AU2012342016A1 - Process for the purification of polyaminocarboxylates - Google Patents
Process for the purification of polyaminocarboxylates Download PDFInfo
- Publication number
- AU2012342016A1 AU2012342016A1 AU2012342016A AU2012342016A AU2012342016A1 AU 2012342016 A1 AU2012342016 A1 AU 2012342016A1 AU 2012342016 A AU2012342016 A AU 2012342016A AU 2012342016 A AU2012342016 A AU 2012342016A AU 2012342016 A1 AU2012342016 A1 AU 2012342016A1
- Authority
- AU
- Australia
- Prior art keywords
- acid
- polyaminocarboxylate
- resin
- employed
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 22
- 238000000746 purification Methods 0.000 title claims abstract description 14
- WDLRUFUQRNWCPK-UHFFFAOYSA-N Tetraxetan Chemical compound OC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 WDLRUFUQRNWCPK-UHFFFAOYSA-N 0.000 claims abstract description 10
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 claims abstract description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- 229920005989 resin Polymers 0.000 claims description 20
- 239000011347 resin Substances 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000013522 chelant Substances 0.000 claims description 4
- 229920001429 chelating resin Polymers 0.000 claims description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- 239000012535 impurity Substances 0.000 claims description 3
- 150000002500 ions Chemical class 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 239000011877 solvent mixture Substances 0.000 claims description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- 150000003863 ammonium salts Chemical class 0.000 claims description 2
- 125000000129 anionic group Chemical group 0.000 claims description 2
- 239000003637 basic solution Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims 4
- 239000007864 aqueous solution Substances 0.000 claims 2
- 229920005646 polycarboxylate Polymers 0.000 claims 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 12
- 239000007787 solid Substances 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000010979 pH adjustment Methods 0.000 description 4
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 3
- 229910052688 Gadolinium Inorganic materials 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-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
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 3
- 229940106681 chloroacetic acid Drugs 0.000 description 3
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- QBPPRVHXOZRESW-UHFFFAOYSA-N 1,4,7,10-tetraazacyclododecane Chemical group C1CNCCNCCNCCN1 QBPPRVHXOZRESW-UHFFFAOYSA-N 0.000 description 2
- ZPDFIIGFYAHNSK-CTHHTMFSSA-K 2-[4,10-bis(carboxylatomethyl)-7-[(2r,3s)-1,3,4-trihydroxybutan-2-yl]-1,4,7,10-tetrazacyclododec-1-yl]acetate;gadolinium(3+) Chemical compound [Gd+3].OC[C@@H](O)[C@@H](CO)N1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 ZPDFIIGFYAHNSK-CTHHTMFSSA-K 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- OCDAWJYGVOLXGZ-VPVMAENOSA-K gadobenate dimeglumine Chemical compound [Gd+3].CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.OC(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC(O)=O)C(C([O-])=O)COCC1=CC=CC=C1 OCDAWJYGVOLXGZ-VPVMAENOSA-K 0.000 description 2
- 229960004455 gadobenic acid Drugs 0.000 description 2
- 229960003411 gadobutrol Drugs 0.000 description 2
- IZOOGPBRAOKZFK-UHFFFAOYSA-K gadopentetate Chemical compound [Gd+3].OC(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O IZOOGPBRAOKZFK-UHFFFAOYSA-K 0.000 description 2
- 229940005649 gadopentetate Drugs 0.000 description 2
- 229960003823 gadoteric acid Drugs 0.000 description 2
- GFSTXYOTEVLASN-UHFFFAOYSA-K gadoteric acid Chemical compound [Gd+3].OC(=O)CN1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 GFSTXYOTEVLASN-UHFFFAOYSA-K 0.000 description 2
- 238000005342 ion exchange Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- GOBUYIKQNYUPDZ-ZDUSSCGKSA-N (2S)-2-[2-(2-aminoethylamino)ethoxy-benzylamino]-3-hydroxypropanoic acid Chemical compound NCCNCCON([C@@H](CO)C(=O)O)CC1=CC=CC=C1 GOBUYIKQNYUPDZ-ZDUSSCGKSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- BDDLHHRCDSJVKV-UHFFFAOYSA-N 7028-40-2 Chemical compound CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O BDDLHHRCDSJVKV-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 239000002616 MRI contrast agent Substances 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- -1 ammonium ions Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229960005063 gadodiamide Drugs 0.000 description 1
- HZHFFEYYPYZMNU-UHFFFAOYSA-K gadodiamide Chemical compound [Gd+3].CNC(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC(=O)NC HZHFFEYYPYZMNU-UHFFFAOYSA-K 0.000 description 1
- 229960002059 gadoversetamide Drugs 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- DRKHJSDSSUXYTE-UHFFFAOYSA-L oxidanium;2-[bis[2-[carboxylatomethyl-[2-(2-methoxyethylamino)-2-oxoethyl]amino]ethyl]amino]acetate;gadolinium(3+) Chemical compound [OH3+].[Gd+3].COCCNC(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC(=O)NCCOC DRKHJSDSSUXYTE-UHFFFAOYSA-L 0.000 description 1
- 229960003330 pentetic acid Drugs 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 229940086542 triethylamine Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/26—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one amino group bound to the carbon skeleton, e.g. lysine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
- C07C227/42—Crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
- C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
- C07C229/16—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of hydrocarbon radicals substituted by amino or carboxyl groups, e.g. ethylenediamine-tetra-acetic acid, iminodiacetic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/24—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one carboxyl group bound to the carbon skeleton, e.g. aspartic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The present invention relates to an improved process for the purification of polyaminocarboxylates such as DOTA, DTPA, DO3A-butrol, BOPTA.
