WO1998028261A1 - A process for the purification of an intermediate useful in the synthesis of iodinated contrast media - Google Patents
A process for the purification of an intermediate useful in the synthesis of iodinated contrast media Download PDFInfo
- Publication number
- WO1998028261A1 WO1998028261A1 PCT/EP1997/007077 EP9707077W WO9828261A1 WO 1998028261 A1 WO1998028261 A1 WO 1998028261A1 EP 9707077 W EP9707077 W EP 9707077W WO 9828261 A1 WO9828261 A1 WO 9828261A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- water
- soluble
- compound
- purification
- alcohol solvent
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having carbon atoms of carboxamide groups, amino groups and at least three atoms of bromine or iodine, bound to carbon atoms of the same non-condensed six-membered aromatic ring
Definitions
- the present invention relates to a process for the purification of an intermediate useful in the synthesis of iodinated contrast media, more particularly to a process for the purification of the compound -5-(2- acetoxy-propionylamino)-2,4,6-triiodo-isophthaloyl di- chloride (hereinafter referred to as compound A).
- Compound A disclosed in British Patent n° 1,472,050 (Savac AG), is an intermediate for the synthesis of ( S )-N,N ' -bis[2-hydroxy-( 1-hydroxymethyl )- ethyl]-5-( 2-hydroxypropionylamino )-2 ,4 , 6-triiodo-iso- phthalamide, an X-ray non-ionic contrast medium, also known under the non-proprietary name iopamidol.
- the industrial synthesis of compound A still follows the synthetic scheme disclosed in British Patent n° 1,472,050, consisting in the following steps:
- the recovery of crude compound A according to what described in British Patent n. 1,472,050 is effected by partial evaporation of the solvent, treatment with water and ice and filtration of the crystalline precipitate which has however to be further purified by suspension in warm chloroform.
- the warm treatment with a chlorinated, highly toxic solvent is clearly industrially unsuitable from the economic and environmental point of views.
- the resulting compound A is particularly pure, having a high enantiomeric purity, i.e. an e. e. higher than 92%.
- the water-soluble C 2 ⁇ C 5 alcohol solvent is selected from propanol, isopropanol, n-butanol, sec-butanol, isobutanol, tert-butanol , 2-ethoxyethanol ( cellosolve ) , 2-methoxyethanol ( ethylcellosolve ) .
- 2-Ethoxyethanol (cellosolve) is preferably used.
- the amount of water- soluble C,-Cr alcohol solvent generally ranges from 20% to 80% on the basis of the reaction mixture volume, preferably from 40% to 60%.
- the dilution of the reaction mixture with a water-soluble C 3 -C 5 alcohol solvent is carried out at low temperatures, generally from 0°C to 20°C, preferably from 5°C to 10°C.
- the resulting solution is added to a water amount 2-5 times the volume of the solution itself.
- the addition to water is carried out at a temperature from 10°C to 20°C, preferably from 15°C to 20°C.
- the resulting suspension is filtered to obtain pure compound A.
- the whole purification process is extremely simple and involves no separation of the phases, i.e. it makes use of water-soluble organic solvents.
- the solvent used in the purification process of the present invention is an alcohol solvent which could react directly with compound A thus yielding side- products.
- compound A is obtained in a pure form.
- this process allows to obtain compound A with a high enantio eric purity, i.e. an enantiomeric purity degree suitable for the subsequent use in the synthesis of iopamidol, to obtain iopamidol with a rotatory power fulfilling the requirements of Pharmacopoeia.
- the process of the invention is also suitable for the purification and the recovery of compound A from reaction mixtures containing halo acids.
- a further object of the invention is a process for the preparation of iopamidol, which process comprises the preparation of compound L-5-( 2-acetoxypropio- nylamino)-2,4, 6-triiodoisophthaloyl dichloride by reaction between L-2-acetoxypropionyl chloride and 5- amino-2,4,6-triiodo-isophthaloyl dichloride in N,N- dimethylaceta ide and the purification thereof diluting the reaction mixture with a water-soluble 3 ⁇ C 5 alcohol solvent, adding the resulting solution to a suitable amount of water and filtering.
- the present invention is further illustrated by the following example.
