EP0628024A1 - Synthesis of ioversol using a minimal excess of acetoxyacetylchloride - Google Patents
Synthesis of ioversol using a minimal excess of acetoxyacetylchlorideInfo
- Publication number
- EP0628024A1 EP0628024A1 EP93907271A EP93907271A EP0628024A1 EP 0628024 A1 EP0628024 A1 EP 0628024A1 EP 93907271 A EP93907271 A EP 93907271A EP 93907271 A EP93907271 A EP 93907271A EP 0628024 A1 EP0628024 A1 EP 0628024A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- triiodoisophthalamide
- bis
- diacetoxypropyl
- reaction mixture
- organic 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- Withdrawn
Links
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
Definitions
- the present invention relates to the use of a minimal excess of acetoxyacetylchloride as a reagent in the synthesis of ioversol.
- Ioversol is disclosed as a useful nonionic x-ray contrast agent in U.S. Patent No. 4,396,598.
- 5-acetoxyacetamido-N,N'-bis(2,3-diacetoxypropyl)-2,4,6-triiodoisophthalamide having the following structure:
- 5-acetoxyacetamido-N,N'-bis(2,3-diacetoxypropyl)-2,4,6-triiodoisophthalamide may be produced by adding acetoxyacetylchloride (AAC) to a N,N-dimethylacetamide and 1,1,2-trichloroethane solution of a compound of the following structure: and stirring until the reaction is complete. The reaction mixture is then diluted with 1,1,2-trichloroethane and extracted with aqueous sodium bicarbonate solutions and aqueous sodium chloride solutions.
- AAC acetoxyacetylchloride
- the dilution procedure using 1,1,2-trichloroethane may alternatively be carried out using an organic solvent such as, but not limited to, carbon tetrachloride, dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2-trichloroethylene, 1,1,2-trichloroethane, 1,1,1-trichloroethane and tetrachloroethylene, but most preferably 1,1,2-trichloroethane.
- an organic solvent such as, but not limited to, carbon tetrachloride, dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2-trichloroethylene, 1,1,2-trichloroethane, 1,1,1-trichloroethane and tetrachloroethylene, but most preferably 1,1,2-trichloroethane.
- the present invention is a method of producing ioversol using only approximately 7 to 36%, but preferably a 12% excess, of acetoxyacetylchloride (AAC) as opposed to a 100% excess as taught by prior art.
- AAC acetoxyacetylchloride
- the procedure begins with a solvent solution of 5-amino-N,N'-bis(2,3-diacetoxypropyl)-2,4,6-triiodoisophthalamide(1).
- Compound 1 may be prepared for use in this reaction by distilling off some of the solvent to remove and/or reduce impurities, or alternatively, the solvent solution may be used directly without distillation.
- N,N-dimethylacetamide (DMAC) and acetoxyacetylchloride (AAC), are then added to between 1 to 3 grams, but preferably 1.72 grams, of 5-amino-N,N'-bis(2,3-diacetoxypropyl)-2,4,6-triiodoisophthalamide (1) plus up to 5 milliliters, but preferably 1 milliliter of suitable solvent to form a highly concentrated solution.
- the concentrated solution is then stirred at a temperature within the range of 40° C to 66° C but preferably at the optimal temperature of 50°C, as opposed to the temperature of 37° C taught by prior art, until the reaction is complete.
- Hydrochloric acid is produced as a waste product of this reaction.
- the DMAC present in the solution is mildly basic and thereby reacts with the hydrochloric acid generated to form a DMAC ⁇ HCl complex. After dilution with an organic solvent, the reaction solution is extracted with aqueous sodium bicarbonate solution(s) and aqueous sodium chloride solution(s).
- the resulting 5-(acetoxyacetamido)-N,N' -bis (2 , 3-diacetoxypropyl) -2 , 4 , 6-triiodoisophthalamide(2) may be used without further purification as an intermediate in the production of N,N'-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)glycolamido]- 2,4,6-triiodoisophthalamide (ioversol) (4) according to the reactions illustrated in Scheme 1 below.
- the final product, ioversol (4), produced through the use of only a 12% excess of AAC has an equivalent or increased purity, approximately 95%, as compared to that produced through the use of 100% excess AAC as previously believed necessary to reach such levels of purity.
