Title of Invention	A PROCESS FOR THE PREPATION OF TETRAAZACYCLODODECANE TETRAACETIC ACID DERIVATIVE
Abstract	This invention relates to a process for the preparation of tetraazacyclododecane acetic acid derivatives from 2a, 4a, 6a, 8a - decahydrotetraazacyclopent (fg) acenaphthylene comprising alkylation of said acenaphthylene compound under basic conditions and hydrolysis of the acyl group if desired

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ves of formula (VI) both disubstituted at the 1- and 7- positions, and tetrasubstituted, Without need for the macrocycle itself as an expensive starting product for the synthesis. Accordingly the present invention provides a process for the preparation of 1,4,7,10 -tetra-azacyclododecane 1,4,7,10-tetraacetic acid derivative of the formula I and its corresponding diacetic acid derivatives of 1,4,7,10-tetraazacyclododecane 1,7 diacetic derivative of the formula II according to the reaction scheme shown below: in which R is a hydrogen atom, a straight, branched or cyclic C1-C 6 alkyl group, unsubstituted or substituted with 1 to 10 oxygen atoms, R1 indeoendentlv of R, has the same meanings as R, or is a group R3, in which Rj is a C1-C20 alkyl group, optionally interrupted by a phenylene, aphenyloxy or phenylenedioxy, in its turn substituted with a straight or branched C\-C6 alkyl group, unsubstituted or substituted with 1 to 7 hydroxy groups or 1 to 3 C1-C7 groups; the aromatic group can be unsubstituted or substituted with alkoxy groups or halogens, carboxy, carbamoyl, alkoxycarbonyl, sul&moyl, hydroxyalkyl, amino, acylamino, acyl, hydroxyacyl groups; X is a halogen or a sulfonic acid reactive residue and Y is a -OH or -OR3 group, wherein R3 is a straight or branched C1-C4 group, in which: Step a) is the alkylation reaction of compound (III) with the acid of formula (VII), in aqueous solution and at basic pH, to give the compounds of formula (II), and Step b) is the alkylation reaction of compounds of formula (II), according to known methods, with an RrCH(X)-COY alkylating agent of formula (VIQ), followed by hydrolysis of any ester groups present, to give compounds (I). reaction is completed, pH is adjusted to 2 with 34% HCl to precipitate a white solid, which is filtered through a porous filter, washed with a water/acetone 1.5/1 mixture and dried. The crude product is dissolved in water and percolated on PVP resin (0.5 L) at 0.5 BV/h flow. After elution with water, the fractions containing the product and free from inorganic salts are combined and concentrated to dryness to obtain the desired product as a white solid (44.4 g; 0.110 mol). Yield: 95% (HPLC assay 98%) The iH-NMR, 13C-NMR, IR and MS spectra are consistent with the indicated structure. Analogously to the procedure described in Example 7, compound (III) is reacted with 2-bromopropionic acid, to obtain the desired product. Yield: 80% (HPLC assay 97%) The 1H-NMR, 13C-NMR, IR and MS spectra are consistent with the indicated structure. Reference is given to copending application N0.1646/MAS/98 which relates to a process for the preparation of 1,4,7»10-tetraazacyclododecane 1,7-diacetic acid. WE CLAIM: 1. A process for the preparation of 1,4,7,10 -tetra-azacyclododecane 1,4,7,10-tetraacetic acid derivative of the formula I and its corresponding diacetic acid derivatives of 1,4,7,10-tetraazacyclododecane 1,7 diacetic derivative of die formula II according to the reaction scheme shown below: in which R is a hydrogen atom, a straight, branched or cyclic Ci-C 6 alkyl group, unsubstihited or substituted with 1 to 10 oxygen atoms, R1 independently of R, has the same meanings as R, or is a group Ra, in which F.2 is a C1-C20 alkyl group, optionally interrupted by a phenylene, aphenyloxy or phenylenedioxy, in its turn substituted with a straight or