DK175034B1 - Iodized, nonionic triiodobenzene compounds and contrast agent containing them - Google Patents
Iodized, nonionic triiodobenzene compounds and contrast agent containing them Download PDFInfo
- Publication number
- DK175034B1 DK175034B1 DK198902595A DK259589A DK175034B1 DK 175034 B1 DK175034 B1 DK 175034B1 DK 198902595 A DK198902595 A DK 198902595A DK 259589 A DK259589 A DK 259589A DK 175034 B1 DK175034 B1 DK 175034B1
- Authority
- DK
- Denmark
- Prior art keywords
- formula
- compound
- compounds
- mol
- hydroxyethyl
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
-
- 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
-
- G—PHYSICS
- G21—NUCLEAR PHYSICS; NUCLEAR ENGINEERING
- G21H—OBTAINING ENERGY FROM RADIOACTIVE SOURCES; APPLICATIONS OF RADIATION FROM RADIOACTIVE SOURCES, NOT OTHERWISE PROVIDED FOR; UTILISING COSMIC RADIATION
- G21H5/00—Applications of radiation from radioactive sources or arrangements therefor, not otherwise provided for
- G21H5/02—Applications of radiation from radioactive sources or arrangements therefor, not otherwise provided for as tracers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Physics & Mathematics (AREA)
- High Energy & Nuclear Physics (AREA)
- Engineering & Computer Science (AREA)
- General Engineering & Computer Science (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Production Of Liquid Hydrocarbon Mixture For Refining Petroleum (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
i DK 175034 B1in DK 175034 B1
Den foreliggende opfindelse angår forbindelser, der kan anvendes i kontrastmedier til radiografi.The present invention relates to compounds which can be used in contrast media for radiography.
Jodbenzenforbindelser indeholdende flere jodatomer i benzenkernen, i reglen 3 jodatomer pr. benzenkerne, og forskellige 5 andre substituenter har været anvendt i lang tid som kontrastmedium. Disse andre substituenter er farmakologisk acceptable grupper, der gør det muligt, at forbindelserne kan administreres til mennesker og dyr. Generelt vælges disse substituenter på den ene side for at bibringe tilstrækkelig opløselighed i 10 vand for forbindelsen, således at de kan administreres i vandig opløsning, og på den anden side for at bibringe disse forbindelser tilstrækkelig tolerance til, at de kan tolereres af den menneskelige organisme.Iodine benzene compounds containing several iodine atoms in the benzene nucleus, usually 3 iodine atoms per the benzene nuclei and various other substituents have been used for a long time as a contrast medium. These other substituents are pharmacologically acceptable groups which allow the compounds to be administered to humans and animals. Generally, these substituents are selected, on the one hand, to provide sufficient solubility in water for the compound so that they can be administered in aqueous solution and, on the other hand, to confer these tolerances sufficient tolerance to be tolerated by the human organism. .
Til dette formål har der været foreslået ikke-ioniske strukturer, 15 dvs. ^odbenzenderivater, der har ikke-ioniske substituenter.For this purpose, nonionic structures, i.e. ^ odbenzene derivatives having nonionic substituents.
Der er således i fransk patent nr. 2.053.037 beskrevet carbamoyl-jodbenzenforbindelser indeholdende ialt mindst én N-hydroxyalkyl-gruppe og mindst to hydroxygrupper.Thus, French Patent No. 2,053,037 discloses carbamoyl iodobenzene compounds containing at least one N-hydroxyalkyl group and at least two hydroxy groups.
En forbindelse, der illustrerer denne klasse, er metrizamid, 20 der imidlertid har vist sig at være af begrænset stabilitet.One compound illustrating this class is metrizamide, 20 which, however, has been found to be of limited stability.
I WO 88/09328 beskrives en fremgangsmåde til fremstilling af 5-acylamino-2,4,6-trijod-benzoesyrederivater, der har anven-J delse som kontrastmidler. Heller ikke disse forbindelser ud viser tilfredsstillende stabilitet i vandig opløsning.WO 88/09328 discloses a process for the preparation of 5-acylamino-2,4,6-triiodobenzoic acid derivatives having use as contrast agents. Neither of these compounds show satisfactory stability in aqueous solution.
25 Den foreliggende opfindelse tilsigter at tilvejebringe hidtil ukendte ikke-ioniske forbindelser, som tåles godt af den menneskelige organisme, er meget stabile i vandig opløsning, som har en høj opløselighed i vand, og som udviser lav viskositet i opløsning.The present invention aims to provide novel non-ionic compounds that are well tolerated by the human organism, are very stable in aqueous solution which has a high solubility in water and which exhibits low viscosity in solution.
30 Til dette formål angår opfindelsen forbindelser med formlen 2 DK 175034 B1 ?3 CO-N - R2 R4-?AV'^Rl CO 2For this purpose, the invention relates to compounds of formula 2 DK-175034 B1? 3 CO-N - R2 R4-? AV
I^CH OH CH ZI ^ CH OH CH Z
hvori ^CH OHwherein ^ CH OH
R-L er en gruppe med formlen - N - CO - R5 5 R6 hvor R5 er C1-C4alkyl, C1-C4hydroxyalkyl eller C1-C4poly-hydroxyalkyl, og Rg er hydrogen, C1-C4alkyl, C1-C4hydroxy-alkyl eller ^-C4polyhydroxyalkyl, eller R-j^ er en gruppe med formlen 10 Rfl i - CO - N - R7 hvor R7 er Ct-C4hydroxyalkyl eller C1-C4polyhydroxyalkyl, og Rg er hydrogen eller C1-C4alkyl, 15 R2 er hydrogen, C1-C4hydroxyalkyl eller C1-C4polyhydroxy-alkyl, R2 er hydrogen eller C^-C^^alkyl, og R4 er hydrogen, C1-C4alkyl, C1-C4hydroxyalkyl eller C-l-C^ polyhydroxyalkyl.R 1 is a group of formula - N - CO - R 5 R 6 where R 5 is C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl or C 1 -C 4 polyhydroxyalkyl, and R 9 is hydrogen, C 1 -C 4 alkyl, C 1 or R 1 is a group of formula 10 R 1 i - CO - N - R 7 where R 7 is C 1 -C 4 hydroxyalkyl or C 1 -C 4 polyhydroxyalkyl and R 9 is hydrogen or C 1 -C 4 alkyl, R 2 is hydrogen, C 1 alkyl, R 2 is hydrogen or C 1 -C 4 alkyl, and R 4 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl or C 1 -C 4 polyhydroxyalkyl.
20 I den foreliggende ansøgning menes med polyhydroxyalkylgruppe en lineær eller forgrenet polyhydroxyalkylgruppe.In the present application, polyhydroxyalkyl group means a linear or branched polyhydroxyalkyl group.
3 DK 175034 B13 DK 175034 B1
En foretrukken forbindelse med formlen I er forbindelsen med formlen I, hvori R = -CO-NH-CH2-CH2OH, R2 = -CH2-CH2OH, R3 = H, og r4 = -ch2-choh-ch2oh.A preferred compound of formula I is the compound of formula I wherein R = -CO-NH-CH2-CH2OH, R2 = -CH2-CH2OH, R3 = H, and r4 = -ch2-choh-ch2oh.
