloride.
- the main objective of the present invention provides a process for the preparation of crystalline form A of Trientine tetrahydrochloride (I).
- Another objective of the present invention provides crystalline form A of Trientine Tetrahydrochloride (I) with high yield.
- step 1) heating the reaction mass of step 1), optionally adding anti-solvent, and
- In another aspect of the present invention is to provide crystalline form A of Trientine tetrahydrochloride (I) with high yield.
- Figure 1 illustrates X-Ray Diffraction (XRD) pattern of crystalline form A of Trientine tetrahydrochloride (I)
- FIG. 2 illustrates Differential Scanning Calorimetry of crystalline form A of Trientine tetrahydrochloride (I)
- Figure 3 illustrates Therapeutic Goods Administration of crystalline form A of Trientine tetrahydrochloride (I)
- Figure 4 illustrates Raman spectra of crystalline form A of Trientine tetrahydrochloride (I)
- step a) of the present invention involves the addition of 2- chloroacetonitrile (VI) to ethane- 1 ,2-diamine (V) in the presence of a base in a suitable aprotic solvent at 25-30 °C to obtain 2,2'-(ethane-l,2-diylbis(azanediyl) diacetonitrile (IV),
- step b) of the present invention proceeds by protecting the amino groups of intermediate (IV) using suitable protecting groups.
- the reaction filtrate obtained in step a) containing intermediate (IV) was cooled and reacted with a suitable protecting group.
- the final residue was washed with different volumes of a suitable aprotic solvent and dried under vacuum to obtain Di- tert-butyl ethane- 1 ,2-diyl bis(cyanomethyl carbamate) (III).
- the suitable amino protecting groups were selected from a group comprising of Fluorenyl methyloxy carbonyl (Fmoc), tert-butyloxycarbonyl (BOC), phthalimide, toluene sulfonyl (Ts), methane sulfonyl (Ms), triphenylmethyl (Trityl), carboxy benzyl (CBZ) or the like, tert-butyloxycarbonyl (Boc) was used in the present invention.
- step c) of the present invention proceeds with the reduction of the cyano group of intermediate (III) with methanolic ammonia and catalyst, preferably Raney-nickel was used as a catalyst.
- methanolic ammonia and catalyst preferably Raney-nickel was used as a catalyst.
- the residue so obtained was treated with fumaric acid dissolved in a protic solvent and heated at 50-70 °C.
- the reaction mixture was cooled and the solid so formed was washed with a mixture of protic solvents and an aprotic solvent to obtain Di-tert-butyl ethane- 1,2- diylbis(2-aminoethylcarbamate) difumarate (II).
- step d) involves deprotection of amino group from intermediate (II), and conversion of fumarate salt to Trientine tetrahydrochloride crude (la), which was reacted with concentrated hydrochloric acid and heated at 50-70 °C. On completion of reaction, reaction mass was cooled.
- the conversion of difumarate salt (II) to Trientine tetrahydrochloride crude (la) as described above is not reported in any prior art, which improves the purity of intermediate (II).
- step e) involves purifying Trientine tetrahydrochloride crude (la) to obtain crystalline form A of Trientine Tetrahydrochloride (I), wherein the purification process comprises:
- step 1) heating the reaction mass of step 1), optionally adding anti-solvent, and
- the suitable bases used in step a) and step c) were selected from potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine, aqueous ammonia, methanolic ammonia, group of metal alkoxides comprising of sodium methoxide, sodium ethoxide; potassium methoxide, potassium ethoxide, sodium butoxide, potassium butoxide, potassium-t-butoxide, sodium tertiary butoxide or the like.
- potassium carbonate, methanolic ammonia, sodium hydroxide, sodium carbonate, sodium methoxide and the like Preferably potassium carbonate, methanolic ammonia, sodium hydroxide, sodium carbonate, sodium methoxide and the like.
- step a), step b), step c), and step d) carried out in a solvent selected from aprotic or protic solvent or mixtures thereof.
- the suitable aprotic solvent used in step a), step b), step c), and step d) were selected from acetone, acetonitrile, 1,4-dioxane, diethyl ether, dichloromethane, ethyl acetate, N, N-dimethylformamide, methyl tertiary butyl ether, hexane, cyclohexane, toulene, tetrahydrofuran or the like, preferably acetone, acetonitrile, dichloromethane, ethyl acetate, cyclohexane, or mixtures thereof.
