Title of Invention	A PROCESS FOR THE PREPARATION OF 1,4,7,10-TETRAAZACYCLODODECANE-1,7-DIACETIC ACID
Abstract	This invention relates to a process for tie preparation of 1,4,7 10-tetraazacyclododecane-l,7-diacetic acid 2a, 4a, 6a, 8a, decafaydrotetr azacyclopent (fig) acne ethylene is calculated with a reactive acetic acid derivative such as halo or siphon acetic acid. The product is recovered from the reaction mixture in a known manner.

Full Text

This invention relates to a process for the preparation of 1,4,7,10-tetraazacyclododecane 1,7-diacetic acid. Particularly preferred is the process of the present invention for the preparation of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid of formula (IV) and of 1,4,7, lO-tetraazacyclododecane-l,7-diacetic acid of formula (V) (also named D02A), according to the following scheme: 1,4,7,10-Tetraazacyclododecane-l,4,7,10-tetraacetic acid of formula (IV) includes, among its various synthetic applications, the use thereof for the preparation of Dotage (gadolinium complex of 1,4,7,10-tetraazacyclododecane-l,4,7,10-tetraacetic acid melamine salt), a commercially available contrast agent for magnetic resonance topography, and it can be prepared starting from 1,4,7,10-tetraazacyclododecane of formula (VI) by reaction with a halo acetic acid. This synthesis, although not particularly complex, makes use, however, of compound (VI) as starting material, which is not easy to prepare. For example, 1,4,7,10-tetraazacyclododecane can be synthesized conventionally, according to the procedure by Richman-Atkins (see for example US 4,085,106), which is based on the use of tonsil derivatives. This synthesis is poorly attractive for industrial processes, mainly for economic and environmental reasons, due to the type of wastes to be disposed, which contain large amounts of p-toluenesulfonic acid and of inorganic salts. Possible alternatives to Richman-Atkins's synthesis are synthetic approaches starting from triethylenete-traamine, such as the process described in WO 95/14726, or that according to WO 96/28432 as well as those described in Italian Patent application MI 96A 001257. These synthesis do not make use of polyamines tosyl derivatives, and they are based on the preparation of polycyclic intermediates which can be converted to the desired macro cycle in hydrolytic (WO 95/14726; WO 96/2843 2) or oxidizing (MI 96A 001257) conditions, as summarized in the following: When 1,4,7,lO-tetraazacyclododecane disubstituted derivatives, such as the acid of formula (V), are desired, the synthetic route starting from macro cycle (VI) is extremely complex, as it is described, for example, in WO 93/12097, and is based on a series of selective protections, which use reactive poorly suitable for any industrial applications, above all due to economic and environmental reasons. WO 93/12097 What stated above clearly shows that synthetic routes to compound (IV) or to compound (V), which do not require the use of 1,4,7,10-tetraazacyclododecane (VI) , would, on one hand, be a remarkable improvement in the processes for the synthesis of Dotage , and, on the other hand, open a way to the preparation of novel contrast agents for magnetic resonance topography, which are, at present, available with difficulty due to the above cited selectivity problems characterizing the conversion of (VI) to (V). It has now surprisingly been found, and this is the object of the present invention, a process for the preparation of the compounds of general formula (I), comprising the steps represented in Scheme 1: Scheme 1 R is a hydrogen atom, a straight, branched or cyclic alkyl group, unsubstantiated or substituted with 1 to 10 oxygen atoms, R-1 independently of R, has the same meanings as R, or is a group R2/ in which R2 is a C alkyl group, optionally interrupted by a phenyl, phonology or phenylenedioxy, in its turn substituted with a straight or branched alkyl group, unsubstantiated or substituted with 1 to 7 hydroxy groups or 1 to 3 groups; the aromatic group can be unsubstantiated or substituted with alloy groups or halogens, carboxyl, carbamoyl, alkoxycarbonyl, subfamily, hydroxyalky1, amino, acclaiming, acy1, hydroxyacy1 