5 En foretrukken gruppe forbindelser med formlen I er endvidere den, der udgøres af forbindelserne af den symmetriske diamino-type, dvs. forbindelser med formlen CO-N-R2 'jot V”''S'r'7'R4Further, a preferred group of compounds of formula I is that constituted by the compounds of the symmetrical diamino type, i.e. compounds of the formula CO-N-R2 'jot V' '' S'r'7'R4
CO _ COCO _ CO
L iL i
CirCH20H Ch'CH20H "'-ci^oh '^•ch2oh 1q Forbindelserne med formlen I kan fremstilles på standardmåde, især ved acy lerings- og/eller alky le ringsreaktioner, gående ud fra kendte forbindelser.The compounds of formula I can be prepared in a standard manner, especially by acylation and / or alkylation reactions, starting from known compounds.
Forbindelserne af den symmetriske diaminotype (forbindelser med formlen II) kan således fremstilles ved a) acylering af en diaminoforbindelse med formlen C0N-R2, 'Ί& H2N/VY^H2 1 25 4 DK 175034 B1 hvor 1*2» repræsenterer en R2~gruppe, hvis hydroxy grupper er blevet beskyttet, med et syrechlorid med formlen RCOC1 (IV)Thus, the compounds of the symmetric diamine type (compounds of formula II) can be prepared by a) acylating a diamino compound of formula C0N-R2, Ί & H2N / VY ^ H2 1 where 1 * 2 represents a R2 group whose hydroxy groups have been protected with an acid chloride of formula RCOC1 (IV)
hvor R repræsenterer en ^ CH2-OHwhere R represents a ^ CH 2 -OH
5 -CH gruppe, hvis hydroxygrupper er beskyttet, ^ ch2-oh b) om nødvendigt, alkylering af den fremkomne forbindelse med et alkyleringsreagens med formlen R4,Z (V) hvor R4, har den tidligere anførte betydning (undtagen hydrogen), og Z er en labil gruppe såsom et chlor-, brom- eller jodatom, i 10 nærværelse af en base såsom natriummethylat, natriumethylat, natriumhydrid eller natriumhydroxid, c) fjernelse af beskyttelsen.5 -CH group, the hydroxy groups of which are protected, chCH₂-OH b) if necessary, alkylation of the resultant compound with an alkylation reagent of formula R4, Z (V) wherein R4 is as previously defined (except hydrogen), and Z is a labile group such as a chlorine, bromine or iodine atom, in the presence of a base such as sodium methylate, sodium ethylate, sodium hydride or sodium hydroxide; c) removal of the protection.
Forbindelser med formlen III er beskrevet i fransk patentansøgning nr. 2.614.299.Compounds of formula III are described in French Patent Application No. 2,614,299.
15 De andre forbindelser med formlen III kan fremstilles på analog måde, gående ud fra især et alkyl-3,5-dinitrobenzoat med formlen COOR1 jol <vi) 02N^^ no2 hvor R' er en C^-C^alkylgruppe såsom methyl.The other compounds of formula III can be prepared in an analogous manner starting from, in particular, an alkyl-3,5-dinitrobenzoate of formula COOR1jol (vi) O2N2O2 where R 'is a C1-C4 alkyl group such as methyl.
5 DK 175034 B15 DK 175034 B1
Asyrainetriske diaminoforbindelser kan også fremstilles ved at gå ud fra en forbindelse med formlen VI ved a) reaktion med en amin med formlen NH-R- i (VII) R3 til dannelse af en forbindelse med formlen R3 con-r2 IO I (vm) ο2ΛΑο2 5 b) reduktion ved hjælp af ammoniumsulfid til dannelse af en forbindelse med formlen h CON-R2Asymmetric diamino compounds can also be prepared by starting from a compound of formula VI by a) reacting with an amine of formula NH-R- in (VII) R3 to form a compound of formula R3 con-r2 IO I (vm) ο2ΛΑο2 B) reduction by ammonium sulfide to give a compound of formula h CON-R2
SpX <ix) c) acylering af forbindelsen med formlen IX med et syrechlorid med formlen RCOC1 (IV) til dannelse af en forbindelse meld formlen ?3 CON-R2 R-CO-HN N02 6 DK 175034 B1 d) reduktion og jodering af forbindelsen med formlen X til dannelse af en forbindelse med formlen C0N-R_SpX (ix) c) Acylation of the compound of Formula IX with an acid chloride of Formula RCOC1 (IV) to form a compound Melt Formula 3 of formula X to form a compound of formula CON-R
IY^VIIn the Y ^ VI
To I (XI)To I (XI)
HN-/\rX\NH2 CO IHN - / \ rX \ NH2 CO I
R * e) om nødvendigt, alkylering af forbindelsen med formlen XI med et alkyleringsreagens med formlen V til dannelse af en for- 5 bindelse med formlen *3 CON-R2 'Yof1 (XII,R * e), if necessary, alkylating the compound of formula XI with an alkylation reagent of formula V to form a compound of formula * 3 CON-R2 'Yof1 (XII,
COR 1 ICOR 1 I
f) fjernelse af beskyttelsen fra forbindelsen med formlen XII , g) acylering af den for beskyttelse befriede forbindelse med et syrechlorid med formlen C1-C0-R5, (XIII) hvor R5, repræsenterer en gruppe R5, hvis hydroxygrupper er 10 beskyttet, til dannelse, efter fjernelse af beskyttelsen, af en forbindelse med formlen 7 DK 175034 B1 h CON-R2f) removing the protection from the compound of formula XII; g) acylating the compound liberated for protection with an acid chloride of formula C1-CO-R5, (XIII) wherein R5 represents a group R5, whose hydroxy groups are protected, to form , after removal of the protection, of a compound of formula 7 DK 175034 B1 h CON-R2
ZpX <xiv) flH-COR,- 4 . I 5 CO τZpX <xiv) flH-COR, - 4. At 5 CO τ
|^CH ^DH CH| ^ CH ^ DH CH
CH OH 2 idet trinene f og g kan udføres i omvendt rækkefølge, og om nødvendigt, h) alkylering til dannelse af en forbindelse med formlen I, hvor Rg har den anførte betydning (undtagen hydrogen).CH OH 2, in which steps f and g can be carried out in reverse order, and if necessary, h) alkylation to form a compound of formula I wherein Rg has the stated meaning (except hydrogen).
5 Symmetriske forbindelser af isophthalsyretypen (forbindelser med formlen I, hvor R^ = -CO-N-R2), kan fremstilles ved *3 a) acylering af en amin med formlen COC1 (XV) H2Nx/ivN^XvC0C1 med et syrechlorid med formlen RCOC1 (IV) til dannelse af en forbindelse med formlen COC1 'ΎρΥ1 <WI>Isophthalic acid type symmetric compounds (compounds of formula I wherein R 1 = -CO-N-R 2) may be prepared by * 3 a) acylation of an amine of formula COC1 (XV) H2Nx / ivN RCOC1 (IV) to form a compound of formula COC1 'ΎρΥ1 <WI>
R-CO-HN ^^X^^COCl IR-CO-HN ^^ X ^^ COCl I
8 DK 175034 B1 b) reaktion af forbindelsen med formlen xvi med en amin med formlen H-N-R^ (VII) til dannelse af en forbindelse med formlen *3 ?3 C0N-R2B) reaction of the compound of formula xvi with an amine of formula H-N-R 2 (VII) to give a compound of formula * 3? 3 CON-R2
IpT (XVII) R-C0-NH''/\^/^'v CO-N-R2 i og derefter, om ønsket, enten c) alkylering af forbindelsen med formlen XVII med et alkylerings-5 reagens med formlen R^,Z såsom det tidligere angivne og til slut d) fjernelse af de beskyttende grupper fra -CH(CH20H)øgruppen eller e) fjernelse af de beskyttende grupper fra -CH(CH2OH)2-gruppen og, om ønsket, 10 f) alkylering af den for beskyttelse befriede forbindelse med et alkyleringsreagens R^,Z.IpT (XVII) R-C0-NH4 / CO / N-CO in and then, if desired, either c) alkylating the compound of formula XVII with an alkylation reagent of formula R Z such as the aforementioned and finally d) removing the protecting groups from the -CH (CH 2 OH) islet or e) removing the protecting groups from the -CH (CH 2 OH) 2 group and, if desired, f) alkylating the for protection liberated compound with an alkylating reagent R 2, Z.
