EP0888287A1 - 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 mediaInfo
- 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- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims abstract description 22
- 238000000746 purification Methods 0.000 title claims abstract description 14
- 230000015572 biosynthetic process Effects 0.000 title description 6
- 238000003786 synthesis reaction Methods 0.000 title description 6
- 239000000193 iodinated contrast media Substances 0.000 title description 2
- 239000002904 solvent Substances 0.000 claims abstract description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 13
- -1 compound L-5-(2-acetoxypropionylamino)-2,4,6-triiodoisophthaloyl dichloride Chemical class 0.000 claims abstract description 6
- 239000011541 reaction mixture Substances 0.000 claims description 12
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 claims description 8
- FBJVWRITWDYUAC-UHFFFAOYSA-N 5-amino-2,4,6-triiodobenzene-1,3-dicarbonyl chloride Chemical compound NC1=C(I)C(C(Cl)=O)=C(I)C(C(Cl)=O)=C1I FBJVWRITWDYUAC-UHFFFAOYSA-N 0.000 claims description 7
- ALHZEIINTQJLOT-VKHMYHEASA-N [(2s)-1-chloro-1-oxopropan-2-yl] acetate Chemical compound ClC(=O)[C@H](C)OC(C)=O ALHZEIINTQJLOT-VKHMYHEASA-N 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 7
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 238000007865 diluting Methods 0.000 claims description 5
- XQZXYNRDCRIARQ-LURJTMIESA-N iopamidol Chemical compound C[C@H](O)C(=O)NC1=C(I)C(C(=O)NC(CO)CO)=C(I)C(C(=O)NC(CO)CO)=C1I XQZXYNRDCRIARQ-LURJTMIESA-N 0.000 claims description 5
- 229960004647 iopamidol Drugs 0.000 claims description 5
- 229940093475 2-ethoxyethanol Drugs 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims description 4
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 4
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 3
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical group CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- 229940126062 Compound A Drugs 0.000 description 17
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 17
- 239000000243 solution Substances 0.000 description 9
- 230000003197 catalytic effect Effects 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 125000001475 halogen functional group Chemical group 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- JEZJSNULLBSYHV-UHFFFAOYSA-N 5-amino-2,4,6-triiodobenzene-1,3-dicarboxylic acid Chemical compound NC1=C(I)C(C(O)=O)=C(I)C(C(O)=O)=C1I JEZJSNULLBSYHV-UHFFFAOYSA-N 0.000 description 1
- KBZFDRWPMZESDI-UHFFFAOYSA-N 5-aminobenzene-1,3-dicarboxylic acid Chemical compound NC1=CC(C(O)=O)=CC(C(O)=O)=C1 KBZFDRWPMZESDI-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- RERHJVNYJKZHLJ-UHFFFAOYSA-N bis(2-hydroxyethyl)azanium;2-(3,5-diiodo-4-oxopyridin-1-yl)acetate Chemical compound OCCNCCO.OC(=O)CN1C=C(I)C(=O)C(I)=C1 RERHJVNYJKZHLJ-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 229940039231 contrast media Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000026045 iodination Effects 0.000 description 1
- 238000006192 iodination reaction Methods 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000003690 nonionic contrast media Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
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)
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 (en) | 1996-12-24 | 1997-12-17 | A process for the purification of an intermediate useful in the synthesis of iodinated contrast media |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0888287A1 true EP0888287A1 (en) | 1999-01-07 |
Family
ID=11375488
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP97953838A Withdrawn EP0888287A1 (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 (enrdf_load_stackoverflow) |
| AU (1) | AU5759098A (enrdf_load_stackoverflow) |
| IN (1) | IN184019B (enrdf_load_stackoverflow) |
| IT (1) | IT1289521B1 (enrdf_load_stackoverflow) |
| NO (1) | NO308698B1 (enrdf_load_stackoverflow) |
| WO (1) | WO1998028261A1 (enrdf_load_stackoverflow) |
| ZA (1) | ZA9711505B (enrdf_load_stackoverflow) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH608189A5 (enrdf_load_stackoverflow) * | 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 |
| DE773925T1 (de) * | 1995-05-23 | 1997-12-18 | Fructamine Spa | Verfahren zur herstellung von dicarbonsäure-dichlorid |
-
1996
- 1996-12-24 IT IT96MI002737A patent/IT1289521B1/it active IP Right Grant
-
1997
- 1997-12-17 WO PCT/EP1997/007077 patent/WO1998028261A1/en not_active Application Discontinuation
- 1997-12-17 EP EP97953838A patent/EP0888287A1/en not_active Withdrawn
- 1997-12-17 AU AU57590/98A patent/AU5759098A/en not_active Abandoned
- 1997-12-22 ZA ZA9711505A patent/ZA9711505B/xx unknown
- 1997-12-22 IN IN2960MA1997 patent/IN184019B/en unknown
-
1998
- 1998-08-21 NO NO983872A patent/NO308698B1/no not_active IP Right Cessation
Non-Patent Citations (1)
| Title |
|---|
| See references of WO9828261A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1998028261A1 (en) | 1998-07-02 |
| NO983872L (no) | 1998-10-22 |
| ZA9711505B (en) | 1998-06-25 |
| IN184019B (enrdf_load_stackoverflow) | 2000-06-03 |
| NO308698B1 (no) | 2000-10-16 |
| IT1289521B1 (it) | 1998-10-15 |
| AU5759098A (en) | 1998-07-17 |
| NO983872D0 (no) | 1998-08-21 |
| ITMI962737A1 (it) | 1998-06-24 |
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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 |