Description
WO 2013/076743 PCT/IN2012/000768 PROCESS FOR THE PURIFICATION OF POLYAMINOCARBOXYLATES Background The invention relates to the purification of polyaminocarboxylate chelating agents which can be used as MRI contrast agents. Polyaminocarboxylates are part of several drugs which include gadoteric acid, gadobutrol, gadobenic acid, gadopentetate, gadoversetamide, gadodiamide. The key ingredient to all the gadolinium based drugs is the chelate to which the gadolinium binds. Having a highly pure chelate free of any salts and metals is the basis for the preparation of the pure gadolinium based MRI agents. Some of the chelates include 1,4,7,10-tetraazocyclododecane-,1,4,7,10 tetraacetic acid (DOTA) for gadoteric acid, Pentetic acid (DTPA) for gadopentetate, BOPTA for gadobenic acid, 10-(1-hydroxymethyl-2,3 dihydroxypropyl)-1,4,7-tris(carboxymethyl)-1,4,7,1 0-tetraazocyclododecane (DO3A-butrol) for gadobutrol. State of the art Some of the chelates reported in the literature involve complex and expensive purification methods which involve resins of various kinds. US5922862 describes a procedure for the purification of DOTA and other cyclen substituted derivatives. It describes a procedure for the removal of inorganic salts by elution of the crude product dissolved in water over PVP resin. Inorg. Chem. 1980, 19, 1319 describes a procedure for the purification of DOTA using Dowex 50W-X4 resin. 1 WO 2013/076743 PCT/IN2012/000768 Inorg. Chem. 1997, 36, 6086 describes a procedure for the purification of DO3A-butrol with IR120H+ resin to remove salts. Likewise several other resins are reported for the purification of the chelates to remove inorganic salts. The resin methods involved are expensive and some of the chelates bind to the resins, which then require washing with ammonia solution or formic acid solutions. Removal of ammonium ions becomes particularly difficult as the ligand forms ammonium salts. The manufacturing of the chelates becomes difficult when large ion-exchange columns are required at commercial scale manufacturing. Since most of the chelates have high water solubility the distillation of water becomes time consuming and also leads to potential degradation products. Summary of the invention One of the objects of the invention was to provide a process for the preparation of the chelates in the pure form without the presence of impurities such as inorganic salts and other ions such as chloride, bromide, sulphate or the like. Yet another object of the invention was to develop a process with low cycle time, which is commercially viable, inexpensive and which utilizes none or minimal amount of resin. Detailed description of the invention The purification procedure of chelates without ion-exchange column purifications are particularly advantageous as they are less time consuming and are rather inexpensive. It has now surprisingly been found that polyaminocarboxylate compounds when isolated under highly acidic conditions preferably below 0.75 are 2 WO 2013/076743 PCT/IN2012/000768 isolated as their acid salts and upon purification of these salts by recrystallization from water or water solvent mixtures result in polyaminocarboxylate with a content of any inorganic salts or ions such as sodium, potassium or the like below 200 ppm. The acid employed for the salt formation can be hydrochloric acid, hydrobromic acid, sulfuric acid and the like. The acid is preferably hydrochloric acid and the salt isolated is as hydrochloride salt. The water solvent mixtures employed are water/acetone, water/ethanol, water/methanol or the like to obtain a product free of undesired chloride or bromide ions, which have very stringent specifications. The salt thus obtained is dissolved in water and is then adjusted to the desired pH either with an aqueous basic solution or alternatively a resin. It is noteworthy to mention here that the amount of resin employed is minimal and is used to adjust the pH of the solution about 1.5 - 3.0, thereby eliminating the chance for any additional inorganic salt formation. As the resin employed is in minimal amounts the process does not suffer from the drawbacks of the prior art. The pH is preferably adjusted with a basic anionic resin. The resirns that are empIoyed in the current process are resin in the hydroxide form such as Amberlyst A26 OH resin and the like. The bases that can be employed for the pH adjustment are potassium hydroxide, sodium hydroxide, ammonium hydroxide, triethyl amine or the like. An example of the process schematics is shown below for DOTA. The example described for DOTA is not limiting and a similar purification process can be applied to any polyaminocarboxylate. 