De asymmetriske forbindelser af isophthalsyretypen (forbindelser med formlen I, hvor R1 = -CO-N-R7, hvor R7 ^ R2, og/eller Rg ^ R3), Rg 15 kan fremstilles ved a) acylering af en amin med formlen 9 DK 175034 B1 *3 CON-R2The asymmetric compounds of the isophthalic acid type (compounds of formula I wherein R 1 = -CO-N-R 7, where R 7, R 2, and / or R 9, R 3), R 9 can be prepared by a) acylating an amine of formula 9 B1 * 3 CON-R2
Tof *7 (XVIII) CON-Rg med et syrechlorid med formlen RCOC1, b) om ønsket, alkylering med et alkyleringsreagens med formlen R4.Z og c) fjernelse af de beskyttende grupper fra -CH- (CH2OH) 2~ 5 gruppen.Tof * 7 (XVIII) CON-Rg with an acid chloride of formula RCOC1, b) if desired, alkylation with an alkylation reagent of formula R4.Z and c) removal of the protecting groups from the -CH- (CH2OH) 2 ~ 5 group.
Forbindelsen med formlen XVIII kan fås som beskrevet i EP-0 015.867.The compound of formula XVIII can be obtained as described in EP-0 015,867.
Som et alternativ kan de asymmetriske forbindelser af isophthal-syretypen fremstilles ved 10 a) acylering af en amin med formlen COC1 Ίοΐ1 <xix) H2N^V>V|X CON-R7,Alternatively, asymmetric isophthalic acid-type compounds can be prepared by a) acylating an amine of the formula COC1 Ίοΐ1 <xix) H2N ^ V> V | X CON-R7,
I RSI RS
hvor R?I repræsenterer en R7-gruppe, hvor hydroxygrupperne er beskyttet, med et syrechlorid med formlen RC0C1 (IV) til dannelse af en forbindelse med formlen 10 DK 175034 B1 COClwherein R 1 represents an R 7 group wherein the hydroxy groups are protected, with an acid chloride of formula RC0C1 (IV) to form a compound of formula 10
ToT <χχ> "TV^con-R,,ToT <χχ> "TV ^ con-R ,,
CO ] RCO] R
i 1 b) reaktion af forbindelsen med formlen XX med en amin med formlen hn-r2 (VII) *3 til dannelse af en forbindelse med formlen *3 I O I (XXI) C0N-R7, ?° T *8b) reaction of the compound of formula XX with an amine of formula hn-r2 (VII) * 3 to give a compound of formula * 3 I O I (XXI) CON-R7, T ° 8
R IR I
og derpå, om ønsket, enten 5 c) alkylering af forbindelsen med formlen XXI med et alkyle-ringsreagens med formlen R4,Z som tidligere angivet, og til slut d) fjernelse af de beskyttende grupper fra -CH- (Ci^OH) 2~ gruppen eller 10 e) fjernelse af de beskyttende grupper fra -CH-(CH2OH)2-gruppen og, om Ønsket , 11 DK 175034 B1 f) alkylering af den for beskyttelse befriede forbindelse med et alkyleringsreagens R^,Z.and then, if desired, either c) alkylating the compound of formula XXI with an alkylation reagent of formula R4, Z as previously indicated, and finally d) removing the protecting groups from -CH- (C1- OH) 2 (e) removal of the protecting groups from the -CH- (CH 2 OH) 2 group and, if desired, f) alkylating the compound liberated for protection with an alkylating reagent R 2, Z.
En anden side af opfindelsen angår et kontrastmedium, som indeholder mindst én forbindelse med formlen I.Another aspect of the invention relates to a contrast medium containing at least one compound of formula I.
5 Disse kontrastmedier anvendes i mennesker og dyr til radiologi ske formål.5 These contrast media are used in humans and animals for radiological purposes.
Den foretrukne farmaceutiske form for kontrastmaterialerne ifølge opfindelsen består af vandige opløsninger af forbindelserne.The preferred pharmaceutical form of the contrast materials of the invention consists of aqueous solutions of the compounds.
De vandige opløsninger indeholder i reglen ialt fra 5 til 100 g 10 forbindelser med formlen I pr. 100 ml, og det rumfang af en sådan opløsning, der skal injiceres, varierer i reglen fra 1 til 1000 ml.The aqueous solutions generally contain from 5 to 100 g of 10 compounds of formula I per ml. The volume of such a solution to be injected usually ranges from 1 to 1000 ml.
Den vandige opløsning af forbindelserne med formlen I kan også indeholde visse additiver såsom: 15 Natriumchlorid i koncentrationer mellem 0,1 og 10 mM/liter. Dinatrium-EDTA i koncentrationer mellem 0,1 og 2 mM/liter. Natriumcitrat i koncentrationer mellem 0,1 og 10 mM/liter. Heparin i doser mellem 10 og 100 enheder pr. 100 ml opløsning.The aqueous solution of the compounds of formula I may also contain certain additives such as: Sodium chloride at concentrations between 0.1 and 10 mM / liter. Disodium EDTA at concentrations between 0.1 and 2 mM / liter. Sodium citrate at concentrations between 0.1 and 10 mM / liter. Heparin in doses between 10 and 100 units per 100 ml solution.
Disse forbindelser kan administreres ad alle veje, der traditio-20 nelt anvendes til joderede, ikke-ioniske kontrastmedier. De kan således administreres ad den enterale vej eller den parenterale vej (intravenøs vej, intraarteriel vej, uigennemsigtiggørelse af hulrummene) og især i det subarachnoide rum.These compounds can be administered by all routes traditionally used for iodinated, nonionic contrast media. Thus, they can be administered by the enteral or parenteral route (intravenous route, intra-arterial route, cavity opacification) and especially in the subarachnoid space.
Et eksempel på midlet ifølge opfindelsen er angivet nedenfor.An example of the agent according to the invention is given below.
25 Middel:Average:
Middel ifølge eksempel 1 65 gAgent of Example 1 65 g
Vand til injicerbart præparat qs 100 ml 12 DK 175034 B1Water for injectable preparation qs 100 ml 12 DK 175034 B1
De følgende eksempler illustrerer fremstillingen af forbindelserne med formlen I.The following examples illustrate the preparation of the compounds of formula I.
EKSEMPEL 1.EXAMPLE 1.
Fremstilling af 5-[3-hydroxy-2-(hydroxymethyl)-N-(2,3-5 dihydroxypropyl)propionamido]-N’,N"-bis-(2-hydroxyethyl)- 2.4.6- trijodisophthalamid.Preparation of 5- [3-hydroxy-2- (hydroxymethyl) -N- (2,3-5 dihydroxypropyl) propionamido] -N ', N "-bis- (2-hydroxyethyl) -2,4,6- triiodisophthalamide.
a) Fremstilling af 5-[2-isopropyl-l,3-dioxan-5-carboxamido]- 2.4.6- trijodisophthaloyldichlorid.a) Preparation of 5- [2-isopropyl-1,3-dioxane-5-carboxamido] -2,4,6-triiodoisophthaloyl dichloride.