groups; X is a halogen or a sulfuric acid reactive residue. and Y is a -OH, or -OR3 group, wherein R3 is a straight or branched alkyl group, and in which: step a) is the alkylation’s reaction of compound (III) with the acid of general formula (VII), in aqueous solution and at basic pH, to give the compounds of general formula (II), and step b) is the alkylation’s reaction of compounds formula (II), according to known methods, with an R^-CH(X)-COY alkyl ting agent of general formula (VIII), followed by a hydrolysis reaction of any ester groups present, to give the compounds of general formula (I). When Y is -OR3, a hydrolysis step of the ester groups, according to known methods, is also included, so as to obtain the compounds of formula (I). In this case, it may be convenient to also transform the acid group present in compound (II) into the ester group -OR3, to promote the alkylation’s reaction, depending on the reactivity of the alkylating agent itself. The amount of alkylating agent of general formula (VII) or (VIII) used in step a) ranges from 2 to 2.3 molts of reagent per mol of substrate and, in step b), it ranges from 2 to 3 mols of reagent per mol of substrate. The reaction temperature in step a) and in step b), when R is the same as R, ranges from room temperature to 80°C, depending on the reactivity of the selected alkylating agent, in the conditions indicated. The basic pH in step a) and in step b), in case the alkylating agent of formula (VIII) is an acid, is preferably obtained by addition of an alkali or alkaline-earth metal hydroxide to the aqueous solution of compounds (III) and (II). Particularly preferred are sodium and potassium hydroxides. On the other hand, when the alkylation’s reaction is carried out with an ester derivative of compound (VIII), the reaction solvent can be suitably selected from dipolar aortic solvents, in particular dimethylforma-mide (DMF), dimethylacetamide (DMA), dimethylsulfoxide (DMSO), acetonitrile (CH3CN) and N-methylpyrrolidone, and the reaction is carried out in the presence of an organic base, preferably an aliphatic tertiary amine selected from triethylamine (TEA), di sopropylethylamine and tributylamine. The reaction temperature can range, in this case, from 0 to SO'C, depending in any cases on the reactivity of the selected alkylating agent. In this case, the alkylation’s reaction will be followed by basic hydrolysis of the resulting dieter, in conventional conditions, to obtain the desired compound of general formula (I). The alkylating agents of general formula (VII) or (VIII) can be selected from the compounds which either are already commercially available or can be prepared as already described in literature (see for example WO 93/24469 or EP 3257 62), or, among those still to be synthesized, using for example known methods for the preparation of suitable precursors (e.g. for acid chlorides a-halogen derivatives see: Harp et al., J, Org. Chem., 40, 3420, 1975), and subsequent transformation into the desired product. Preferably, R can be 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, as defined above. R2 can preferably be selected from the group consisting of: phenyl, benzyl, phenylmethoxymethyl. Ro can preferably be selected from the group consisting of: methyl, ethyl, isopropyl, butyl, tart-butyl. The reactive group X can be selected, for example, from the group consisting of halogens (CI, Br, I), or it is the maculate group (MeS020"), the benzenesulfonyloxy group (PhS020"), the nitrobenzenesulfonyloxy group (p-N02PhS020~), the tessellate group (Two"), the trifoliate group (CF3S03~). Particularly preferred are the compounds in which X is a halogen, more particularly a bromide. Particularly preferred are the alkylating agents of formula (VII) or (VIII) corresponding to bromoacetic acid (commercially available product), 2-bromopropionic acid (commercially available product), 2-bromobutyric acid (commercially available product). When R2 is present in the alkylating agent of general formula (VIII), particularly preferred are 3-(phenylmethoxy)propanoic acid reactive derivatives, such as 2-bromo-3-(phenylmethoxy)propanoic