3 WO 2013/076743 PCT/IN2012/000768 OH 1. Chloroacetic acid, N -NH HN -NaOHIH 2 0 O 2. Conc. HCI HO (00 NH NHN N - 4.c HO pH adjustment O, OH N N OH HO O The following examples describe the process in greater detail. Example 1: Synthesis of DOTA Charge 100 ml of water and 100 g cyclen HCI to a flask. Cool the reaction mass to 0-10 *C and adjust the pH of the solution to 10-10.5 with sodium hydroxide. Charge chloroacetic acid to the reaction with continuous pH adjustment to 10-10.5 with sodium hydroxide solution. Slowly raise the reaction to 70-75 *C and maintain until the completion of reaction. Cool the reaction mass and adjust the pH of the reaction to below 0.75 with conc. HCI and filter the solid separated which is DOTA hydrochloride. Recrystallize the solid from water and check the content of sulfated ash to be below 0.10%. The solid is then dissolved in 800 ml water and the pH of the solution adjusted to around 2.5 to 3.0 with amberlyst A26 OH resin to obtain a chelate free of hydrochloride salt. The mass is then filtered, and the filtrate obtained is distilled to 200-300 ml water and the solid is precipitated by adding acetone. The solid is filtered and dried to give the title product with desired purity 4 WO 2013/076743 PCT/IN2012/000768 having sulfated ash content below 0.1% and the sodium and chloride content below 200 ppm Example 2: Synthesis of BOPTA To a flask were charged 100 ml of water and 50 g of N-[2-[(2 aminoethyl)amino]ethyl]-O-(phenylmethyl)serine. Cool the reaction mass to 0 10 *C and adjust the pH of the solution to 10.5-11.5 with sodium hydroxide solution. Charge chloroacetic acid to the reaction with continuous pH adjustment to 10.5-11.5 with sodium hydroxide solution. Slowly raise the reaction temperature to 70-75 *C and maintain until the completion of reaction. Cool the reaction mass and adjust the pH of the reaction to below 0.75 with Conc. HCI and charge acetone. Filter the solid separated which is BOPTA hydrochloride salt. Recrystallize the solid from water and check the sulfated ash content to be below 0.10%. The solid is then dissolved in 800 ml water and the pH of the solution adjusted to around 2.0 with amberlyst A26 OH resin. The mass is then filtered and the filtrate is distilled to 200-300 ml water and the solid is precipitated by adding acetone. The solid thus obtained is filtered and dried to give the product with desired purity having sulfated ash below 0.1%. 5
Claims (7)
1. A process for the purification of polyaminocarboxylates like DOTA, DTPA, DO3A-butrol, BOPTA which comprises: a) treating an aqueous solution polyaminocarboxylate with an inorganic acid, wherein the pH of the solution is below 0.75 b) recrystallizing the precipitated polyaminocarboxylate acid salt in water or water solvent mixtures c) treating the aqueous solution of polyaminocarboxylate acid salt with a resin or a basic solution to maintain pH at 1.5 to 3.0 d) isolating the pure polyaminocarboxylate chelate
2. The process of claim 1 wherein the inorganic acid employed is selected from hydrochloric acid, hydrobromic acid, sulfuric acid
3. The process of claim 1 wherein the polycarboxylate purified is DOTA and the inorganic acid employed is Hydrochloric acid.
4. The process of claim 1 wherein the polycarboxylate purified is BOPTA and the inorganic acid employed is Hydrochloric acid.
5. The process of claim 1 wherein the resin employed is basic anionic resin such as amberlyst A26 OH resin.
6. The process of claim 1 wherein the polyaminocarboxylate isolated contains sodium, potassium, sulfate, chloride, bromide, ammonium salt impurities below 200 ppm.