137 g 5-amino-2,4,6-trijodisophthaloylchlorid (0,23 mol) oplø-10 ses i 460 ml DMAC, hvortil sættes 110 g (0,57 mol) 2-isopropyl- 1,3-dioxan-5-carboxylsyrechlorid. Reaktionsblandingen omrøres under argon ved omgivelsernes temperatur i 4 dage. DMAC fjernes i vakuum. Den fremkomne olie ekstraheres med 3 liter ethyl-acetat og vaskes to gange med 1 liter iskoldt vand. Den orga-15 niske fase tørres og koncentreres til tørhed. Produktet krystalliseres af 200 ml CI^Clj. Efter filtrering fås 110 g fast stof.137 g of 5-amino-2,4,6-triiododisophthaloyl chloride (0.23 mol) is dissolved in 460 ml of DMAC, to which 110 g (0.57 mol) of 2-isopropyl-1,3-dioxane-5 is added. carboxylic acid. The reaction mixture is stirred under argon at ambient temperature for 4 days. The DMAC is removed in vacuo. The resulting oil is extracted with 3 liters of ethyl acetate and washed twice with 1 liter of ice-cold water. The organic phase is dried and concentrated to dryness. The product is crystallized by 200 ml of Cl 2 Cl 2. After filtration, 110 g of solid are obtained.
Udbytte: 64%.Yield: 64%.
TLC: Si02 CH2C12.TLC: SiO 2 CH 2 Cl 2.
20 Rf: 0,13.Rf: 0.13.
(60 F 254) SiC>2 ether/petroleumsether 50/50.(60 F 254) SiC> 2 ether / petroleum ether 50/50.
Rf: 0,52.Rf: 0.52.
b) Fremstilling af 5-[2-isopropyl-l,3-dioxan-5-carboxamido]-N' ,Ν''-bis- (2-hydroxyethyl)-2,4,6-tri jodisophthalamid.b) Preparation of 5- [2-isopropyl-1,3-dioxane-5-carboxamido] -N ', Ν' '- bis- (2-hydroxyethyl) -2,4,6-triiodoisophthalamide.
25 130 g af produktet fremkommet i a (0,173 mol) opløses i en op løsning af 750 ml DMAC og 75 ml (0,534 mol) triethylamin.25 g of the product obtained in α (0.173 mol) are dissolved in a solution of 750 ml of DMAC and 75 ml (0.534 mol) of triethylamine.
33,7 g ethanolamin (0,552 mol) sættes dråbevis til reaktionsblandingen. Reaktionsblandingen omrøres så i 3 timer ved omgi- 13 DK 175034 B1 velsernes temperatur. Triethylamin-hydrochloridet fjernes ved filtrering, og DMAC fjernes i vakuum. Den fremkomne olie krystalliseres af 1 liter vand. Produktet frafiltreres og tørres i vakuum.33.7 g of ethanolamine (0.552 mol) is added dropwise to the reaction mixture. The reaction mixture is then stirred for 3 hours at ambient temperature. The triethylamine hydrochloride is removed by filtration and the DMAC is removed in vacuo. The resulting oil is crystallized by 1 liter of water. The product is filtered off and dried in vacuo.
5 Udbytte: 95%.Yield: 95%.
TLC: Si02, Rf: 0,25. CH2Cl2/methanol 9/1.TLC: SiO 2, Rf: 0.25. CH 2 Cl 2 / methanol 9/1.
(60 F 254) Si02, Rf: 0,67. CH2Cl2/methanol 8/2.(60 F 254) SiO 2, Rf: 0.67. CH 2 Cl 2 / methanol 8/2.
% I: 45,6 (fundet), 47,6 (teoretisk).% I: 45.6 (found), 47.6 (theoretical).
Hypersil C8, 5^i / 15 cm.Hypersil C8, 5 µ / 15 cm.
10 HPLC, renhed: 97%. 0,01 M NaH2P04 * 50.HPLC, purity: 97%. 0.01 M NaH 2 PO 4 * 50.
Methanol = 50.Methanol = 50.
c) Fremstilling af 5-[3-hydroxy-2-hydroxymethyl-N-(2,3-dihydroxypropyl)propionamido]-N',N"-bis-(2-hydroxyethyl)- 2,4,6-trijodisophthalamid.c) Preparation of 5- [3-hydroxy-2-hydroxymethyl-N- (2,3-dihydroxypropyl) propionamido] -N ', N "-bis- (2-hydroxyethyl) -2,4,6-triiododisophthalamide.
15 Til en suspension af 100 g af produktet fremkommet i b (0,125 mol) i 350 ml ethylenglycol sættes dråbevis 125 ml (0,5 mol) 4 N methylat ved 60°C, efterfulgt af 65 g (0,625 mol) l-chlor-2,3-propandiol. Efter en time ved 60°C er massen af reaktionsblandingen forøget. 100 ml (0,4 mol) 4 N methylat og 55,2 g 20 (0,5 mol) l-chlor-2,3-propandiol tilsættes. Blandingen holdes natten over ved 60°C. Der foretages en yderligere tilsætning af 31 ml (0,125 mol) 4 N methylat og 20,7 g l-chlor-2,3-propandiol. Omrøring opretholdes i 4 timer ved 60°C. Mineralsaltene fjernes ved filtrering. Ethylenglycolen afdampes i vakuum.To a suspension of 100 g of the product obtained in b (0.125 mol) in 350 ml of ethylene glycol is added dropwise 125 ml (0.5 mol) of 4 N methylate at 60 ° C, followed by 65 g (0.625 mol) of 1-chloro-2 , 3-propanediol. After one hour at 60 ° C, the mass of the reaction mixture is increased. 100 ml (0.4 mol) of 4N methylate and 55.2 g of 20 (0.5 mol) of 1-chloro-2,3-propanediol are added. The mixture is kept overnight at 60 ° C. A further addition of 31 ml (0.125 mol) of 4 N methylate and 20.7 g of 1-chloro-2,3-propanediol is made. Stirring is maintained for 4 hours at 60 ° C. The mineral salts are removed by filtration. The ethylene glycol is evaporated in vacuo.
25 Destillationsresten optages i 800 ml 10 N HC1, og opløsningen omrøres natten over ved omgivelsernes temperatur. Reaktionsblandingen koncentreres til tørhed, og remanensen optages i 300 ml ethanol. Mineralsaltene fjernes ved filtrering. Ethano-len afdampes i vakuum, og remanensen krystalliseres af 1 liter 30 isopropylalkohol. Bundfaldet frafiltreres og renses ved HPLC (RP 18) (eluering med vand).The distillation residue is taken up in 800 ml of 10 N HCl and the solution is stirred overnight at ambient temperature. The reaction mixture is concentrated to dryness and the residue is taken up in 300 ml of ethanol. The mineral salts are removed by filtration. The ethanol is evaporated in vacuo and the residue is crystallized by 1 liter of isopropyl alcohol. The precipitate is filtered off and purified by HPLC (RP 18) (elution with water).
14 DK 175034 B114 DK 175034 B1
Samlet udbytte (alkylering - fjernelse af beskyttelse - rensning): 52%.Total yield (alkylation - removal of protection - purification): 52%.
1) TLC (silica 60 F 254): CH2Cl2/methanol 7/3. Rf: 0,4.1) TLC (silica 60 F 254): CH 2 Cl 2 / methanol 7/3. Rf: 0.4.
2) HPLC, Hyper sil C8, 5/U, 15 cm.2) HPLC, Hyper will C8, 5 / U, 15 cm.
5 Stødpude: 0,01 M NaH2P04 = 97.5 Buffer: 0.01 M NaH2 PO4 = 97.
Methanol = 3.Methanol = 3.
Renhed: 97%.Purity: 97%.