acid, the preparation of which is described in Grossman et al. , Chem. Ber., 91, 538, 1958, and 2-chloro-3-(phenyl-ethoxy)propane acid (CAS RN 124628-32-6), prepared analogously to the ruminated derivative, or the corresponding esters thereof and the trifled derivatives thereof at the 2- position, most preferred being 2-bromo-3-(phenylmethoxy)propanoic acid or 2-trifluo-romethanesulfonate-3-(phenylmethoxy)propanoic acid methyl ester. Particularly preferred is the process, according to scheme 1, for the preparation of compounds (IX) , 1,4,7,lO-tetraazacyclododecane-l,7-diacetic acid derivatives, as represented in the following Scheme 2: Scheme 2 in which R and X have the meanings defined above, and step b) is the alkylation’s reaction of compounds (II), in aqueous solution at basic pH, with an excess of an alkylating agent X-CH2COOH, to give compounds (IX). Examples of compounds of general formula (II) and (IX), the preparation of which, according to scheme 2, is reported in the Experimental section, are the following: a,a'-Dimethyl-1,4,7,10-tetraazacyclododecane-l,7- diabetic acid a,a'-Diethyl-1,4,7,10-tetraazacyclododecane-l,7-diacetic acid 1 al,a7-Dimethyl-l,4,7,10-tetraazacyclododecane-l,4,7,10-tetraacetic acid al,a7-Diethyl-l,4,7,10-tetraazacyclododecane-l,4,7,10- Particularly preferred is the process, according to scheme 1, for the preparation of compound (V) by alkylation’s of compound (III), in which the alkylating agent of formula {VII) corresponds to an acetic acid derivative XCH2COOH, as represented in Scheme 3. Scheme 3 The conversion of compound (III) to compound (V) involves heating of (III) in aqueous solution at temperatures ranging from 25°C to 50 , at basic pH (preferably pH 10-11), in the presence of a halo acetic acid added in amounts of 2 mol/mol of compound (III). At the end of the reaction, the mixture is neutralized and concentrated to dryness. The residue can be purified from inorganic anions by ion exchange. Elates are suitably concentrated to dryness, to obtain a product at high quality (HPLC assay 97%), which can optionally be recrystallized from acetone-methanol, to obtain a purity higher than 99% (HFLC assay. The resulting compound of formula (V) can then be preferably calculated with compound (VIII) to give compounds (IX), according to the conditions described above, as represented in Scheme 4: Scheme 4 This process is particularly preferred when, in compound (VIII), R^ corresponds to R2. It is, in fact, more convenient to react the alkylating agent of formula (VIII) with the preformed 1,7-D02A acid, than directly to react the tetra cycle of formula (III) with the alkylating agent itself. Particularly preferred is the process according to scheme 4 for the preparation of al,a7-bis[(phenylmetho-xy)methyl]-!,4,7,10-tetraazacyclododecane-l,4,7,10-te-traacetic acid, using as alkylating agent of formula (VIII) 2-bromo-3-(phenylmethoxy)propanoic acid methyl ester or 2-trifluoromethanesulfonate-3-(phenylmethoxy )propanoic acid methyl ester: useful to obtain, after compellation with the suitable paramagnetic metal ion, preferably gadolinium, a contrast medium for magnetic resonance topography, as described in EP 325762. It is a further object of the present invention the process for the preparation of the compounds of general formula (X), by complete alkylation’s reaction with the acid of general formula (VII), as represented in Scheme 5. Scheme 5 in which R and X have the same meanings as defined above. The amount of alkylating agent of formula (VII) ranges from 4 to 4.3 mols of reagent per mol of substrate. The reaction temperature can vary from room temperature to 80'C, depending on the reactivity of the selected alkylating agent in the indicated conditions. The basic pH in the reaction is preferably obtained by addition of an alkali or alkaline-earth metal hydroxide to the aqueous solution of compound (III) . Particularly preferred are sodium and potassium hydroxides. Particularly preferred are the alkylating agents of formula (VII) in which the R group can be selected from the group consisting of: H or a straight alkyl group, such as a methyl, ethyl, propyl, isopropyl, butyl group, in its turn substituted by hydroxy groups or interrupted by oxygen atoms, as defined above. The reactive group X can be selected, as above, from the group consisting of halogens (CI, Br, I), or it is a maculate, benzenesulfonyloxy, nitrobenzene-sulfonyloxy, or tessellate group. Particularly preferred are the compounds in which X is a halogen, more particularly a bromide, and the compounds of general formula (VII) deriving from bromoacetic or 2-bromopropionic acid. Particularly preferred is the process for the preparation of compound (IV) by alkylation of compound (III) at basic pH with an acetic acid reactive derivative as represented in Scheme 6. The conversion of compound (III) to compound {IV) requires heating (III) in aqueous solution at temperatures from 25 to 50 at basic pH (preferably pH 10-11), in the presence of an acetic acid reactive derivative, preferably a haloacetic acid, added in amounts of at least 4 mols per mol of compound (III). At the end of the reaction, crude compound (IV) is precipitated by acidification, then it can be purified through ion exchange and water-recrystallization processes . In the Experimental section, the synthesis of a,a',a',a'-tetrametil-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid according to scheme 5 is reported in which compound (III) is reacted with 2-bromopropionic acid. In substance, intermediate (III) is a key intermediate to obtain 1,4,7,10-tetraazacyclododecane derivative- vest of formula (VI) both disubstituted at the 1- and 7- positions, and tetra substituted, without need for the macro cycle itself as an expensive starting product for the symbiosis. Accordingly the present invention provides a process for the preparation of 1, 4, 7, 10-tetraazacyclododecane-l, 7-diacetic acid of the formula V comprising the steps of alkylating 2a, 4a, 6a, 8a, decal hydrotetraazacyclopent (fig) acenaphthylene of the formula III as represented by the following reaction scheme with an acetic acid reactive agent XCH2CX)H, in which X is halogen or a euphonic acid reactive residue, in an aqueous medium under the pH range of 10 to 11 and recovering the said compound of formula V in a known manner from the reaction mixture. In the following, some examples of preparation according to the invention are reported. The progress of the reactions is monitored by HPLC, using the following method: Column: Polymer Labs PLRP-S 250 x 4 mm Elation: isocratic Mobile phase: A/B = 99/1 A: 50mM NH4H2PO4 adjusted to pH 4 with 85% H3PO4 B: Methanol Temperature: 30"C Detection: 270 nm Flow: 0.5 mL/min Preparation of the sample: about 2 mg of product are placed in a 20 mL beaker, then 0.5 ml of an about O.IM solution of CUCI2 X 2H2O are added, dramatizing for 15 min. at 35'C. The fluent is then added to the required volume. Experimental section EXAMPLE 1 Preparation of 1,4,7,lO-tetraazacyclododecane-l,7- diacetic acid 225 g (1.16 mol) of (fall) (prepared as described in MI 96A 001257 and in MI 97A 000783) are dissolved in 200 g of water. Bromoacetic acid (80% sol. ) (403 g; 2.32 mol) and 30% Noah (to pH 10.3) are added at the same time, while keeping temperature at 20-25*0. The solution is heated to 50 and stirred at pH 10.3 for 5h. When the reaction is completed, pH is adjusted to 6 with 34% HCl and the mixture is concentrated to dryness. The residue is dissolved in 2 50 ml of demonized water and percolated on IRA 420 resin (6 L) at a 0.03 BV/h flow, eluting with water and subsequently with IN Hull. The fractions containing the product are concentrated and percolated on PVP resin (5 L) at a 0.07 BV/h flow. After elution with water, the fractions containing the product are combined and concentrated to dryness to obtain the desired product as a white solid (310 g; 1.075 mol). Yield: 93% The product can be crystallized from a Methanol: Acetone 8:2 v/v mixture. Crystallization yield: 85%. The -NMR, -NMR, IR and MS spectra are consistent with the indicated structure. EXAMPLE 2 Preparation of a,a -dimethyl-1,4,7,10- tetraazacyclododecane-1,7-diacetic acid Analogously to the procedure described in Example 1, compound (III) is reacted with 2-bromopropionic acid to give the desired product. Yield: 85% The 1H-NMR, -NMR, IR and MS spectra are consistent with the indicated structure. EXAMPLE 3 Preparation of a,a'-diethyl-1,4,7,10- tetraazacyclododecane-l,7-diacetic acid Analogously to the procedure described in Example 1, compound (III) is reacted with 2-bromobutyric acid to give the desired product. Yield: 82% The ^H-NMR , IR and MS spectra are consistent with the indicated structure, EXAMPLE 4 Preparation of al,a7-dimethyl-l,4,7 lO-tetraazacyclododecane-l ,4,7 ,10-tetraacetic acid The basic aqueous solution of a,a -dimethyl- 1,4,7,10-tetraazacyclododecane-l,7-diacetic acid, prepared as described in Example 2, is reacted with bromoacetic acid, to obtain the desired product. The IR-NMR , , IR and MS spectra are consistent with the indicated structure. EXAMPLE 5 Preparation of al,a7-diethYl-l,4 , 7 ,10- tetraazacyclododecane-l,4,7,10-tetraacetic acid The basic aqueous solution of a,a'-diethyl-1,4,7,10-tetraazacyclododecane-l,7-diacetic acid, prepared as described in Example 3, is reacted with bromoacetic acid, to obtain the desired product. IR and MS spectra are consistent with the indicated structure, EXAMPLE 6 Preparation of al,a7-bis[(phenylmethoxy)methyl]- 1,4,7,10-tetraa2acyclododecane-l,4,7,10-tetraacetic acid 1,4,7 ^lO-Tetraazacyclododecane-l,7-diacetic acid, prepared as described in Example 1, is reacted with 2-trifluoromethanesulfonate-3-{phenylmethoxy)propanoic acid methyl ester (prepared starting from the corresponding hydroxy derivative) in acetonitrile, in inert atmosphere at ICC and in the presence of diisopropylethylamine. At the end of the reaction, the mixture is concentrated to a residue which is dissolved in a Noah aqueous solution and washed with chloroform to remove the excess of alkylating agent and diisopropylethylamine. The ester groups of the product contained in the alkaline aqueous phase are hydrolyzed according to procedures known in literature. At the end of the hydrolysis, the product is precipitated by acidification to pH 3.5. The solid is filtered, washed with water on the filter and dried under vacuum, to obtain the desired product. The H-NMR, , IR and MS spectra are consistent with the indicated structure. EXAMPLE 7 Preparation of 1,4,7,10-tetraazacyclododecane-l,4,7,10- tetra acetic acid Into a reactor containing a solution of (III) (22.5 g; 0,116 mol) in 100 g of water, bromoacetic acid (sol, 80%) (80.6 g; 0.464 mol) and 30% Noah (to pH 11) are dropped simultaneously at room temperature. The solution is heated to 45'C and stirred at pH 11 for 5h. When the 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 ^H-NMR, , IR and MS spectra are consistent with the indicated structure. EXAMPLE 8 tetraa2acyclododecane-l,4,7,10-tetraacetic acid 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 ^H-NMRMS spectra are consistent with the indicated structure. In our Indian Patent Application No.l646/MAS/98, we have claimed a process for the preparation of 1,4,7f 10-tetra-a2abicyclo[8.2.2j tetradecane-2-'On6. This application has been divided out of IPA No.l645/MAS/9e which relates to a process for the preparation of tetraaza-dodecane acetic acid derivatives We claim: 1. A process for the preparation of 1,4,7,10- tetraazacyclododecane-1, 7-diacetic acid of the formula V comprising the steps of alkylating 2a, 4a, 6a, 8a, dace hydrotetraazacyclopent (figs) acenaphtfaylene of the formula III as represented by the following reaction scheme with an acetic acid reactive agent XCH2OOH, in which X is helots or a euphonic acid reactive residue, in an aqueous medium under the pH range of 10 to 11 and recovering the said compound of formula V in a known manner from the reaction mixture. 2. The process as claimed in claim 1 wherein Age reaction is carried out at a temperature of 25 to 3. The process as claimed in claim 1 and 2, wherein the acetic acid reactive agent is halo acetic acid and is added in amounts of 2 molls per molls of the compound of formula III. 4. A process few preparation of 1,4,7,10-tetraazacyclododecane-1, 7-diacetic acid substantially as hymns described and exemplified.

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