- the suitable protic solvent used in step b), step c), step d) and step e) were selected from a group comprising of water, methanol, ethanol, isopropyl alcohol (IP A), n- propanol, n-butanol, or the like, preferably water, methanol, ethanol, isopropyl alcohol, or mixtures thereof.
- crystalline form A of Trientine tetrahydrochloride ( 1 ) obtained according to the present invention is characterized by X-ray powder diffractions (XRD) pattern as shown in figure 1 and 2 theta values as provided in Table 1:
- the crystalline form A of Trientine tetrahydrochloride (1) has a melting temperature of about 270° C as measured by Differential Scanning Calorimetry.
- EXAMPLE 2 Preparation of Di-tert-butyl ethane- 1,2-diylbis (cyanomethyl carbamate) (III) 1088 g (4.99 moles) of tertiary-butyl carbamate (Boe) anhydride was added to the filtrate containing 2,2'-(ethane-l,2-diylbis(azanediyl)) diacetonitrile (IV) obtained in the example-1 over a period of 40-60 min at 15-20 °C. The reaction mass was maintained for 12-14 hrs. On completion of the reaction, the solvent was distilled off under vacuum below 55 °C and the residue was cooled to 25-30 °C.
- reaction mass After completion of the reaction, the reaction mass allowed to settle for 20-30 min at 25-30 °C and filtered through Hyflo. The filtrate was distilled under vacuum and 200 mL of isopropyl alcohol was added to the residue. The solvent was distilled under vacuum below 45 °C and the residue obtained was cooled to 25-30 °C. 700 mL of isopropyl alcohol and 100g of fumaric acid dissolved in 300mL of methanol were added to the residue at 25-30 °C. The reaction mass was heated for 45-60 min at 60-65 °C and then cooled to 25-30 °C. It was further cooled to 0-5 °C for 5-6 hrs.
- the precipitated solid was filtered and washed with chilled isopropyl alcohol: methanol solvent mixture (7:3) and 200 mL of chilled acetone and dried under vacuum.
- the solid so obtained was further dissolved in a mixture of (7:3) isopropyl alcohol: methanol at 25-30 °C, heated for 60-90 min at 65-70 °C.
- the reaction mass was then cooled to 25- 30 °C and stirred for 90-120 min. Further the reaction mass was cooled to 0-5 °C for 3- 4hrs.
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Abstract
The present invention relates to a process for the preparation of crystalline form A of N, N'-bis(2-aminoethyl)-1,2-ethanediamine tetrahydrochloride (I).
Description
"A PROCESS FOR THE PREPARATION OF CRYSTALLINE FORM A OF
N, N'-BIS(2-AMINOETHYL)-1,2-ETHANEDIAMINE
TETRAHYDROCHLORIDE' '
FIELD OF THE INVENTION
The present invention provides a process for the preparation of crystalline form A of N, N'-bis(2-aminoethyl)-l,2-ethanediamine tetrahydrochloride (I).
BACKGROUND OF INVENTION
Trientine tetrahydrochloride (I) is N, N'-bis (2-aminoethyl)-l,2-ethanediamine tetrahydrochloride. It is marketed in US as Cuvrior® (300 mg) tablet for oral administration. Cuvrior® is a copper chelator indicated for the treatment of adult patients with stable Wilson’s disease who are de-coppered and tolerant to penicillamine.
The synthesis of Trientine tetrahydrochloride was reported in many patents and nonpatent literature. The contents of which are hereby incorporated as reference in their entirety.
EP 1 778 618 describes synthetic techniques for producing triethylenetetramine and its salts including the 0.2 HC1 salt and the 0.4 HC1 salt. Only the 2 HC1 salt is said to be useful in the treatment of Wilson's disease.
WO 2006/027705 describes the synthesis of triethylene tetr amines, including Form I and Form II triethylenetetramine dihydrochloride. This document does not mention the crystalline forms of triethylenetetramine tetrahydrochloride.
US 10,988,436 claim crystalline form B and discloses crystalline form A of Trientine tetrahydrochloride and process for the preparation thereof.
OBJECTIVE OF THE INVENTION
The main objective of the present invention provides a process for the preparation of crystalline form A of Trientine tetrahydrochloride (I).