3) % I: 45,8 (fundet), 46,4 (teoretisk).3)% I: 45.8 (found), 46.4 (theoretical).
4) NMR (DMSO).4) NMR (DMSO).
10 Dårligt opløst multiplet centreret ved 3,5 ppm (18H), multiplet centreret ved 4,5 ppm (OH), ombyttelig med D20 (6H), bred top ved 8,4 ppm (NH), ombyttelig med D20 (2H).10 Poorly dissolved multiplet centered at 3.5 ppm (18H), multiplet centered at 4.5 ppm (OH), interchangeable with D20 (6H), broad peak at 8.4 ppm (NH), interchangeable with D20 (2H).
EKSEMPEL 2.EXAMPLE 2.
Fremstilling af 5-glycolamido-3-[3-hydroxy-2-hydroxymethyl-N-15 (2,3-dihydroxypropyl)propionamido]-2,4,6-trijod-N-hydroxyethyl- benzamid.Preparation of 5-glycolamido-3- [3-hydroxy-2-hydroxymethyl-N-15 (2,3-dihydroxypropyl) propionamido] -2,4,6-triiodo-N-hydroxyethylbenzamide.
a) Fremstilling af 3,5-dinitro-N-(2-hydroxyethyl)benzamid.a) Preparation of 3,5-dinitro-N- (2-hydroxyethyl) benzamide.
750 g (3,32 mol) methyl-3,5-dinitrobenzoat suspenderes i 2 liter methanol i nærværelse af 222,7 g (3,65 mol) ethanolamin. Reak- 20 tionsblandingen opvarmes under tilbagesvaling i 48 timer, indtil esteren er forsvundet. Efter 4 timer ved stuetemperatur fra- 3 filtreres det krystallinske produkt, vaskes med 500 cm methylen-chlorid og tørres så i en ovn ved 60°C i vakuum i 4 timer. Dette fører til udvinding af 718 g produkt i et udbytte på 85%.750 g (3.32 mole) of methyl 3,5-dinitrobenzoate are suspended in 2 liters of methanol in the presence of 222.7 g (3.65 mole) of ethanolamine. The reaction mixture is heated under reflux for 48 hours until the ester has disappeared. After 4 hours at room temperature, the crystalline product is filtered off, washed with 500 ml of methylene chloride and then dried in an oven at 60 ° C in vacuum for 4 hours. This leads to the recovery of 718 g of product in a yield of 85%.
25 Smeltepunkt: 140°C.Melting point: 140 ° C.
TLC (toluen/methylethylketon/myresyre 60/25/25). Rf: 0,5.TLC (toluene / methyl ethyl ketone / formic acid 60/25/25). Rf: 0.5.
15 DK 175034 B1 b) Fremstilling af 3-nitro-5-amino-N-(2-hydroxyethyl)benzamid.B) Preparation of 3-nitro-5-amino-N- (2-hydroxyethyl) benzamide.
Til en suspension af 25,5 g (0,5 mol) 3,5-dinitro-N-(2-hydroxyethyl) benzamid i 135 cm^ vand sættes ved 70°C 12,25 g (0,18 mol) ammoniumsulfid. Efter endt tilsætning er blandingen homogen, 5 men der sker genudfældning efter 1/2 time ved 70°C. Reaktionsblandingen får lov at afkøle til omgivelsernes temperatur, og omrøring fortsættes i 2 timer. Bundfaldet frafiltreres, vaskes med methanol (70 cm^) og tørres så i en ovn (60°C).To a suspension of 25.5 g (0.5 mole) of 3,5-dinitro-N- (2-hydroxyethyl) benzamide in 135 cm 2 of water is added 12.25 g (0.18 mole) of ammonium sulfide. After the addition is complete, the mixture is homogeneous, but re-precipitation occurs after 1/2 hour at 70 ° C. The reaction mixture is allowed to cool to ambient temperature and stirring is continued for 2 hours. The precipitate is filtered off, washed with methanol (70 cm 2) and then dried in an oven (60 ° C).
Udbytte: 15,1 g = 67%.Yield: 15.1 g = 67%.
10 TLC (toluen/methylethylketon/myresyxe 60/25/25). Rf: 0,3.10 TLC (toluene / methyl ethyl ketone / formic acid 60/25/25). Rf: 0.3.
NMR (DMSO): 3,4 ppm (multiplet, 4H, CH^ alifatisk), 4,65 ppm (multiplet, H ombyttelig med D2O, NH2), 5,9 ppm (singlet, H ombyttelig med D^O, OH), 7,4-7,7 ppm (2 multipletter, 3H, .aromatiske protoner), 8,6 ppm (multiplet, IH, NH).NMR (DMSO): 3.4 ppm (multiplet, 4H, CH 2 aliphatic), 4.65 ppm (multiplet, H interchangeable with D 2 O, NH 2), 5.9 ppm (singlet, H interchangeable with D , 7.4-7.7 ppm (2 multiples, 3H, aromatic protons), 8.6 ppm (multiplet, 1H, NH).
15 c) Fremstilling af 3-nitro-5-[2-isopropyl-l,3-dioxan-5-carboxamido]-N-hydroxyethylbenzamid.C) Preparation of 3-nitro-5- [2-isopropyl-1,3-dioxane-5-carboxamido] -N-hydroxyethylbenzamide.
40 g (0,177 mol) 3-nitro-5-amino-N-(2-hydroxyethyl)benzamid op-3 løses i 400 cm DMAC. Tilsætning af 74,9 g (0,389 mol) 2-isopropyl-l, 3-dioxan-5-carboxylsyrechlorid i nærværelse af triethyl-20 amin (54,6 cm^) giver anledning til en eksoterm reaktion.40 g (0.177 mol) of 3-nitro-5-amino-N- (2-hydroxyethyl) benzamide dissolve 3 in 400 cm DMAC. Addition of 74.9 g (0.389 mol) of 2-isopropyl-1,3-dioxane-5-carboxylic acid chloride in the presence of triethylamine (54.6 cm 2) gives rise to an exothermic reaction.
Reaktionsblandingen holdes under argon i 18 timer ved omgivelsernes temperatur. Blandingen filtreres, og filtratet fortyndes med vand og ekstraheres med ethylacetat. Remanensen, der fremkommer efter afdampning af opløsningsmidlet, behandles med 25 kaliumcarbonat (12 g) i 300 cm"* methanol. Efter at være omrørt ved omgivelsernes temperatur i 48 timer koncentreres blandingen og ekstraheres så med ethylacetat. Det fremkomne rå produkt omkrystalliseres af en blanding af ether og ethylacetat (80/20). Der isoleres 37,8 g produkt i et udbytte på 56%.The reaction mixture is kept under argon for 18 hours at ambient temperature. The mixture is filtered and the filtrate is diluted with water and extracted with ethyl acetate. The residue obtained after evaporation of the solvent is treated with 25 potassium carbonate (12 g) in 300 cm 2 of methanol. After being stirred at ambient temperature for 48 hours, the mixture is concentrated and then extracted with ethyl acetate. The resulting crude product is recrystallized from a mixture of ether and ethyl acetate (80/20) 37.8 g of product are isolated in 56% yield.
30 TLC (ethylacetat), Rf: 0,48.TLC (ethyl acetate), R f: 0.48.
HPLC, Hypersil C8, 5/i , 15 cm.HPLC, Hypersil C8, 5 µ, 15 cm.
Stødpude: 0,01 M NaH2P04 = 50%.Cushion: 0.01 M NaH2 PO4 = 50%.
MeOH = 50%.MeOH = 50%.
