EP1051391A1 - N-alkylation of 5-amino-2,4,6-triiodo-isophthalamides - Google Patents

N-alkylation of 5-amino-2,4,6-triiodo-isophthalamides

Info

Publication number
EP1051391A1
EP1051391A1 EP98955788A EP98955788A EP1051391A1 EP 1051391 A1 EP1051391 A1 EP 1051391A1 EP 98955788 A EP98955788 A EP 98955788A EP 98955788 A EP98955788 A EP 98955788A EP 1051391 A1 EP1051391 A1 EP 1051391A1
Authority
EP
European Patent Office
Prior art keywords
isophthalamide
acylamino
triiodo
dihydroxypropyl
ionic
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.)
Withdrawn
Application number
EP98955788A
Other languages
German (de)
French (fr)
Inventor
Robert W. Erwin
Christopher Kopach
William H. Thielking
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
GE Healthcare AS
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
Publication of EP1051391A1 publication Critical patent/EP1051391A1/en
Withdrawn legal-status Critical Current

Links

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

The present 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 in a solvent and in the presence of up to 7 mole percent of a strong base.

Description

N-Alkylation of 5-Amino-2.4 , 6- triodo-isophthalaπri rl p
Field of the Invention
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.
Background to the Invention
The use of non-ionic iodinated aromatic compounds as contrast agents in X-ray imaging (eg. CT-imaging) is well established. Several such 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.
While 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. By way of example in the case of iohexol, the aromatic ring carries three 2,3- dihydroxypropyl groups (as substituents on amide nitrogens) .
In the commercial manufacture of iohexol, and other non- ionic X-ray contrast agents, one of these 2 , 3-dihydroxy- propyl groups is introduced in one of the final steps in the multistep synthesis of the chemical drug product.
Conventionally, 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) . This procedure however 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. It should be noted that 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. Moreover the 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.
In any commercial process for pharmaceutical preparation, there is a need to maximize product yield, avoid the production of impurities and optimize the use of reactors and work-up apparatus .
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 .
Summary of the Invention
Thus viewed from one aspect 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. Surprisingly, 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.
Detailed Description of the Invention
The 5-acylamino- isophthalamide starting reagent in the process of the invention is preferably a compound of formula I
(where R1 is an acyl group, preferably a formyl group or a (C1_6 alkyl) -carbonyl group in which the alkyl moiety is optionally hydroxy substituted, eg. a formyl, acetyl, propionyl , lactoyl, glycoloyl, or glyceroyl group;
R2 is an oxirane-reactive (eg. glycidol-reactive) group or atom, preferably a hydrogen atom; and
each R3, which may be the same or different, is λ.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
O )H or an oxirane, eg. oxirane or a 2-acyl-oxirane .
Using a starting material of formula I and glycidol, the N-alkylated product is of formula III
(where R1 and R3 are as defined above) .
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.) . Tertiary alcohols in general (eg. t-butanol) are usable as solvents. The reaction product is typically highly soluble in such solvents and solvent mixtures, indeed it is generally more soluble than the 5-acylamino- isophthalamide reagent and thus the reaction can be performed with the reagents in solution or in a slurry.
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. Particularly desirably 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. Especially preferably, the base is triethylamine.
Particularly preferably, 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. Typically, 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 .
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.
The 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.
In this way the use of expensive deionizing techniques, such as reverse osmosis or the use of ion exchange resins, required by the conventional N-2,3- dihydroxypropylation processes is avoided.
The invention will now be described further with reference to the following non-limiting Example. Example 1
5- (N-2.3 -dihydroxypropyl-acetamino) -2,4, 6-triiodo-N, N1 - bis (2 , 3 -dihydroxypropyl) -isophthalamide
74.7 grams of 5-acetamino-2 , 4 , 6-triiod©-N,N ' -bis (2 , 3- dihydroxypropyl ) -isophthalamide, 75 mL dimethyl - sulphoxide, and 7 mL triethylamine was stirred and warmed to 70-80°C before being cooled to ambient temperature. A single addition of 7 mL of glycidol was made and the reaction mixture was stirred overnight.
The 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
5 -acetamino-2 , 4 , 6-triiodo-N,N' -bis (2 , 3 -dihydroxypropyl) - isophthalamide .
The filtrate was evaporated down to leave the title compound as a residual oil weighing 56.7 grams.