Another objective of the present invention provides crystalline form A of Trientine Tetrahydrochloride (I) with high yield.
SUMMARY OF THE INVENTION
Accordingly, in one aspect of the present invention is to provide a process for the preparation of crystalline form A of Trientine Tetrahydrochloride (1) as shown in scheme 1, the process comprising: a) adding of 2-chloroacetonitrile (VI) to ethane- 1 ,2-diamine (V) in presence of suitable base to form 2,2'-(ethane-l,2-diylbis(azanediyl)) diacetonitrile (IV); b) protecting the free amino groups using suitable protecting groups to obtain the Boc protected Di-tert-butyl ethane- 1 ,2-diy Ibis (cyanomethyl carbamate) (HI); c) reducing intermediate (HI) by hydrogenation using Raney nickel in the presence of methanolic ammonia and converting to difumarate salt by using fumaric acid to yield Boc protected Di-tert-butyl ethane- 1 ,2-diylbis(2-aminoethylcarbamate) difumarate (II); d) deprotecting intermediate (II) by treating with concentrated hydrochloric acid to yield Trientine tetrahydrochloride crude (la); and e) purifying crude Trientine tetrahydrochloride (la) to obtain crystalline form A of Trientine Tetrahydrochloride (I), wherein the purification process comprises:
1. dissolving crude Trientine tetrahydrochloride (la) in a protic solvent,
2. heating the reaction mass of step 1), optionally adding anti-solvent, and
3. isolating crystalline form A of Trientine tetrahydrochloride.
In another aspect of the present invention is to provide crystalline form A of Trientine tetrahydrochloride (I) with high yield.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 illustrates X-Ray Diffraction (XRD) pattern of crystalline form A of Trientine tetrahydrochloride (I)
Figure 2 illustrates Differential Scanning Calorimetry of crystalline form A of Trientine tetrahydrochloride (I)
Figure 3 illustrates Therapeutic Goods Administration of crystalline form A of Trientine tetrahydrochloride (I)
Figure 4 illustrates Raman spectra of crystalline form A of Trientine tetrahydrochloride (I)
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, in one embodiment of the present invention is to provide a process for the preparation of crystalline form A of Trientine tetrahydrochloride (1) as shown in scheme 1
Scheme 1
In another embodiment, the steps involved in the preparation of Trientine
Tetrahydrochloride (1) as shown in scheme lare as follows:
In some embodiment, step a) of the present invention involves the addition of 2- chloroacetonitrile (VI) to ethane- 1 ,2-diamine (V) in the presence of a base in a suitable aprotic solvent at 25-30 °C to obtain 2,2'-(ethane-l,2-diylbis(azanediyl) diacetonitrile (IV),
In another embodiment, step b) of the present invention proceeds by protecting the amino groups of intermediate (IV) using suitable protecting groups. The reaction filtrate obtained in step a) containing intermediate (IV) was cooled and reacted with a suitable protecting group. On completion of reaction, the final residue was washed with different volumes of a suitable aprotic solvent and dried under vacuum to obtain Di- tert-butyl ethane- 1 ,2-diyl bis(cyanomethyl carbamate) (III). The two free amine groups of intermediate (IV) were protected by treating with /-butyl carbamate (Boc) anhydride to yield Di-tert-butyl ethane- 1 ,2-diylbis (cyanomethyl carbamate) (III), which is further purified by preparing slurry in cyclohexane or ethyl diisopropyl ether.
The suitable amino protecting groups were selected from a group comprising of Fluorenyl methyloxy carbonyl (Fmoc), tert-butyloxycarbonyl (BOC), phthalimide, toluene sulfonyl (Ts), methane sulfonyl (Ms), triphenylmethyl (Trityl), carboxy benzyl (CBZ) or the like, tert-butyloxycarbonyl (Boc) was used in the present invention.
In another embodiment, step c) of the present invention proceeds with the reduction of the cyano group of intermediate (III) with methanolic ammonia and catalyst, preferably Raney-nickel was used as a catalyst. On completion of reaction, the residue so obtained was treated with fumaric acid dissolved in a protic solvent and heated at 50-70 °C. The reaction mixture was cooled and the solid so formed was washed with a
mixture of protic solvents and an aprotic solvent to obtain Di-tert-butyl ethane- 1,2- diylbis(2-aminoethylcarbamate) difumarate (II).