16 DK 175034 B116 DK 175034 B1
Renhed: 94%.Purity: 94%.
d) Fremstilling af 5-amino-3-[2-isopropyl-l,3-dioxan-5-carboxamido]-2,4,6-trijod-N-hydroxyethylbenzamid.d) Preparation of 5-amino-3- [2-isopropyl-1,3-dioxane-5-carboxamido] -2,4,6-triiodo-N-hydroxyethylbenzamide.
En methanolisk opløsning (1,4 liter) af 40 g 3-nitro-5-[2-5 isopropyl-1,3-dioxan-5-carboxamido]-N-hydroxyethylbenzamid omrøres under en atmosfære af hydrogen (5xlO^Pa) i 5 timer ved 50°C i nærværelse af 4 g palladiseret trækul. Katalysatoren frafiltreres så, og filtratet inddampes under reduceret 3 tryk. Den fremkomne forbindelse suspenderes i 950 cm vand.A methanolic solution (1.4 liters) of 40 g of 3-nitro-5- [2-5 isopropyl-1,3-dioxane-5-carboxamido] -N-hydroxyethylbenzamide is stirred under an atmosphere of hydrogen (5x10 5 hours at 50 ° C in the presence of 4 g of palladized charcoal. The catalyst is then filtered off and the filtrate is evaporated under reduced pressure. The resulting compound is suspended in 950 cm of water.
3 10 Blandingen gøres homogen ved tilsætning af 20 cm 2 N saltsyre.The mixture is made homogeneous by the addition of 20 cm 2 N hydrochloric acid.
3 63 cm godchlorid (70% jod) tilsættes så dråbevis under kraftig omrøring. Efter 24 timer ved omgivelsernes temperatur frafiltreres bundfaldet, vaskes med vand og -optages i ether.3 63 cm of good chloride (70% iodine) is then added dropwise with vigorous stirring. After 24 hours at ambient temperature, the precipitate is filtered off, washed with water and taken up in ether.
Efter tørring fås 32 g produkt i et udbytte på 42%.After drying, 32 g of product is obtained in 42% yield.
15 TLC (dichlormethan/methanol 90/10), Rf: 0,8.TLC (dichloromethane / methanol 90/10), Rf: 0.8.
e) Fremstilling af 5-amino-3-[N-(2,3-dihydroxypropyl)-2-isopropyl-l , 3-dioxan-5-carboxamido]-2,4,6-trijod-N-hydroxyethyl-benzamid.e) Preparation of 5-amino-3- [N- (2,3-dihydroxypropyl) -2-isopropyl-1,3-dioxane-5-carboxamido] -2,4,6-triiodo-N-hydroxyethyl-benzamide.
Til en opløsning af forbindelsen fremkommet i d (20 g, 0,027 mol) 20 i en blanding af ethylenglycol og dimethylformamid (160 ml) sættes dråbevis 84 cm^ (0,337 mol) 4 N natriummethylat. Blandingen opvarmes til 60°C i 1/2 time, og 36,1 cm^ (0,432 mol) l-chlor-2,3-propandiol tilsættes ved denne temperatur. Reaktionsblandingen holdes ved 60°C under nitrogen i 60 timer.To a solution of the compound obtained in d (20 g, 0.027 mol) 20 in a mixture of ethylene glycol and dimethylformamide (160 ml) is added dropwise 84 cm 2 (0.337 mol) of 4 N sodium methylate. The mixture is heated to 60 ° C for 1/2 hour and 36.1 cm 2 (0.432 mole) of 1-chloro-2,3-propanediol is added at this temperature. The reaction mixture is kept at 60 ° C under nitrogen for 60 hours.
25 Mineralsaltene fjernes ved filtrering. Ethylenglycolen og DMFThe mineral salts are removed by filtration. The ethylene glycol and DMF
afdampes i vakuum. Det fremkomne rå produkt renses på silanise-ret siliciumdioxid (eluering med vand, efterfulgt af vand/me-thanol 50/50). Der isoleres 16,5 g produkt. Udbytte 76%.evaporated in vacuo. The resulting crude product is purified on silanized silica (elution with water, followed by water / methanol 50/50). 16.5 g of product are isolated. Yield 76%.
TLC (dichlormethan/methanol 80/20), Rf: 0,8.TLC (dichloromethane / methanol 80/20), Rf: 0.8.
17 DK 175034 B1 f) Fremstilling af 5-amino-3-[3-hydroxy2-(hydroxymethyl)-N-(2,3-dihydroxypropyl)propionamido]-2,4,6-trijod-N-hydroxy-ethyIbenzamid.F) Preparation of 5-amino-3- [3-hydroxy2- (hydroxymethyl) -N- (2,3-dihydroxypropyl) propionamido] -2,4,6-triiodo-N-hydroxyethylbenzamide.
16 g (0,02 mol) af produktet fremkommet i e befris for beskyt- 3 5 telse i nærværelse af 80 cm 10 N saltsyre i 48 timer ved omgivelsernes temperatur. Efter neutralisation og inddampning under reduceret tryk fældes remanensen med en blanding af methanol og ether (9/1), frafiltreres og renses ved HPLC (RP 18) (eluering med vand og derpå med vand/methanol 90/10). Der 10 isoleres 4 g produkt i et samlet udbytte (fjernelse af beskyttelse, rensning) på 30%.16 g (0.02 mole) of the product obtained in e was frozen for protection in the presence of 80 cm 10 N hydrochloric acid for 48 hours at ambient temperature. After neutralization and evaporation under reduced pressure, the residue is precipitated with a mixture of methanol and ether (9/1), filtered and purified by HPLC (RP 18) (elution with water and then with water / methanol 90/10). 10 g of product are isolated in a total yield (removal of protection, purification) of 30%.
TLC (dichlormethan/methanol 80/20), Rf: 0,25.TLC (dichloromethane / methanol 80/20), Rf: 0.25.
HPLC, Hypersil C8, 5yU, 15 cm.HPLC, Hypersil C8, 5yU, 15 cm.
Stødpude: 0,01 M NaH2P0^ = 90%.Cushion: 0.01 M NaH 2 PO = 90%.
15 MeOH = 10%.MeOH = 10%.
Renhed: 97%.Purity: 97%.
g) Fremstilling af 5-N-glycolamido-3-[3-hydroxy-2-(hydroxymethyl) -N-(2,3-dihydroxypropyl)propionamido]-2,4,6-trijod-N-hydroxyethylbenzamid.g) Preparation of 5-N-glycolamido-3- [3-hydroxy-2- (hydroxymethyl) -N- (2,3-dihydroxypropyl) propionamido] -2,4,6-triiodo-N-hydroxyethylbenzamide.
20 5,5 g O-acetyleret glycolsyrechlorid (0,04 mol) sættes dråbe vis ved omgivelsernes temperatur til en opløsning af 3 g af 3 forbindelsen fremkommet i trin f (0,004 mol) i 30 cm vandfri DMAC. Reaktionsblandingen opvarmes til 40°C i 12 timer og 3 hældes så i 250 cm iskoldt vand. Det fremkomne bundfald fra-25 filtreres og ekstraheres så med ethylacetat. Efter behandling, efterfulgt af inddampning, befris det fremkomne produkt, op- 3 3 •løst i 50 cm methanol, for beskyttelse i nærværelse af 10 cm 1 N natriumhydroxid. Opløsningen omrøres ved omgivelsernes temperatur i 14 timer og afsaltes så ved passage i rækkefølge 30 gennem H+ (IRN 77) og 0H~ (IRN 78) harpikser. Efter inddampning til tørhed optages remanensen i ethylether, filtreres og tørres. Der fås 1,5 g. Samlet udbytte: 47%.5.5 g of O-acetylated glycolic acid chloride (0.04 mol) is added dropwise at ambient temperature to a solution of 3 g of the 3 compound obtained in step f (0.004 mol) in 30 cm of anhydrous DMAC. The reaction mixture is heated to 40 ° C for 12 hours and then poured into 250 cm of ice-cold water. The resulting precipitate is filtered off and then extracted with ethyl acetate. After treatment, followed by evaporation, the resulting product is dissolved, dissolved in 50 cm 3 of methanol, for protection in the presence of 10 cm of 1 N sodium hydroxide. The solution is stirred at ambient temperature for 14 hours and then desalted by passing in sequence 30 through H + (IRN 77) and OH ~ (IRN 78) resins. After evaporation to dryness, the residue is taken up in ethyl ether, filtered and dried. 1.5 g is obtained. Total yield: 47%.