Claims

Claims
1. 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, preferably glycidol, in a solvent and in the presence of up to 7 mole percent, relative to the 5-acylamino isophthalamide, of a strong base.
2. A process as claimed in claim 1 wherein said 5- acylamino- isophthalamide is a compound of formula I
(where R1 is an acyl group, preferably a formyl group or a (C^g alkyl) -carbonyl group in which the alkyl moiety is optionally hydroxy substituted;
R2 is a glycidol-reactive group or atom, preferably a hydrogen atom; and
each R3, which may be the same or different, is an optionally hydoxylated C^g acyl or alkyl group) .
3. A process as claimed in claim 1 for the preparation of 5- (N-2 , 3 -dihydroxypropyl -acetamino) -2,4, 6-triiodo- N,N' -bis (2 , 3 -dihydroxypropyl) -isophthalamide wherein said 5 -acylamino- isophthalamide is 5-acetamino-2 , 4 , 6- triiodo-N,N' -bis (2 , 3 -dihydroxypropyl) -isophthalamide .
4. A process as claimed in any one of claims 1 to 3 wherein as said base is used 0.01 to 7 mole % of a strong base .
5. A process as claimed in claim 4 wherein said base comprises triethylamine.
EP98955788A 1997-11-26 1998-11-26 N-alkylation of 5-amino-2,4,6-triiodo-isophthalamides Withdrawn EP1051391A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9725010 1997-11-26
GBGB9725010.4A GB9725010D0 (en) 1997-11-26 1997-11-26 Process
PCT/GB1998/003535 WO1999026916A1 (en) 1997-11-26 1998-11-26 N-alkylation of 5-amino-2,4,6-triiodo-isophthalamides

Publications (1)

Publication Number Publication Date
EP1051391A1 true EP1051391A1 (en) 2000-11-15

Family

ID=10822683

Family Applications (1)

Application Number Title Priority Date Filing Date
EP98955788A Withdrawn EP1051391A1 (en) 1997-11-26 1998-11-26 N-alkylation of 5-amino-2,4,6-triiodo-isophthalamides

Country Status (4)

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

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NO20033058D0 (en) * 2003-07-03 2003-07-03 Amersham Health As Process
PT103391B (en) * 2005-11-24 2008-10-30 Hovione Farmaciencia S A LOHEXOL MANUFACTURING PROCESS

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1548594A (en) * 1976-06-11 1979-07-18 Nyegaard & Co As Triiodoisophthalic acid amides
US5648536A (en) * 1995-06-07 1997-07-15 Dunn; Thomas Jeffrey Process for producing ioversol
US6596904B1 (en) * 1996-01-29 2003-07-22 Mallinc Krodt Inc Process for producing ioversol

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9926916A1 *

Also Published As

Publication number Publication date
AU1251399A (en) 1999-06-15
GB9725010D0 (en) 1998-01-28
WO1999026916A1 (en) 1999-06-03

Similar Documents

Publication Publication Date Title
US5886219A (en) Process for preparing malonic acid and alkylmalonic acids
RU2237655C2 (en) Method for preparing l-phenylephrine hydrochloride
EP0192480B1 (en) Bis(3-aminophenoxy) aromatics and method of preparing the same
JP4540233B2 (en) Method for producing iopamidol
EP0895985B1 (en) Method for producing 2,2-bis(3-amino-4-hydroxyphenyl)-1,1,1,3,3,3-hexafluoropropane
AU2002226359B8 (en) A process for the preparation of N,N'-substituted 5-amino-1,3-benzenedicarboxamides
AU2002226359A1 (en) A process for the preparation of N,N'-substituted 5-amino-1,3-benzenedicarboxamides
AU2010224945B2 (en) Process for the preparation of triiodinated carboxylic aromatic derivatives
AU723184B2 (en) Process for iohexol manufacture
EA005922B1 (en) A process for the preparation of iopamidol and the new intermediates therein
WO1999026916A1 (en) N-alkylation of 5-amino-2,4,6-triiodo-isophthalamides
KR100539647B1 (en) Process for the Preparation of Contrast Agents
US5840967A (en) Process for the preparation of contrast agents
US5763663A (en) Process for the manufacturing of iodinated contrast agents
JP3985034B2 (en) Iodination method
EP2593423B1 (en) Process for the preparation of contrast agents
JPH05213837A (en) Preparation of arylalkanolamine
KR100567449B1 (en) Process for preparing Iodixanol
US5159101A (en) Cyanoethylation of alcohols
KR960007801B1 (en) Preparation of unionic iodine-containing x-ray contrast agents
WO2001058848A1 (en) A process for the purification of 3-amino-1,2-propanediol and 2-amino-1,3-propanediol
US5202488A (en) Method for the manufacture of 3-aminophenol
KR100574087B1 (en) Process for the preparing Iodixanol as X-ray contrast media
JP2765696B2 (en) Method for producing 5-amino-2,4,6-triiodoisophthalic acid
JPH072809A (en) New process for producing aminothiazoleacetic acid derivative

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20000420

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20020601