In another embodiment, step d) involves deprotection of amino group from intermediate (II), and conversion of fumarate salt to Trientine tetrahydrochloride crude (la), which was reacted with concentrated hydrochloric acid and heated at 50-70 °C. On completion of reaction, reaction mass was cooled. The conversion of difumarate salt (II) to Trientine tetrahydrochloride crude (la) as described above is not reported in any prior art, which improves the purity of intermediate (II).
In another embodiment, step e) involves purifying Trientine tetrahydrochloride crude (la) to obtain crystalline form A of Trientine Tetrahydrochloride (I), wherein the purification process comprises:
1. dissolving crude Trientine tetrahydrochloride (la) in a protic solvent;
2. heating the reaction mass of step 1), optionally adding anti-solvent, and
3. isolating crystalline form A of Trientine tetrahydrochloride.
The suitable bases used in step a) and step c) were selected from potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine, aqueous ammonia, methanolic ammonia, group of metal alkoxides comprising of sodium methoxide, sodium ethoxide; potassium methoxide, potassium ethoxide, sodium butoxide, potassium butoxide, potassium-t-butoxide, sodium tertiary butoxide or the like. Preferably potassium carbonate, methanolic ammonia, sodium hydroxide, sodium carbonate, sodium methoxide and the like.
In another embodiment, step a), step b), step c), and step d) carried out in a solvent selected from aprotic or protic solvent or mixtures thereof.
The suitable aprotic solvent used in step a), step b), step c), and step d) were selected from acetone, acetonitrile, 1,4-dioxane, diethyl ether, dichloromethane, ethyl acetate, N, N-dimethylformamide, methyl tertiary butyl ether, hexane, cyclohexane, toulene, tetrahydrofuran or the like, preferably acetone, acetonitrile, dichloromethane, ethyl acetate, cyclohexane, or mixtures thereof.
The suitable protic solvent used in step b), step c), step d) and step e) were selected from a group comprising of water, methanol, ethanol, isopropyl alcohol (IP A), n- propanol, n-butanol, or the like, preferably water, methanol, ethanol, isopropyl alcohol, or mixtures thereof.
The suitable anti-solvent used in step e) is selected from ethanol, methanol, isopropanol, acetone, or mixtures thereof. In another embodiment, crystalline form A of Trientine tetrahydrochloride ( 1 ) obtained according to the present invention is characterized by X-ray powder diffractions (XRD) pattern as shown in figure 1 and 2 theta values as provided in Table 1:
In another embodiment, the crystalline form A of Trientine tetrahydrochloride (1) has a melting temperature of about 270° C as measured by Differential Scanning Calorimetry.
The following examples further illustrate the present invention but should not be construed in any way as to limit its scope.
EXAMPLES
EXAMPLE 1: Preparation of 2,2'-(Ethane-l,2-diylbis(azanediyl)) diacetonitrile (IV)
100 g (1.663 moles) of ethane- 1,2-diamine (V) was dissolved in 1200 mL of acetonitrile at 25-30 °C, to this 460 g (3.326 moles) of potassium carbonate was added. The reaction mass was cooled to 15-20 °C and 276.8 g (3.658 moles) of 2- chloroacetonitrile (VI) was added to the reaction mass over a period of 40-45 min at 15-20 °C. The temperature of the reaction mass was raised to 25-30 °C and stirred for 22-24hrs. On completion of the reaction, the reaction mass was filtered at 25-30 °C and the solid washed with 200mL of acetonitrile. The filtrate so obtained was cooled to 15- 20 °C to obtain 2,2'-(Ethane-l,2-diylbis(azanediyl)) diacetonitrile (IV). The obtained filtrate was used in the next step without isolation.