Renhed med hensyn til jod: 99%.Iodine Purity: 99%.
18 DK 175034 B1 TLC (ethylacetat/methanol/ammoniak 60/40/1), Rf: 0,25.18 DK 175034 B1 TLC (ethyl acetate / methanol / ammonia 60/40/1), Rf: 0.25.
HPLC, Hypersil C8, 5μ, 15 cm.HPLC, Hypersil C8, 5µ, 15 cm.
Stødpude: 0,01 M NaH2P04 =90%.Cushion: 0.01 M NaH2 PO4 = 90%.
MeOH = 10%.MeOH = 10%.
5 Renhed: 89%.5 Purity: 89%.
EKSEMPEL 3.EXAMPLE 3.
Fremstilling af 3,5-bis-(3-hydroxy-2-hydroxymethylpropionamido)- 2,4,6-trijod-N-(2,3-dihydroxypropyl)benzamid.Preparation of 3,5-bis- (3-hydroxy-2-hydroxymethylpropionamido) -2,4,6-triiodo-N- (2,3-dihydroxypropyl) benzamide.
a) Fremstilling af 3,5-diamino-2,4,6-trijod-N-(2,3-diacetoxy- 10 propyl)benzamid.a) Preparation of 3,5-diamino-2,4,6-triiodo-N- (2,3-diacetoxypropyl) benzamide.
301.5 g (0,5 mol) 3,5-diamino-2,4,6-trijod-N-(2,3-dihydroxypropyl) benzamid suspenderes i 1 liter vandfri pyridin, afkølet til 15°C. Efter tilsætning af 2450 ml eddikesyreanhydrid omrøres opløsningen i 18 timer ved omgivelsernes temperatur 15 og hældes så i syrnet vand. Efter ekstraktion med ethylacetat, tørring af den organiske fase og inddampning fås 270 g produkt i et udbytte på 78,5%.301.5 g (0.5 mole) of 3,5-diamino-2,4,6-triiodo-N- (2,3-dihydroxypropyl) benzamide are suspended in 1 liter of anhydrous pyridine, cooled to 15 ° C. After adding 2450 ml of acetic anhydride, the solution is stirred for 18 hours at ambient temperature 15 and then poured into acidified water. After extraction with ethyl acetate, drying the organic phase and evaporation, 270 g of product is obtained in a yield of 78.5%.
Renhed med hensyn til jod: 98,3%.Iodine Purity: 98.3%.
TLC (toluen/methylethylketon/HCOOH 60/25/35), Rf: 0,70.TLC (toluene / methyl ethyl ketone / HCOOH 60/25/35), Rf: 0.70.
20 b) Fremstilling af 3,5-bis-(2-isopropyl-l,3-dioxan-5- carboxamido)-2,4,6-trijod-N-(2,3-diacetoxypropyl)benzamid.B) Preparation of 3,5-bis- (2-isopropyl-1,3-dioxane-5-carboxamido) -2,4,6-triiodo-N- (2,3-diacetoxypropyl) benzamide.
114.5 g (0,166 mol) af forbindelsen fremkommet i a opløses i 350 ml vandfri DMAC. Tilsætning af 128 g (0,66 mol) 2-isopropyl- 1,3-dioxan-5-carboxylsyrechlorid foretages ved 0°C. Efter om- 25 røring natten over hældes reaktionsmassen i en blanding af is og vand. Bundfaldet frafiltreres, vaskes med vand og tørres så i vakuum ved 50°C.Dissolve 114.5 g (0.166 mol) of the compound obtained in a in 350 ml of anhydrous DMAC. Add 128 g (0.66 mole) of 2-isopropyl-1,3-dioxane-5-carboxylic acid chloride at 0 ° C. After stirring overnight, the reaction mass is poured into a mixture of ice and water. The precipitate is filtered off, washed with water and then dried in vacuo at 50 ° C.
19 DK 175034 B1 c) Fremstilling af 3,5-bis(2-isopropyl-l,3-dioxan-5-carbox-amido)-2,4,6-trijod-N-(2,3-dihydroxypropyl)benzamid.C) Preparation of 3,5-bis (2-isopropyl-1,3-dioxane-5-carboxamido) -2,4,6-triiodo-N- (2,3-dihydroxypropyl) benzamide.
175 g af forbindelsen fremkommet i b, suspenderet i 2,5 liter methanol, omrøres ved omgivelsernes temperatur i nærværelse af 5 45 g kaliumcarbonat natten over. Efter inddampning af reaktions blandingen krystalliserer produktet af vand. Efter filtrering og tørring anvendes de fremkomne krystaller i et udbytte på 85% direkte i næste trin.175 g of the compound obtained in b, suspended in 2.5 liters of methanol, is stirred at ambient temperature in the presence of 5 45 g of potassium carbonate overnight. After evaporation of the reaction mixture, the product crystallizes from water. After filtration and drying, the resulting crystals are used in a yield of 85% directly in the next step.
d) Fremstilling af 3,5-bis-(3-hydroxy-2-hydroxymethylpropion-10 amido)-2,4,6-trijod-N-(2,3-dihydroxypropyl)benzamid.d) Preparation of 3,5-bis- (3-hydroxy-2-hydroxymethylpropionamido) -2,4,6-triiodo-N- (2,3-dihydroxypropyl) benzamide.
Forbindelsen fremkommet i c opløses i 2 liter 5 N HC1 ved 50°C. Efter at være omrørt i 18 timer filtreres den fremkomne suspension. Filtratet koncentreres i vakuum, og remanensen optages i isopropanol.The compound obtained in c is dissolved in 2 liters of 5 N HCl at 50 ° C. After being stirred for 18 hours, the resulting suspension is filtered. The filtrate is concentrated in vacuo and the residue is taken up in isopropanol.
15 Der fås 108 g krystallinsk produkt i 2 udbytter. Samlet udbytte: 94%.15 g of crystalline product is obtained in 2 yields. Total yield: 94%.
TLC SiO^, butanol 60, vand 25, CH^COOH 11, Rf: 0,2.TLC SiO 2, butanol 60, water 25, CH 2 COOH 11, Rf: 0.2.
Produktet renses ved præparativ HPLC på Si02 (RP 18), 15,25 μ, med vand som elueringsmiddel i et udbytte på 47%.The product is purified by preparative HPLC on SiO 2 (RP 18), 15.25 µ, with water as the eluent in 47% yield.
20 Renhed med hensyn til jod: 99,6%.Iodine Purity: 99.6%.
HPLC, renhed: 99,1% (Hypersil C8, 5/U, 15 cm, 0,01 M NaH^PO^ 95,HPLC, purity: 99.1% (Hypersil C8, 5 / U, 15 cm, 0.01 M NaH
MeOH 5).MeOH 5).
