EP0888287A1 - Procede destine a la purification d'un produit intermediaire convenant a la synthese de milieux de contraste iodes - Google Patents

Procede destine a la purification d'un produit intermediaire convenant a la synthese de milieux de contraste iodes

Info

Publication number
EP0888287A1
EP0888287A1 EP97953838A EP97953838A EP0888287A1 EP 0888287 A1 EP0888287 A1 EP 0888287A1 EP 97953838 A EP97953838 A EP 97953838A EP 97953838 A EP97953838 A EP 97953838A EP 0888287 A1 EP0888287 A1 EP 0888287A1
Authority
EP
European Patent Office
Prior art keywords
water
soluble
compound
purification
alcohol solvent
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Withdrawn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
EP97953838A
Other languages
German (de)
English (en)
Inventor
Marco Villa
Maurizio Paiocchi
Fabio Benedetti
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.)
Bracco International BV
Original Assignee
Bracco International BV
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 Bracco International BV filed Critical Bracco International BV
Publication of EP0888287A1 publication Critical patent/EP0888287A1/fr
Withdrawn legal-status Critical Current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
    • C07C231/22—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

L'invention concerne un procédé destiné à la purification du composé dichlorure de L-5-(2-acétoxypropionylamino)-2,4,6-triiodoisophtaloyle, réalisée par traitement avec un solvant alcool en C3-C5 hydrosoluble et de l'eau.
EP97953838A 1996-12-24 1997-12-17 Procede destine a la purification d'un produit intermediaire convenant a la synthese de milieux de contraste iodes Withdrawn EP0888287A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
ITMI962737 1996-12-24
IT96MI002737A IT1289521B1 (it) 1996-12-24 1996-12-24 Processo per la purificazione di un intermedio
PCT/EP1997/007077 WO1998028261A1 (fr) 1996-12-24 1997-12-17 Procede destine a la purification d'un produit intermediaire convenant a la synthese de milieux de contraste iodes

Publications (1)

Publication Number Publication Date
EP0888287A1 true EP0888287A1 (fr) 1999-01-07

Family

ID=11375488

Family Applications (1)

Application Number Title Priority Date Filing Date
EP97953838A Withdrawn EP0888287A1 (fr) 1996-12-24 1997-12-17 Procede destine a la purification d'un produit intermediaire convenant a la synthese de milieux de contraste iodes

Country Status (7)

Country Link
EP (1) EP0888287A1 (fr)
AU (1) AU5759098A (fr)
IN (1) IN184019B (fr)
IT (1) IT1289521B1 (fr)
NO (1) NO308698B1 (fr)
WO (1) WO1998028261A1 (fr)
ZA (1) ZA9711505B (fr)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH608189A5 (fr) * 1974-12-13 1978-12-29 Savac Ag
IT1256162B (it) * 1992-10-27 1995-11-29 Zambon Spa Processo per la preparazione di un intermedio della sintesi organica
CN1068582C (zh) * 1995-05-23 2001-07-18 弗鲁克泰明公司 制备二酰氯的方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9828261A1 *

Also Published As

Publication number Publication date
NO983872D0 (no) 1998-08-21
WO1998028261A1 (fr) 1998-07-02
NO983872L (no) 1998-10-22
NO308698B1 (no) 2000-10-16
AU5759098A (en) 1998-07-17
ITMI962737A1 (it) 1998-06-24
ZA9711505B (en) 1998-06-25
IT1289521B1 (it) 1998-10-15
IN184019B (fr) 2000-06-03

Similar Documents

Publication Publication Date Title
JP4545945B2 (ja) イオジキサノールの製造
USRE36433E (en) Process for the purifying of iopamidol
CA2389379C (fr) Elaboration de 5-carboxyphtalure
AU2005257478B2 (en) Method for producing (Z)-1-phenyl-1-diethylaminocarbonyl-2-aminomethyl cyclopropane hydrochloride
AU2002229575B2 (en) A process for the preparation of 1-(aminomethyl) cyclohexaneacetic acid
EP0888287A1 (fr) Procede destine a la purification d'un produit intermediaire convenant a la synthese de milieux de contraste iodes
CA2543275C (fr) Procede de preparation de la gabapentine
US5817861A (en) Process for the preparation of an intermediate useful in the synthesis of iodinated contrast media
EP0900196A1 (fr) Procede destine a la preparation d'un produit intermediaire utile pour la synthese de milieux de contraste iodes
US5091540A (en) Process for preparing clotrimazole
US20050119351A1 (en) Polymorphic forms of sertraline hydrochloride
JP3042122B2 (ja) Ｎ−シアノアセトアミジン誘導体の製造方法
JP4408634B2 (ja) ニトロイソキノリンの異性体分離方法
JP2000505064A (ja) アミンのラセミ化法
EP0901461B1 (fr) Procede de preparation d'un produit intermediaire utile pour la synthese de milieux de contraste iodes
US6008413A (en) Process for recrystallizing 1,3-bis(aminophenoxy benzene)
US4945161A (en) Process for the preparation of N,N'-bis-(2-hydroxy-ethyl) piperazine
CN115197099A (zh) N-Boc-1，4-苯二胺的制备方法
JPH10101629A (ja) 光学活性酪酸誘導体の製造方法
JPH11335351A (ja) Ｎ−カルボベンゾキシ−ｓ−フェニルシステインの精製方法
JP2000128826A (ja) ｍ−ハロゲノ安息香酸類の精製方法
CA2448300A1 (fr) Procede de preparation d'intermediaires de sertraline
NO327534B1 (no) Fremgangsmate for fremstilling av salter av cyanobenzylamin
JPH05140120A (ja) ２−ヒドロキシキノキサリンの新規製造法
JP2001199969A (ja) キナゾリン化合物の製造方法およびその精製方法

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: 19980826

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): DE ES FR GB IE IT NL PT

17Q First examination report despatched

Effective date: 19991021

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: 20000502