EXAMPLE 2: Preparation of Di-tert-butyl ethane- 1,2-diylbis (cyanomethyl carbamate) (III)
1088 g (4.99 moles) of tertiary-butyl carbamate (Boe) anhydride was added to the filtrate containing 2,2'-(ethane-l,2-diylbis(azanediyl)) diacetonitrile (IV) obtained in the example-1 over a period of 40-60 min at 15-20 °C. The reaction mass was maintained for 12-14 hrs. On completion of the reaction, the solvent was distilled off under vacuum below 55 °C and the residue was cooled to 25-30 °C. 2000 mL of ethyl acetate was added to the residue and stirred for 15-30 min at 25-30 °C. 10% aqueous sodium chloride solution was added to the reaction mass at 25-30 °C, stirred for 15-30 min and then allowed stand for 15-30 min. Again, same procedure was followed with 10% of sodium chloride solution. The organic layer was distilled off completely and 1000 mL of cyclohexane was added to the residue. The reaction mass was stirred and the solid so formed was filtered. Finally, the wet cake so obtained was washed with 200 mL of cyclohexane at 25-30 °C. Again, the wet cake was charged with 1500 mL of cyclohexane in a clean and dry RB flask, stirred at 25-30 °C for 60-90 min. The solid obtained was filtered and washed with 200 mL of cyclohexane followed by suck dried under vacuum below 40 °C to obtain pure tert-butyl ethane- 1 ,2-diylbis (cyanomethyl carbamate) (III). Yield: 71%; Purity by Gas chromatography (GC): 99.0%.
EXAMPLE 3: Preparation of Di-tert-butyl ethane-l,2-diylbis(2- aminoethylcarbamate) difumarate (II)
100 g of tert-butyl ethane l,2diylbis (cyanomethyl carbamate) (III) was charged in a clean and dry autoclave and 1000 mL of methanolic ammonia was added to it at 25-30 °C. 50 g of Raney nickel (rinsed with purified water and methanol) was added to the reaction mass at 25-30 °C, under nitrogen atmosphere. A pressure of 2 - 3 Kg of nitrogen gas was applied to the autoclave and the reaction mass stirred for 5 -10 min at 25-30 °C. The nitrogen gas was released, and again repeated the same procedure. Then, the reaction mass was maintained under hydrogen gas at a pressure of 2-3 Kg for 24- 28 hrs. After completion of the reaction, the reaction mass allowed to settle for 20-30 min at 25-30 °C and filtered through Hyflo. The filtrate was distilled under vacuum and 200 mL of isopropyl alcohol was added to the residue. The solvent was distilled under vacuum below 45 °C and the residue obtained was cooled to 25-30 °C. 700 mL
of isopropyl alcohol and 100g of fumaric acid dissolved in 300mL of methanol were added to the residue at 25-30 °C. The reaction mass was heated for 45-60 min at 60-65 °C and then cooled to 25-30 °C. It was further cooled to 0-5 °C for 5-6 hrs. The precipitated solid was filtered and washed with chilled isopropyl alcohol: methanol solvent mixture (7:3) and 200 mL of chilled acetone and dried under vacuum. The solid so obtained was further dissolved in a mixture of (7:3) isopropyl alcohol: methanol at 25-30 °C, heated for 60-90 min at 65-70 °C. The reaction mass was then cooled to 25- 30 °C and stirred for 90-120 min. Further the reaction mass was cooled to 0-5 °C for 3- 4hrs. The solid so formed was filtered, washed with chilled acetone, and dried under vacuum below 40 °C to obtain di-tert-butyl ethane- 1 ,2-diylbis(2-aminoethylcarbamate) difumarate (II) salt. Yield: 35%; Purity by HPLC: 99.5%
EXAMPLE 4: Preparation of Trientine Tetrahydrochloride crude (la).
To 100g (0.172 moles) of di-tert-butyl ethane- 1 ,2-diylbis(2-aminoethylcarbamate) difumarate salt (II), 300mL of concentrated hydrochloric acid was added at 25-30 °C. The reaction mass was heated at 65-70 °C for l-2hrs, then cooled to 25-30 °C and maintained for 8-10 hrs to obtain Trientine Tetrahydrochloride crude (la).
EXAMPLE 5: Preparation of Crystalline form A of Trientine Tetrahydrochloride (I).
50 g of Trientine tetrahydrochloride crude (la) and 75 ml of water was taken at 25 to 30 °C. The reaction mass was heated to 60 - 65 °C and stirred for 15 to 30 minutes. To this 5.0 g of activated carbon was added and stirred. Filtered the mass and washed with 25 ml of water to get the filtrate. The obtained filtrate was heated to 60-65 °C. To this 500 ml of hot methanol was added and stirred. Cooled the reaction mass to 30 to 35 °C and stirred. Filtered the solid and washed with water. Dried the material to get the titled compound. Yield: 85%.