7. Substantially pure polyaminocarboxylate obtained by the process of claim 1, wherein the sulfated ash is below 0.1% and the ion impurities are below 200 ppm. 6
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN4068/CHE/2011 | 2011-11-25 | ||
| IN4068CH2011 | 2011-11-25 | ||
| PCT/IN2012/000768 WO2013076743A2 (en) | 2011-11-25 | 2012-11-26 | Process for the purification of polyaminocarboxylates |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| AU2012342016A1 true AU2012342016A1 (en) | 2014-06-26 |
| AU2012342016B2 AU2012342016B2 (en) | 2016-05-19 |
| AU2012342016C1 AU2012342016C1 (en) | 2016-09-01 |
Family
ID=48470389
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2012342016A Ceased AU2012342016C1 (en) | 2011-11-25 | 2012-11-26 | Process for the purification of polyaminocarboxylates |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US10106489B2 (en) |
| EP (1) | EP2782900B1 (en) |
| JP (1) | JP6096798B2 (en) |
| KR (1) | KR101832027B1 (en) |
| CN (1) | CN104169252B (en) |
| AU (1) | AU2012342016C1 (en) |
| BR (1) | BR112014012429A2 (en) |
| CA (1) | CA2857014C (en) |
| IL (1) | IL232735A (en) |
| RU (1) | RU2621896C2 (en) |
| WO (1) | WO2013076743A2 (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3102566B1 (en) * | 2014-02-06 | 2018-09-12 | T2Pharma GmbH | Process for purifying 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid |
| KR101693400B1 (en) * | 2014-09-17 | 2017-01-05 | 에스티팜 주식회사 | A Method for Preparing Calcobutrol |
| CN106279220B (en) * | 2015-06-05 | 2018-10-30 | 四川科伦药物研究院有限公司 | A kind of purification process of Gadoversetamide suitable for industrialization |
| DE102015013939A1 (en) | 2015-09-15 | 2017-03-16 | be imaging GmbH | Process for the preparation of gadoteric acid (Gd-DOTA) complexes |
| GB201522412D0 (en) * | 2015-12-18 | 2016-02-03 | Ge Healthcare As | Dota synthesis |
| CN108264491B (en) | 2016-12-30 | 2022-09-16 | 威智医药有限公司 | Preparation method of 1,4,7, 10-tetraazacyclododecane-1, 4,7,10-tetraacetic acid |
| US20230248851A1 (en) * | 2020-06-10 | 2023-08-10 | Justesa Imagen S.A.U. | Procedure for obtaining gadoterate meglumine from high-purity tetraxetan (dota) and its use in the preparation of injectable galenical formulations |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3043867A (en) | 1959-10-16 | 1962-07-10 | Dow Chemical Co | Method for the purification of aminocarboxylic acids |
| US5334729A (en) * | 1989-06-29 | 1994-08-02 | Associated Universities, Inc. | Stable radiometal antibody immunoconjugates |
| US5491259A (en) * | 1994-09-13 | 1996-02-13 | The Dow Chemical Company | Process to produce aminocarboxylic acids containing low residual salt |
| IT1275426B (en) * | 1995-05-16 | 1997-08-07 | Bracco Spa | RECOVERY OF THE GADOLINIUM AND ITS COMPLEX AGENTS FROM AQUEOUS SOLUTIONS CONTAINING THEIR COMPLEXES |
| IT1293777B1 (en) * | 1997-07-25 | 1999-03-10 | Bracco Spa | PROCESS FOR THE PREPARATION OF TETRAAZAMACROCYCLES |
| EP1762563A1 (en) * | 2005-09-13 | 2007-03-14 | BRACCO IMAGING S.p.A. | Process for the preparation of contrast agents |
| RU2425831C2 (en) * | 2005-12-02 | 2011-08-10 | Джи-И Хелткер АС | Multimeric magnetic resonance contrast agents |
| WO2014068589A2 (en) | 2012-10-29 | 2014-05-08 | Biophore India Pharmaceuticals Pvt. Ltd. | Novel process for the preparation of (1-{9-[(4s, 2r, 3r, 5r)-3, 4-dihydroxy-5-(hydroxymethyl) oxolan-2-yl)-6-aminopurin-2-yl} pyrazole-4-yl)-n-methylcarboxamide |
-
2012
- 2012-11-26 KR KR1020147016770A patent/KR101832027B1/en not_active Expired - Fee Related
- 2012-11-26 US US14/360,059 patent/US10106489B2/en not_active Expired - Fee Related
- 2012-11-26 BR BR112014012429A patent/BR112014012429A2/en not_active Application Discontinuation
- 2012-11-26 EP EP12852260.4A patent/EP2782900B1/en active Active
