WO1999026916A1 - N-alkylation de 5-amino-2,4,6-triodo-isophtalamides - Google Patents

N-alkylation de 5-amino-2,4,6-triodo-isophtalamides Download PDF

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Publication number
WO1999026916A1
WO1999026916A1 PCT/GB1998/003535 GB9803535W WO9926916A1 WO 1999026916 A1 WO1999026916 A1 WO 1999026916A1 GB 9803535 W GB9803535 W GB 9803535W WO 9926916 A1 WO9926916 A1 WO 9926916A1
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WO
WIPO (PCT)
Prior art keywords
isophthalamide
acylamino
triiodo
dihydroxypropyl
ionic
Prior art date
Application number
PCT/GB1998/003535
Other languages
English (en)
Inventor
Robert W. Erwin
Christopher Kopach
William H. Thielking
Original Assignee
Nycomed Imaging As
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Nycomed Imaging As filed Critical Nycomed Imaging As
Priority to EP98955788A priority Critical patent/EP1051391A1/fr
Priority to AU12513/99A priority patent/AU1251399A/en
Publication of WO1999026916A1 publication Critical patent/WO1999026916A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups

Definitions

  • the invention relates to a process for the N-alkylation of a non-ionic 5-amino 2 , 4 , 6-triiodo-isophthalamide by base-catalysed reactions with an oxirane.
  • non-ionic iodinated aromatic compounds as contrast agents in X-ray imaging (eg. CT-imaging) is well established.
  • contrast agents are available commercially, eg. iohexol, iopentol, ioxilan, iodixanol, iopamidol and ioversol .
  • the non-ionic iodinated contrast agents have to a large extent replaced the earlier generation ionic contrast agents, at least for parenteral use.
  • the X-ray opacity of such agents derives from the presence of the iodine atom in the contrast agent molecule
  • the water-solubility of the non-ionic agents derives from the substitution of the aromatic ring with polyhydroxyalkyl groups.
  • the aromatic ring carries three 2,3- dihydroxypropyl groups (as substituents on amide nitrogens) .
  • this 2 , 3 -dihydroxypropyl group is introduced by reaction of a 5-acylamino-2 , 4 , 6-triiodo- isophthalamide with chloro-2 , 3 -propanediol (CPD) in the presence of a base (eg. NaOH) .
  • CPD chloro-2 , 3 -propanediol
  • a base eg. NaOH
  • This procedure results in the formation of equimolar quantities of salt which must be removed from the reaction product before it can be used as a non- ionic contrast agent or before it can be used in further process steps. Since the reaction product is highly water soluble, this removal of salt is -not a trivial problem and requires the use of resin treatment and alcoholic work-up or of reverse osmosis.
  • salt by-products are significantly more problematical with the non-ionic iodinated contrast agents than with the earlier ionic agents as the option to purify by crystallization is not so readily available.
  • solubility of the non-ionic iodinated contrast agents in water is similar to that of salt and so fractional crystalization is not a useful option.
  • the present invention addresses the problem of salt generation in the N-2 , 3-dihydroxypropylation of 5- acylamino-2 , 4 , 6-triiodo-N,N' -disubstituted isophthalamides .
  • the invention provides a process for the preparation of a non-ionic 5-(N-2,3- dihydroxypropyl-acylamino) -2,4, 6-triiodo-N,N' - disubstituted- isophthalamide which process comprises reacting a non-ionic 5-acylamino-2 , 4 , 6-triiodo-N,N' - disubstituted- isophthalamide with an oxirane (eg. glycidol) in a solvent and in the presence of up to 7 mole percent (relative to the 5-acylamino reagent), eg. 0.01 to 7 mole percent, of a strong base.
  • an oxirane eg. glycidol
  • the process of the invention makes it possible to quench in a controlled way the excess alkoxide anion which is formed in the reaction, leaving enough unquenched to remove acidic protons or nitrogens and providing the appropriate amount of acetyl-N anion to achieve selectivity. It is thus possible to achieve selectivity with a good reaction rate without provoking undesired side-reactions.
  • the 5-acylamino- isophthalamide starting reagent in the process of the invention is preferably a compound of formula I
  • R 1 is an acyl group, preferably a formyl group or a (C 1 _ 6 alkyl) -carbonyl group in which the alkyl moiety is optionally hydroxy substituted, eg. a formyl, acetyl, propionyl , lactoyl, glycoloyl, or glyceroyl group;
  • R 2 is an oxirane-reactive (eg. glycidol-reactive) group or atom, preferably a hydrogen atom;
  • each R 3 which may be the same or different, is ⁇ . 6 acyl or alkyl group, preferably an acetyl or alkyl group, particularly preferably a polyhydroxyalkyl group, eg. 2 , 3-dihydroxypropyl , 1 , 3-dihydroxyprop-2-yl , 2-hydroxy-3-methoxypropyl, 2 , 3 -dihydroxy-1- hydroxymethylpropyl and 2 -hydroxyethyl ) .
  • the other reagent is glycidol of formula II
  • the starting 5-acylamino-isophthalamide is particularly preferably 5-acetylamino-2 , 4 , 6-triiodo-N,N' -bis (2,3- dihydroxypropyl ) -isophthalamide.
  • the process of the invention is preferably performed in an aqueous or alkanolic solvent or solvent mixture (eg. water, methanol , 2-methoxyethanol , t-butanol, diglyme, etc.) or in a dipolar aprotic solvent or solvent mixture (eg. acetone, DMSO, DMF, DMAc etc.) or in a mixture of such solvents (eg. water/acetone, etc.) .
  • aqueous or alkanolic solvent or solvent mixture eg. water, methanol , 2-methoxyethanol , t-butanol, diglyme, etc.
  • a dipolar aprotic solvent or solvent mixture eg. acetone, DMSO, DMF, DMAc etc.
  • Tertiary alcohols in general eg. t-butanol
  • the reaction product is typically highly soluble in such solvents and solvent mixtures, indeed it is generally more soluble than the 5-acylamino- isophthal
  • the quantity of solvent used may if desired be minimized, eg. being selected to be sufficient to maintain the reaction product in solution at the reaction temperature.
  • the 5-acylamino-isophthalamide and glycidol reagents are conveniently used in molar ratio of from 2:1 to 1:2, preferably 1:1 to 1:1.3, especially preferably about 1:1 to 1:1.1. These reagents are advantageously present in the reaction medium at a concentration of from 0.9 to 2M, especially 1.0 to 1.5M.
  • the base used to catalyse the process of the invention is a strong base, eg. NaOH, KOH, Mg(OH) 2 , triethylamine, BuLi , sodium methoxide, sodium ethoxide, sodium propoxide, potassium tert .butoxide .
  • Sodium and potassium hydroxides and alkoxides are particularly suitable.
  • it should be a base which is physiologically tolerable or which has physiologically tolerable neutralisation products or which is readily removed from the reaction product, eg. by solvent separation techniques, or by application of reduced pressure, eg. the base is quenched out in the water soluble phase after the reaction is completed.
  • the base is triethylamine.
  • the base is a material which does not separate out from the reaction mixture with the N-alkylated reaction product.
  • the base is used in catalytic quantities, eg. up to 7 mole %, preferably 0.01 to 7 mole %, more preferably 0.05 to 5 mole %, especially 0.5 to 4, more especially 1.0 to 3.5 mole % relative to the 5-acylamino- isophthalamide starting reagent.
  • the reaction between the glycidol and 5-acylamino- isophthalamide is conveniently effected at ambient or slightly elevated temperatures, eg. 10 to 50°C, preferably 15 to 30°C, especially preferably 20 to 25°C.
  • the reaction is allowed to proceed until analysis of samples of the reaction mixture shows the concentrations of reagents and reaction product to have stabilized.
  • the reaction time may be a period of hours, eg. 6 to 20 hours.
  • the reaction may be terminated by warming the reaction mixture eg. to 50 to 70°C, especially about 60°C and diluting it with a solvent in which the reaction product is less soluble whereby to cause the reaction product to separate out .
  • the reaction product By adding a solvent which reduces the solubility of the N-2 , 3-dihydroxypropylated reaction product in the solvent system, the reaction product (and the 5- acylamino- isophthalamide reagent) can be caused to separate out from the solvent system while leaving the base catalyst and any excess unreacted glycidol in solution; in this way a substantially base- free reaction product can be obtained without requiring particularly extensive work-up.
  • reaction product can then be worked-up and purified in conventional fashion, for example by recrystallization of unreacted 5 -acylamino reagent from a solvent such as water or an alkanol, followed by solvent evaporation to yield the reaction product.
  • a solvent such as water or an alkanol
  • reaction mixture was then warmed to 60 °C and diluted with 400 mL of isopropanol .
  • An oily product separated out and solidified upon cooling.
  • the liquor was decanted and the solid product was dissolved in warm water, seeded with 5-acetamino-2 , 4 , 6-triiodo-N,N' - bis (2 , 3 -dihydroxypropyl) -isophthalamide and chilled in an ice bath.
  • a solid crystallized and was separated off by filtration. (This solid was 22.5 gram of unreacted