EXAMPLE 6: Preparation of Crystalline Form A of Trientine Tetrahydrochloride (I).
30 g of Trientine tetrahydrochloride crude (la) and 30 ml of water was taken at 25 to 30 °C. The reaction mass was heated at 75 to 80 °C and stirred for 15 to 30 minutes.
To this 300 ml of hot Ethanol was added and stirred. Cooled the reaction mass to 30 to 35 °C and stirred. Filtered the solid and washed with 60 ml of ethanol. Dried the material to get the titled compound. Yield: 86.6%
EXAMPLE 7: Preparation of Crystalline Form A of Trientine Tetrahydrochloride (I).
30 g of Trientine tetrahydrochloride crude (la) and 100 ml of methanol was taken at 25 to 30 °C. The reaction mass was heated at 60 to 65 °C and stirred for 60 to 90 minutes. Cooled the reaction mass to 30 to 35 °C and stirred. Filtered the solid and washed with 20 ml of methanol. Dried the material to get the titled compound. Yield: 91.0%
EXAMPLE 8: Preparation of Crystalline Form A of Trientine Tetrahydrochloride (I).
5.0 g of Trientine tetrahydrochloride crude (la) and 7.5 ml of water was taken at 25 to 30 °C. The reaction mass was heated at 50 to 55 °C and stirred for 15 to 30 minutes. To this 60 ml of hot acetone was added and stirred. Cooled the reaction mass to 30 to 35 °C and stirred. Filtered the solid and washed with 10 ml of acetone. Dried the material to get the titled compound. Yield: 96.0%
EXAMPLE 9: Preparation of Crystalline Form A of Trientine Tetrahydrochloride (I).
10 g of Trientine tetrahydrochloride crude (la) and 15 ml of water was taken at 25 to 30 °C. The reaction mass was heated at 55 to 60 °C and stirred for 15 to 30 minutes. To this 100 ml of hot isopropanol was added and stirred. Cooled the reaction mass to 30 to 35 °C and stirred. Filtered the solid and washed with 20 ml of isopropanol. Dried the material to get the titled compound. Yield: 80%
EXAMPLE 10: Preparation of Crystalline Form A of Trientine Tetrahydrochloride (I).
5.0 g of Trientine tetrahydrochloride crude (la) and 10 ml of water was taken at 25 to 30 °C. The reaction mass was heated at 55 to 60 °C and stirred for 15 to 30 minutes. To this 100 ml of hot isopropanol and methanol (1:1) was added and stirred. Cooled
the reaction mass to 30 to 35 °C and stirred. Filtered the solid and washed with 20 ml of isopropanol and methanol (1: 1). Dried the material to get the titled compound.
Yield: 80%
EXAMPLE 11: Preparation of Crystalline Form A of Trientine Tetrahydrochloride (I).
100 g of Di-tert-butyl ethane- 1 ,2-diylbis((2-aminoethyl) carbamate) difumarate (II), 300 ml of cone, hydrochloric acid were added at room temperature. The reaction temperature was raised to 65-70 °C and stirred for 1-2 hours at the same temperature. Cooled the reaction mass slowly to room temperature and maintained for 8-10 hours at the same temperature. Equal volumes of isopropyl alcohol and acetone were added at room temperature. Cooled the reaction mass to 10-15 °C and stirred at the same temperature. Filtered the mass, dried, and washed with equal volumes of Isopropyl alcohol and Acetone. Dried the solid and again washed with acetone. Dried the solid for 45-60 minutes. 500 ml of methanol was added to the wet cake at room temperature. Heated the reaction mass to 70-75 °C and maintained for 60-90 minutes at the same temperature. Cooled the reaction mass slowly to 0-5 °C and stirred. Filtered the solid and washed with 100 ml of chilled Methanol. Dried the solid and again washed with 100 ml of chilled Acetone. The solid was dried under vacuum for 8-10 hours at 35-40 °C. 75 ml of water was added at room temperature. The reaction mass was heated to 60-65 °C and maintained for 20-30 minutes at the same temperature. Activated carbon was added to the reaction mass at 60-65 °C and maintained for 20-30 minutes. Filtered the mass under vacuum and washed with 25 ml of water. 400 ml of methanol was added to the reaction mass at 60-65 °C and maintained for 15-30 minutes at the same temperature. Cooled the reaction mass to 30-35 °C and maintained for 30-45 minutes. Filtered the solid, washed with methanol and dried under vacuum to get the title compound. Yield: 70-80%