- 2012-11-26 JP JP2014542999A patent/JP6096798B2/en not_active Expired - Fee Related
- 2012-11-26 CA CA2857014A patent/CA2857014C/en not_active Expired - Fee Related
- 2012-11-26 AU AU2012342016A patent/AU2012342016C1/en not_active Ceased
- 2012-11-26 WO PCT/IN2012/000768 patent/WO2013076743A2/en active Application Filing
- 2012-11-26 RU RU2014125548A patent/RU2621896C2/en active
- 2012-11-26 CN CN201280057802.5A patent/CN104169252B/en not_active Expired - Fee Related
-
2014
- 2014-05-21 IL IL232735A patent/IL232735A/en active IP Right Grant
Also Published As
| Publication number | Publication date |
|---|---|
| IL232735A0 (en) | 2014-08-03 |
| WO2013076743A3 (en) | 2014-05-30 |
| KR101832027B1 (en) | 2018-04-04 |
| JP2015501807A (en) | 2015-01-19 |
| CA2857014C (en) | 2018-08-14 |
| JP6096798B2 (en) | 2017-03-15 |
| AU2012342016C1 (en) | 2016-09-01 |
| KR20140097411A (en) | 2014-08-06 |
| RU2621896C2 (en) | 2017-06-08 |
| US10106489B2 (en) | 2018-10-23 |
| IL232735A (en) | 2017-05-29 |
| AU2012342016B2 (en) | 2016-05-19 |
| EP2782900A2 (en) | 2014-10-01 |
| CN104169252A (en) | 2014-11-26 |
| US20140323719A1 (en) | 2014-10-30 |
| RU2014125548A (en) | 2015-12-27 |
| CN104169252B (en) | 2017-03-22 |
| BR112014012429A2 (en) | 2017-06-06 |
| WO2013076743A2 (en) | 2013-05-30 |
| EP2782900A4 (en) | 2015-08-12 |
| EP2782900B1 (en) | 2018-01-10 |
| CA2857014A1 (en) | 2013-05-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2857014C (en) | Process for the purification of polyaminocarboxylates | |
| EP2948449B1 (en) | Process for producing 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid and complexes thereof | |
| EP4083026A1 (en) | Process for the preparation of 2,2',2''-(10-((2r,3s)-1,3,4-trihydroxy butan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid and its complexes | |
| US20230339945A1 (en) | Method for preparing a chelating ligand derived from pcta | |
| ES2950118T3 (en) | Complex of gadolinium and a diastereoisomerically enriched PCTA-derived chelating ligand and method of preparation and purification | |
| HUP0400997A2 (en) | Multidentate aza ligands able to complex metal ions and the use thereof in diagnostics and therapy | |
| CA2431976C (en) | Lithium complexes of n-(1-hydroxymethyl-2,3-dihydroxypropyl)-1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane, their production and use | |
| ES2929699T3 (en) | Gadolinium complex and a diastereoisomerically enriched PCTA-derived chelating ligand and method of synthesis | |
| JP2018537506A (en) | DOTA synthesis | |
| CA3088955A1 (en) | Method for producing calcobutrol | |
| KR101979836B1 (en) | Process for the preparation of calcobutrol | |
| CA3039053C (en) | Method for purifying p1,p4-di(uridine 5'-)tetraphosphate | |
| AU2020423724B2 (en) | Method for synthesizing zirconium complex | |
| WO2012105814A2 (en) | Triazanonane derivative or pharmaceutically acceptable salt thereof for enhanced fluorine-18 labeling | |
| WO2016135523A1 (en) | New substituted ethylene-diamine-tetraacetic-acid-bis(amide) derivatives and use thereof as ligand containing mn (ii) of mri contrast agent | |
| RU2779668C1 (en) | Method for producing calcobutrol | |
| HK40063372B (en) | Complex of gadolinium and a chelating ligand derived from diastereoisomerically enriched pcta and method for preparing and purifying same | |
| WO2017201581A1 (en) | Non-toxic iron chelators with neuroprotective potential |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| DA2 | Applications for amendment section 104 |
Free format text: THE NATURE OF THE AMENDMENT IS AS SHOWN IN THE STATEMENT(S) FILED 19 MAY 2016 . |
|
| DA3 | Amendments made section 104 |
Free format text: THE NATURE OF THE AMENDMENT IS AS SHOWN IN THE STATEMENT(S) FILED 19 MAY |
|
| FGA | Letters patent sealed or granted (standard patent) | ||
| MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |