Process for the preparation of exametazime
AssigneeJubilant Life Sciences Limited
InventorsSujay BISWAS, Vikas BANSAL, Rohit CHAKRAVARTY, Mokkapati Umamaheshwar PRASAD, Mukesh MASAND, Dharam VIR
Life of this patent
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Abstract
The present invention provides an improved process for the preparation of exametazime, which is used as ligand in preparation of technetium-99m complex.
Claims10
An improved process for the preparation of exametazime (formula I),
- which comprises the steps of:
- a) reacting 2,3-butanedione monoxime (formula II) with 2,2-dimethyl-1,3-propanediamine (formula III), in a suitable solvent, in presence of dehydrating agent to afford diimine derivative 4,8-diaza-3,6,6,9-tetramethylundecane-3,8-diene-2,10-dione bisoxime (formula IV),
- b) reducing diimine derivative 4,8-diaza-3,6,6,9-tetramethylundecane-3,8-diene-2,10-dione bisoxime (formula IV) with a suitable reducing agent in a suitable solvent to afford a mixture of ‘d’, ‘l’ and meso isomers,
- c) optionally, purifying the mixture of ‘d’, ‘l’ and meso isomers,
- d) treating the mixture of ‘d’, ‘l’ and meso isomers with d or 1 chiral resolving acid to form the corresponding acid addition salts and separating said one of the enantiomers of exametazime as acid addition salt,
- e) optionally, purifying the acid addition salt obtained in step (d),
- f) treating the mother liquor of step (d) with a suitable base,
- g) isolating a mixture of ‘d’ or ‘l’ enantiomer and meso isomer,
- h) purifying the mixture obtained in step (g),
- i) treating the mixture from step (h) with l or d chiral resolving acid to form the corresponding acid addition salts and separating said other enantiomer of exametazime as an acid addition salt,
- j) optionally, purifying the acid addition salt obtained in step (i),
- k) mixing the acid addition salt of step (d) or (e) and step (i) or (j),
- l) optionally, purifying the mixture of acid addition salts obtained in step (k),
- m) treating the mixture of acid addition salts of step (k) or (l) with a suitable base to afford exametazime and,
- n) optionally, purifying the exametazime.
An improved process for the preparation of exametazime (formula I),
- which comprises the steps of:
- a) reacting 2,3-butanedione monoxime (formula II) with 2,2-dimethyl-1,3-propanediamine (formula III), in a suitable solvent, in presence of dehydrating agent to afford diimine derivative 4,8-diaza-3,6,6,9-tetramethylundecane-3,8-diene-2,10-dione bisoxime (formula IV),
- b) reducing diimine derivative 4,8-diaza-3,6,6,9-tetramethylundecane-3,8-diene-2,10-dione bisoxime (formula IV) with a suitable reducing agent in a suitable solvent to afford a mixture of ‘d’, ‘l’ and meso isomers,
- c) optionally, purifying the mixture of ‘d’, ‘l’ and meso isomers,
- d) treating the mixture of ‘d’, ‘l’ and meso isomers with d and l mixture of chiral resolving acid in a suitable solvent to afford acid addition salts and separating the acid addition salts of exametazime (d and l enantiomers),
- e) purifying the acid addition salts of exametazime (d and l enantiomers) obtained in step (d),
- f) treating the acid addition salts of exametazime with a suitable base to afford exametazime and,
- g) optionally purifying the exametazime.
An improved process for the preparation of exametazime (formula I),
- which comprises:
- a) treating a mixture of ‘d’, ‘l’ and meso isomers,
- with a d or l chiral resolving acid to form the corresponding acid addition salt,
- b) separating said one of the enantiomers of exametazime as acid addition salt,
- c) optionally, purifying the acid addition salt obtained in step (b),
- d) treating the mother liquor of step (b) with a suitable base,
- e) isolating a mixture of d′ or ‘l’ enantiomer and meso isomer,
- f) purifying the mixture obtained in step (e),
- g) treating the mixture from step (f) with l or d chiral resolving acid to form the corresponding acid addition salt and separating said other enantiomer of exametazime as an acid addition salt,
- h) optionally, purifying the acid addition salt obtained in step (g),
- i) mixing the acid addition salts of step (b) or (c) and step (g) or (h),
- j) optionally, purifying the mixture of acid addition salts obtained in step (i),
- k) treating the mixture of acid addition salts of step (i) or (j) with a suitable base to afford exametazime and,
- l) optionally, purifying the exametazime.
An improved process for the preparation of exametazime (formula I),
- which comprises:
- a) treating a mixture of ‘d’, ‘l’ and meso isomers,
- with d and l mixture of chiral resolving acid in a suitable solvent to afford acid addition salt,
- b) separating and purifying the acid addition salt of exametazime (d and l enantiomers) obtained in step (a),
- c) treating the acid addition salt of exametazime with a suitable base to afford exametazime and,
- d) optionally purifying the exametazime.
An improved process for the preparation of exametazime (formula I),
- which comprises:
- a) reducing diimine derivative 4,8-diaza-3,6,6,9-tetramethylundecane-3,8-diene-2,10-dione bisoxime (formula IV),
- with a suitable reducing agent in anhydrous alcohol or aqueous alcohol to afford a mixture of ‘d’, ‘l’ and meso isomers,
- b) converting the mixture of ‘d’, ‘l’ and meso isomers to exametazime.
The process according to any of the preceding claims, wherein the dehydrating agents is selected from calcium hydride, molecular sieves, magnesium sulphate and sodium sulphate.
The process according to any of the preceding claims, wherein the chiral resolving acid is selected from L-(+) tartaric acid, D-(−) tartaric acid, L-malic acid, D-malic acid, S-(+) mandelic acid, R-(−) mandelic acid, S-(+)-O-acetyl mandelic acid, R-(−)-O-acetyl mandelic acid, (−)-naproxen, (+)-naproxen, (1R)-(−)-camphor sulfonic acid, (1S)-(+)-camphor sulfonic acid, (1R)-(+)-bromocamphor-10-sulfonic acid, (1S)-(−)-bromocamphor-10-sulfonic acid, (−)-Dibenzoyl-L-tartaric acid, (−)-Dibenzoyl-L-tartaric acid monohydrate, (+)-Dibenzoyl-D-tartaric acid, (+)-Dibenzoyl-D-tartaric acid monohydrate, (+)-dipara-tolyl-D-tataric acid, (−)-dipara-tolyl-L-tataricacid, L(−)-pyroglutamic acid, L(+)-pyroglutamic acid, (+)-lactic acid, (−)-lactic acid, (S)-(+)-2-chloromandelic acid, (R)-(+2-chloromandelic acid.
The process according to any of the preceding claims, wherein the and ‘l’ mixture of chiral resolving acid is selected from (±) tartaric acid, (±) malic acid, (±) ascorbic acid, (±) mandelic acid, (±)-O-acetyl mandelic acid, (±) naproxen, (±) camphor sulfonic acid, (±) bromocamphor-10-sulfonic acid, (±) Dibenzoyl-tartaric acid, (±) dipara-tolyl-tataric acid, (±) pyroglutamic acid, (±) lactic acid, (±)-2-chloromandelic acid.
The process according to any of the preceding claims, wherein the suitable bases is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, either alone or as their aqueous solutions.
The process according to any of the preceding claims, wherein the suitable solvents is selected from nitriles, alcohols, esters, halogenated hydrocarbons, ethers, amides, dialkylsulfoxides, hydrocarbons, water or the mixtures thereof;
- proviso that ketones/nitriles are not used during the reduction reaction of diimine derivative 4,8-diaza-3,6,6,9-tetramethylundecane-3,8-diene-2,10-dione bisoxime (formula IV);
- and water is avoided in condensation of 2,3-butanedione monoxime (formula II) with 2,2-dimethyl-1,3-propanediamine (formula III).
Dependencies are inferred from the claim text.