- AAC Acetoxyacetylchloride
- DMAC N,N-dimethylacetamide
- TCE 1,1,2-trichloroethane
- DMSO Dimethylsulfoxide
- AAC Acetoxyacetylchloride
- DMAC N,N-dimethylacetamide
- TCE 1,1,2-trichloroethane
- DMSO Dimethylsulfoxide
- AAC Acetoxyacetylchloride
- DMAC N,N-dimethylacetamide
- TCE 1,1,2-trichloroethane
- DMSO Dimethylsulfoxide
- AAC Acetoxyacetylchloride
- this particular method combines two reaction steps into one simplified reaction step, namely the production of 5-amino-N,N'-bis(2,3-diacetoxypropyl)-2,4,6-triiodoisophthalamide(1), in the production of ioversol(4).
- This step-saving and time-saving method begins by adding N,N-dimethyl-acetamide (DMAC) and acetoxyacetylchloride (AAC) to 5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (5) and stirring until the reaction is complete.
- DMAC N,N-dimethyl-acetamide
- AAC acetoxyacetylchloride
- Elimination of the need for the 100% excess of acetoxyacetylchloride is important to reduce the costs of production and to provide alternative routes of production for N,N'-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)-glycolamido]-2,4,6-triiodoisophthalamide(4). Additionally, the need for acetic anhydride is likewise eliminated through the process illustrated in Scheme 2 which reduces the cost of production even further.
- 5-acetoxyacetamido-N,N'-bis(2,3-diacetoxypropyl)-2,4,6-triiodoisophthalamide (2) may be prepared according to the present invention by first distilling off some of the solvents from 5-amino-N,N'-bis(2,3-diacetoxypropyl)-2,4,6-triiodoisophthalamide(1) to reduce and/or remove any solvent impurities therefrom. This distillation of solvent(s) from compound 1 is optional.
- N,N-dimethylacetamide (DMAC) and a 7 to 36%, but preferably a 12%, excess of acetoxyacetychloride is then added to the previously distilled solution and stirred at preferably 50°C until the acylation reaction is complete.
- the optimal temperature is within the range of 40° C to 66° C, however, 50° C was determined to be most preferable based on the experimental results illustrated in Table 1 below.
- An organic solvent such as for example toluene, a halocarbon solvent or a chlorocarbon solvent is used for the dilution.
- suitable solvents for dilution also include, but are not limited to carbon tetrachloride, dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2-trichloroethylene, 1,1,2-dichloroethane, 1,1,1-trichloroethane and tetrachloroethylene, but preferably 1,1,2-trichloroethane.
- the solvent is extracted with aqueous sodium bicarbonate solution(s) (preferably containing approximately 10-15% sodium bicarbonate) and/or aqueous sodium chloride solutions (preferably containing approximately 10-15% sodium chloride).
- aqueous sodium bicarbonate solution(s) preferably containing approximately 10-15% sodium bicarbonate
- aqueous sodium chloride solutions preferably containing approximately 10-15% sodium chloride
- the resulting 5-acetoxyacetamido-N,N'-bis(2,3-diacetoxypropyl)-2,4,6-triiodoisophthalamide(2) may be used as an intermediate to produce N,N'-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)glycolamido]-2,4,6-triiodoisophthalamide (ioversol) (4) as illustrated in Scheme 1 above.
- N,N'-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)glycolamido]-2,4,6-triiodoisophthalamide (ioversol) (4) from 5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide(5) stirred with acetoxyacetylchloride (AAC), N,N-dimethylacetamide (DMAC) and optionally 4-dimethylaminopyridine (DMAP) likewise may be used as an intermediate to produce ioversol as is illustrated in Scheme 2 above.
- AAC acetoxyacetylchloride
- DMAC N,N-dimethylacetamide
- DMAP 4-dimethylaminopyridine
- DMAC N,N-dimethyl-acetamide
- Acetoxyacetylchloride (0.55 g mole, 7.45 g) is added slowly with stirring and the reaction temperature is controlled at 40-66°C. After completing the addition, the reaction solution is allowed to stir at approximately 50°C to complete the reaction, i.e., approximately three hours.
- TCE 1,1,2-trichloroethane
- aqueous sodium carbonate solution approximately 0.6 moles, 52 g in a 13% w/v solution is slowly added to the stirred TCE solution at a rate which will maintain the temperature at less than 27°C.
- reaction mixture containing TCE, DMAC, AAC, 5-amino-N,N-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide is transferred to a separatory funnel and the organic layer is separated from the aqueous layer. The organic layer is washed with a 10% w/v sodium chloride solution in a similar manner.
- the resulting TCE solution of the product is suitable for conversion to N,N-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)glycolamido]-2,4,6-triiodoisophthalamide (ioversol) as shown in Scheme 2 above.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
L'invention se rapporte à l'utilisation d'un excédent minimal de chlorure d'acetoxyacétyle en tant que réactif dans la synthèse de N,N'-bis (2,3-dihydroxypopyle)-5-N-(2-hydroxyethyle) glycolamido-2,4,6-triiodoisophtalamide.The invention relates to the use of a minimum excess of acetoxyacetyl chloride as a reagent in the synthesis of N, N'-bis (2,3-dihydroxypopyle) -5-N- (2-hydroxyethyl) glycolamido-2,4,6-triiodoisophthalamide.