- Example L-2-acetoxypropionyl chloride (2 g; 166 mmoles) is added in 15 minutes to N,N-dimethylacetamide (23 ml), keeping the temperature at 10 - 15°C. The solution is heated to 23°C and, keeping this temperature, a solution of 5-ammmino-2 , 4 , 6-triiodoisophthaloyl dichloride (50 g; 84 mmoles) in N,N-dimethylacetamide (75 ml) is added in 6 hours. When the addition is completed, the mixture is kept under stirring for 15 hours. After this time, the starting product is lower than 1%.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Removal Of Specific Substances (AREA)
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP97953838A EP0888287A1 (en) | 1996-12-24 | 1997-12-17 | A process for the purification of an intermediate useful in the synthesis of iodinated contrast media |
AU57590/98A AU5759098A (en) | 1996-12-24 | 1997-12-17 | A process for the purification of an intermediate useful in the synthesis of iodinated contrast media |
NO983872A NO308698B1 (en) | 1996-12-24 | 1998-08-21 | A method of purifying an intermediate useful in the synthesis of iodinated contrast agents, as well as a method of preparing Iopamidol |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ITMI96A002737 | 1996-12-24 | ||
IT96MI002737A IT1289521B1 (en) | 1996-12-24 | 1996-12-24 | INTERMEDIATE PURIFICATION PROCESS |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1998028261A1 true WO1998028261A1 (en) | 1998-07-02 |
Family
ID=11375488
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1997/007077 WO1998028261A1 (en) | 1996-12-24 | 1997-12-17 | A process for the purification of an intermediate useful in the synthesis of iodinated contrast media |
Country Status (7)
Country | Link |
---|---|
EP (1) | EP0888287A1 (en) |
AU (1) | AU5759098A (en) |
IN (1) | IN184019B (en) |
IT (1) | IT1289521B1 (en) |
NO (1) | NO308698B1 (en) |
WO (1) | WO1998028261A1 (en) |
ZA (1) | ZA9711505B (en) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1472050A (en) * | 1974-12-13 | 1977-04-27 | Savac Ag | Non-ionic x-ray contrast agents |
GB2271990A (en) * | 1992-10-27 | 1994-05-04 | Zambon Spa | Process for the preparation of L-5-(2-acetoxy-propionyl-amino)-2,4,6-triiodo- isophthalic acid dichloride |
WO1996037460A1 (en) * | 1995-05-23 | 1996-11-28 | Fructamine S.P.A. | Process for the preparation of a dicarboxylic acid dichloride |
-
1996
- 1996-12-24 IT IT96MI002737A patent/IT1289521B1/en active IP Right Grant
-
1997
- 1997-12-17 EP EP97953838A patent/EP0888287A1/en not_active Withdrawn
- 1997-12-17 AU AU57590/98A patent/AU5759098A/en not_active Abandoned
- 1997-12-17 WO PCT/EP1997/007077 patent/WO1998028261A1/en not_active Application Discontinuation
- 1997-12-22 IN IN2960MA1997 patent/IN184019B/en unknown
- 1997-12-22 ZA ZA9711505A patent/ZA9711505B/en unknown
-
1998
- 1998-08-21 NO NO983872A patent/NO308698B1/en not_active IP Right Cessation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1472050A (en) * | 1974-12-13 | 1977-04-27 | Savac Ag | Non-ionic x-ray contrast agents |
GB2271990A (en) * | 1992-10-27 | 1994-05-04 | Zambon Spa | Process for the preparation of L-5-(2-acetoxy-propionyl-amino)-2,4,6-triiodo- isophthalic acid dichloride |
WO1996037460A1 (en) * | 1995-05-23 | 1996-11-28 | Fructamine S.P.A. | Process for the preparation of a dicarboxylic acid dichloride |
Also Published As
Publication number | Publication date |
---|---|
ITMI962737A1 (en) | 1998-06-24 |
IN184019B (en) | 2000-06-03 |
EP0888287A1 (en) | 1999-01-07 |
ZA9711505B (en) | 1998-06-25 |
IT1289521B1 (en) | 1998-10-15 |
NO983872L (en) | 1998-10-22 |
AU5759098A (en) | 1998-07-17 |
NO983872D0 (en) | 1998-08-21 |
NO308698B1 (en) | 2000-10-16 |
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