Claims
1. A process for the preparation of crystalline form A of Trientine Tetrahydrochloride (1),
wherein the process comprising: a) adding of 2-chloroacetonitrile (VI)
to ethane- 1 ,2-diamine (V)
in the presence of a base to form 2,2'-(ethane-l,2-diylbis(azanediyl)) diacetonitrile (IV);
b) protecting the free amino groups using suitable protecting groups to obtain the Boc protected Di-tert-butyl ethane- 1 ,2-diy Ibis (cyanomethyl carbamate) (III);
Boc
(III)
c) reducing intermediate (III) by hydrogenation using Raney nickel in the presence of methanolic ammonia and converting to difumarate salt by using fumaric acid to yield Boc protected Di-tert-butyl ethane- 1 ,2-diylbis(2-aminoethylcarbamate) difumarate (II);
Boc
(H) d) deprotecting intermediate (II) by treating with concentrated hydrochloric acid to yield Trientine tetrahydrochloride crude (la); and
e) purifying crude Trientine tetrahydrochloride (la) to obtain crystalline form A of Trientine Tetrahydrochloride (I), wherein the purification process comprises:
1. dissolving crude Trientine tetrahydrochloride (la) in a protic solvent,
2. heating the reaction mass of step 1), optionally adding anti-solvent, and
3. isolating crystalline form A of Trientine tetrahydrochloride.
2. The process as claimed in claim 1 , wherein the base used in step (a) is selected from potassium carbonate or sodium carbonate.
3. The process as claimed in claim 1, wherein the anti-solvent used in step e) is selected from ethanol, methanol, isopropanol, acetone, or mixtures thereof.
4. The process as claimed in claim 1, wherein step a), step b), step c), and step d) of carried out in a solvent selected from aprotic or protic solvent or mixtures thereof.
5. The process as claimed in claim 1, wherein the aprotic solvent used in step a), step b), step c), and step d) were selected from acetone, acetonitrile, 1,4-dioxane, diethyl ether, dichloromethane, ethyl acetate, N, N-dimethylformamide, methyl tertiary butyl ether, hexane, cyclohexane, toulene, tetrahydrofuran or the like, preferably
acetone, acetonitrile, dichloromethane, ethyl acetate, cyclohexane or mixtures thereof. The process as claimed in claim 1, wherein the protic solvent used in step b), step c), step d) and step e) were selected from a group comprising of water, methanol, ethanol, isopropyl alcohol (IPA), n-propanol, n-butanol or the like, preferably water, methanol, ethanol, isopropyl alcohol or mixtures thereof.
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006027705A2 (en) * | 2004-07-19 | 2006-03-16 | Protemix Corporation Limited | Synthesis of triethylenetetramines |
WO2018193482A1 (en) * | 2017-04-22 | 2018-10-25 | Biophore India Pharmaceuticals Pvt. Ltd. | Improved method for the synthesis of 1,2-ethanediamine, n, n'-bis(2-aminoethyl)-dihydrochloride(trientine dihydrochloride) |
US10988436B2 (en) * | 2018-05-04 | 2021-04-27 | Orphalan S.A. | Crystalline form of triethylenetetramine tetrahydrochloride and its pharmaceutical use |
-
2023
- 2023-07-19 WO PCT/IB2023/057358 patent/WO2024018394A1/en unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006027705A2 (en) * | 2004-07-19 | 2006-03-16 | Protemix Corporation Limited | Synthesis of triethylenetetramines |
WO2018193482A1 (en) * | 2017-04-22 | 2018-10-25 | Biophore India Pharmaceuticals Pvt. Ltd. | Improved method for the synthesis of 1,2-ethanediamine, n, n'-bis(2-aminoethyl)-dihydrochloride(trientine dihydrochloride) |
US10988436B2 (en) * | 2018-05-04 | 2021-04-27 | Orphalan S.A. | Crystalline form of triethylenetetramine tetrahydrochloride and its pharmaceutical use |
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