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US84404292A | 1992-02-28 | 1992-02-28 | |
PCT/US1993/002033 WO1993016981A1 (en) | 1992-02-28 | 1993-02-23 | Synthesis of ioversol using a minimal excess of acetoxyacetylchloride |
US844042 | 2001-04-27 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0628024A1 true EP0628024A1 (en) | 1994-12-14 |
EP0628024A4 EP0628024A4 (en) | 1995-03-22 |
Family
ID=25291646
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP93907271A Withdrawn EP0628024A4 (en) | 1992-02-28 | 1993-02-23 | Synthesis of ioversol using a minimal excess of acetoxyacetylchloride. |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0628024A4 (en) |
JP (1) | JPH07504419A (en) |
AU (1) | AU3793293A (en) |
CA (1) | CA2130829A1 (en) |
WO (1) | WO1993016981A1 (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IT1286522B1 (en) * | 1996-12-04 | 1998-07-15 | Dibra Spa | PROCESS FOR THE PREPARATION OF DERIVATIVES OF 5-AMINO-2,4,6- TRIIODO-1,3-BENZENEDICICARBOXYLIC ACID |
CN114409566B (en) * | 2022-01-17 | 2022-11-22 | 安庆朗坤药业有限公司 | Preparation method of ioversol hydrolysate |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4256729A (en) * | 1979-03-23 | 1981-03-17 | Mallinckrodt, Inc. | N,N'-Bis-(2,3-dihydroxypropyl)-2,4,6-triiodo-5-(2-keto-L-gulonamido)isophthalamide and radiological compositions containing same |
US5043152A (en) * | 1988-06-02 | 1991-08-27 | Guerbet S.A. | Novel iodinated non-ionic triiodobenzene compounds and contrast media containing them |
-
1993
- 1993-02-23 JP JP5515135A patent/JPH07504419A/en active Pending
- 1993-02-23 EP EP93907271A patent/EP0628024A4/en not_active Withdrawn
- 1993-02-23 AU AU37932/93A patent/AU3793293A/en not_active Abandoned
- 1993-02-23 WO PCT/US1993/002033 patent/WO1993016981A1/en not_active Application Discontinuation
- 1993-02-23 CA CA002130829A patent/CA2130829A1/en not_active Abandoned
Non-Patent Citations (2)
Title |
---|
No further relevant documents disclosed * |
See also references of WO9316981A1 * |
Also Published As
Publication number | Publication date |
---|---|
CA2130829A1 (en) | 1993-09-02 |
JPH07504419A (en) | 1995-05-18 |
AU3793293A (en) | 1993-09-13 |
WO1993016981A1 (en) | 1993-09-02 |
EP0628024A4 (en) | 1995-03-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1150943B1 (en) | Preparation of iodixanol | |
US5648536A (en) | Process for producing ioversol | |
US5371278A (en) | Synthesis of ioversol using a minimal excess of acetoxyacetylchloride | |
EP0886634B1 (en) | Process for producing ioversol | |
EP0598751B1 (en) | Synthesis of ioversol using chloroacetyl chloride | |
JP4039700B2 (en) | Production of triiodobenzene compounds | |
EP0628024A1 (en) | Synthesis of ioversol using a minimal excess of acetoxyacetylchloride | |
EP0640067B1 (en) | Improved synthesis of ioversol | |
NO322141B1 (en) | Process for the preparation of contrast agents | |
EP0580783A1 (en) | Use of azeotropic distillation in process to dry 5-amino-n,n'bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide | |
KR960007801B1 (en) | Preparation of unionic iodine-containing x-ray contrast agents | |
CN114213273A (en) | Synthesis method of iomeprol | |
HUT65118A (en) | Process for preparation of 2-oxo-1-piperidinyl-derivatives | |
CN116854610A (en) | Process for the preparation of impurities K and H of iopamidol and intermediates thereof | |
EP2281807A1 (en) | Decolorizing 5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide, a contrast media intermediate | |
DK200100402A (en) | Process for removing desmethyl citalopram from a citalopram product |
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: 19940907 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LI NL PT SE |
|
RHK1 | Main classification (correction) |
Ipc: C07C231/02 |
|
A4 | Supplementary search report drawn up and despatched |
Effective date: 19950203 |
|
AK | Designated contracting states |
Kind code of ref document: A4 Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LI 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: 19950425 |