branched C\-C6 alkyl group, unsubstituted or substituted with 1 to 7 hydroxy groups or 1 to 3 Q-C7 groups; the aromatic group can be unsubstituted or substituted with alkoxy groups or halogens, carboxy, carbamoyl, alkoxycarbonyl, sulfamoyl, hydroxyalkyl, amino, acylamino, acyl, hydroxyacyl groups; X is a halogen or a sulfonic acid reactive residue and Y is a -OH or -OR3 group, wherein R3 is a straight or branched C1-C4 group, in which: Step a) is the alleviation reaction of compound (HI) with the acid of formula (VII), in aqueous solution and at basic pH, to give the compounds of formula (II), and Step b) is the alleviation reaction of compounds of formula (II), according to known methods, with an Rj-CH(X)-COY alkylating agent of formula (VIII), followed by hydrolysis of any ester groups present, to give compounds (I). 2. Hie process as claimed in claim 1, in which the amount of alkylating agent of formula (VII) or (VIII) used ranges in step a) from 2 to 2.3 mols of reagent per mol of substrate and in step b) from 2 to 3 mols of reagent per mol of substrate. 3. The process as claimed in claims 1-2, in which the basic pH in step a) and in step b), when the alkylating agent of formula (VIII) is an acid, is obtained by addition of an alkali or alkaline-earth metal hydroxide to the aqueous solution of compounds (HI) and (II). 4. The process as claimed in claim 3, in which the alkali or alkaline-earth metal hydroxides are selected from sodium and potassium hydroxides. 5. Hie process as claimed in claim 1, in which, when the alkylating agent of formula (VIII) is an ester derivative, me reaction solvent is selected from dimethylformamide, dimetbyiacetamide, dimethylsulfoxide, acetonitrile and N-methylpyrrolidone, and the reaction is carried out in the presence of an aliphatic tertiary amine selected from triethylamine, diisopropylethylamine and tributylamine. 6. The process as claimed in claim 5, in which the alkylation reaction in step (b) is followed by basic hydrolysis of the resulting diester, in conventional conditions, to obtain compound (I). 7. Hie process as claimed in claims 1-6, in which, in the alkylating agents of formula (VII) or (VHI), R is selected from the group consisting of: H or a straight or branched alkyl group, such as a methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, in its turn substituted with hydroxy groups or interrupted by oxygen atoms; Ra is selected from the group consisting of: phenyl, benzyl, phenylmethoxymethyl; R3 is selected from the group consisting of: methyl, ethyl, isopropyl, butyl, tert-butyl; the reactive group X is selected from the group consisting of halogens (CI, Br, I), or is a mesylate, benzenesulfonyloxy, nitrobenzenesulfonyloxy, tosylate or triflate group. 8. Ihe process as claimed in claim 7, in which X is a bromide or a triflate group. . 9. Ihe process as claimed in claim 7, in which the alkylating agents of formula (VD) and (Vm) are selected from the group consisting of: bromoacetic acid, 2-bromopropionic acid, 2-bromobutyric acid 0. The process as claimed in claim 7, in which the alkylating agent of formula (VHI) is selected from 2-bromo-3-phenylmethoxy) propanoic acid methyl eater and 2-trifluoromethanesulfonate-3-(phenylmethoxy) propanoic acid methyl ester. 11. A process for the preparation of 1,4,7,10-tetra-azacyclododecane 1,4,7,10-tetraacetic acid derivative and its corresponding diacetic acid derivative substantially as herein described and exemplified.

Documents:

1645-mas-1998 abstract.pdf

1645-mas-1998 claims.pdf

1645-mas-1998 correspondence others.pdf

1645-mas-1998 correspondence po.pdf

1645-mas-1998 description (complete).pdf

1645-mas-1998 form-2.pdf

1645-mas-1998 form-26.pdf

1645-mas-1998 form-4.pdf

1645-mas-1998 form-6.pdf

1645-mas-1998 others.pdf

1645-mas-1998 petition.pdf