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

Cette invention se rapporte à un procédé servant à préparer un 5-(N-2, 3-dihydroxypropyl -acylamino)-2,4, 6-tri-iodo-N,N'-disubstitué -isophtalamide non ionique, ce procédé consistant à faire réagir un 5-acylamino-2, 4,6-tri-iodo-N, N'-disubstitué -isophtalamide non ionique avec un oxirane dans un solvant et en présence d'une base forte dans une proportion maximum de 7 % en mole.
PCT/GB1998/003535 1997-11-26 1998-11-26 N-alkylation de 5-amino-2,4,6-triodo-isophtalamides WO1999026916A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP98955788A EP1051391A1 (fr) 1997-11-26 1998-11-26 N-alkylation de 5-amino-2,4,6-triodo-isophtalamides
AU12513/99A AU1251399A (en) 1997-11-26 1998-11-26 N-alkylation of 5-amino-2,4,6-triiodo-isophthalamides

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9725010.4A GB9725010D0 (en) 1997-11-26 1997-11-26 Process
GB9725010.4 1997-11-26

Publications (1)

Publication Number Publication Date
WO1999026916A1 true WO1999026916A1 (fr) 1999-06-03

Family

ID=10822683

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1998/003535 WO1999026916A1 (fr) 1997-11-26 1998-11-26 N-alkylation de 5-amino-2,4,6-triodo-isophtalamides

Country Status (4)

Country Link
EP (1) EP1051391A1 (fr)
AU (1) AU1251399A (fr)
GB (1) GB9725010D0 (fr)
WO (1) WO1999026916A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005003080A1 (fr) * 2003-07-03 2005-01-13 Amersham Health As Procede de production d'iohexol
JP2009517373A (ja) * 2005-11-24 2009-04-30 ホビオネ インテル リミテッド イオヘキソールの製造方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2726196A1 (de) * 1976-06-11 1977-12-22 Nyegaard & Co As Jodhaltige isophthalamidderivate, deren herstellung und radiologische mittel
WO1996040286A1 (fr) * 1995-06-07 1996-12-19 Mallinckrodt Medical, Inc. Procede de production de l'ioversol
WO1997027172A1 (fr) * 1996-01-29 1997-07-31 Mallinckrodt Medical, Inc. Procede de preparation d'ioversol

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2726196A1 (de) * 1976-06-11 1977-12-22 Nyegaard & Co As Jodhaltige isophthalamidderivate, deren herstellung und radiologische mittel
WO1996040286A1 (fr) * 1995-06-07 1996-12-19 Mallinckrodt Medical, Inc. Procede de production de l'ioversol
WO1997027172A1 (fr) * 1996-01-29 1997-07-31 Mallinckrodt Medical, Inc. Procede de preparation d'ioversol

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005003080A1 (fr) * 2003-07-03 2005-01-13 Amersham Health As Procede de production d'iohexol
JP2009517373A (ja) * 2005-11-24 2009-04-30 ホビオネ インテル リミテッド イオヘキソールの製造方法

Also Published As

Publication number Publication date
EP1051391A1 (fr) 2000-11-15
AU1251399A (en) 1999-06-15
GB9725010D0 (en) 1998-01-28

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