1H NMR, 200 MHz (DMSO): 8.5 ppm (m, IH, ombyttelig med D20, O-CONH), 25 9,9 ppm (t, 2H, ombyttelig med D20, O-NH-CO), 4.6 ppm (m, 6H), ombyttelig, OH), 3-4 ppm (m, 13H, CH), 2.7 ppm (m, 2H, NH-CH2).1 H NMR, 200 MHz (DMSO): 8.5 ppm (m, 1H, interchangeable with D20, O-CONH), 9.9 ppm (t, 2H, interchangeable with D20, O-NH-CO), 4.6 ppm (m , 6H), interchangeable, OH), 3-4 ppm (m, 13H, CH), 2.7 ppm (m, 2H, NH-CH2).
DK 175034 B1 20 EKSEMPEL 4.Example 17.
Fremstilling af 5-[3-hydroxy-2-(hydroxymethyl)-N-(2-hydroxy-ethyl)propionamido]-N-{2-hydroxyethy1)-N'-(2,3-dihydroxy-propyl)-2,4,6-trijod-isophthaiamid.Preparation of 5- [3-hydroxy-2- (hydroxymethyl) -N- (2-hydroxyethyl) propionamido] -N- (2-hydroxyethyl) -N '- (2,3-dihydroxy-propyl) -2 4,6-triiodo-isophthaiamid.
5 a) Fremstilling af 5- (2-isopropyl-l,3-dioxan-5-carboxamido)- 2.4.6- trijod-3-N'- (2-acetoxyethy1)carbamoy1-benzoylchlorid.5 a) Preparation of 5- (2-isopropyl-1,3-dioxane-5-carboxamido) -2,4,6-triiodo-3-N'- (2-acetoxyethyl) carbamoyl-benzoyl chloride.
5,36 g 2-isopropyl-l,3-dioxan-5-carboxylsyre (0,0308 mol) opløses i 18 ml DMAC. Reaktionsblandingen afkøles til 5°C, og 2,55 ml (0,0350 mol) SOC^ tilsættes dråbevis, således at tem-10 peraturen forbliver under 15°C. Efter endt tilsætning henstilles reaktionsblandingen i 3 timer ved omgivelsernes temperatur.Dissolve 5.36 g of 2-isopropyl-1,3-dioxane-5-carboxylic acid (0.0308 mol) in 18 ml of DMAC. The reaction mixture is cooled to 5 ° C and 2.55 ml (0.0350 mole) of SOC 3 is added dropwise so that the temperature remains below 15 ° C. After the addition is complete, the reaction mixture is left for 3 hours at ambient temperature.
Derpå tilsættes 6,0 g (0,00906 mol) 5-amino-2,4,6-trijod-3-(N- 2-acetoxyethyl)carbamoyl-benzoylchlorid. Reaktionsblandingen holdes under argon i 4 dage ved omgivelsernes temperatur.Then 6.0 g (0.00906 mol) of 5-amino-2,4,6-triiodo-3- (N-2-acetoxyethyl) carbamoyl-benzoyl chloride is added. The reaction mixture is kept under argon for 4 days at ambient temperature.
15 DMAC fjernes i vakuum. Den fremkomne olie optages i ethylacetat. Den organiske fase vaskes med vand, tørres og koncentreres til tørhed. Produktet krystalliseres af 100 ml ether.DMAC is removed in vacuo. The resulting oil is taken up in ethyl acetate. The organic phase is washed with water, dried and concentrated to dryness. The product is crystallized from 100 ml of ether.
Efter frafil-trering og tørring fås 1,8 g produkt i et udbytte på 24%.After filtration and drying, 1.8 g of product is obtained in a yield of 24%.
20 TLC (silica 60 F 254): Ethylacetat/petroleumsether 80/20. Rf:0,83.TLC (silica 60 F 254): Ethyl acetate / petroleum ether 80/20. Rf: 0.83.
b) Fremstilling af 5- (2-isopropyl-l,3-dioxan-5-carboxamido)- 2.4.6- trijod-N-(2-acetoxyethyl)-N*-(2,3-dihydroxypropyl)iso-phthalamid.b) Preparation of 5- (2-isopropyl-1,3-dioxane-5-carboxamido) -2,4,6-triiodo-N- (2-acetoxyethyl) -N * - (2,3-dihydroxypropyl) iso-phthalamide.
1 g (0,00122 mol) af produktet fremkommet i a opløses i 100 ml 25 DMAC, og derefter tilsættes 0,26 ml triethylamin (0,00189 mol). 0,18 g (0,00196 mol) 3-amino-l,2-propandiol sættes dråbevis til reaktionsblandingen. Efter endt tilsætning omrøres reaktionsblandingen under argon ved omgivelsernes temperatur i 24 timer.Dissolve 1 g (0.00122 mol) of the product obtained in a in 100 ml of DMAC and then add 0.26 ml of triethylamine (0.00189 mol). 0.18 g (0.00196 mole) of 3-amino-1,2-propanediol is added dropwise to the reaction mixture. Upon completion of the addition, the reaction mixture is stirred under argon at ambient temperature for 24 hours.
21 DK 175034 B121 DK 175034 B1
Triethylamin-hydrochloridet frafiltreres, og derpå afdampes DMAC. Den fremkomne olie krystalliseres af 20 ml ether.The triethylamine hydrochloride is filtered off and then DMAC is evaporated. The resulting oil is crystallized from 20 ml of ether.
Efter frafiltrering og tørring fås 0,8 g produkt i et udbytte på 75,5%.After filtration and drying, 0.8 g of product is obtained in 75.5% yield.
5 TLC (siliciumdioxid 60 F 254): CHCl3/MeOH/NH4OH 53/30/10.TLC (silica 60 F 254): CHCl 3 / MeOH / NH 4 OH 53/30/10.
Rf: 0,77.Rf: 0.77.
c) Fremstilling af 5-[3-hydroxy-2-(hydroxymethyl)-N-(2-hydroxyethyl)propionamido]-N-(2-hydroxyethy1)-N * -(2,3-dihydroxy-propyl)-2,4,6-trijodisophthaiamid.c) Preparation of 5- [3-hydroxy-2- (hydroxymethyl) -N- (2-hydroxyethyl) propionamido] -N- (2-hydroxyethyl) -N * - (2,3-dihydroxy-propyl) -2 4,6-trijodisophthaiamid.
10 0,4 g (0,000458 mol) af produktet fremkommet i b opløses i 0,7 ml ethylenglycol og 0,69 ml (0,00275 mol) af en 4 N ppløs-ning af natriummethylat. Til denne opløsning sættes 0,18 ml (0,00275 mol) chlorethanol. Reaktionsblandingen opvarmes til 40°C i 5 timer. 0,34 ml 4 N natriummethylat og 0,1 ml chlor-15 ethanol tilsættes. Blandingen holdes ved 40°C natten over.Dissolve 0.4 g (0.000458 mol) of the product obtained in b in 0.7 ml of ethylene glycol and 0.69 ml (0.00275 mol) of a 4 N solution of sodium methylate. To this solution is added 0.18 ml (0.00275 mol) of chloroethanol. The reaction mixture is heated to 40 ° C for 5 hours. 0.34 ml of 4 N sodium methylate and 0.1 ml of chloro-ethanol are added. The mixture is kept at 40 ° C overnight.
Reaktionsblandingens pH-værdi bringes til 7,00 ved tilsætning af fortyndet saltsyre.The pH of the reaction mixture is brought to 7.00 by the addition of dilute hydrochloric acid.
Ethylenglycolen afdampes i vakuum.The ethylene glycol is evaporated in vacuo.
Efter destillation optages remanensen i 6 ml vand og 5 ml kon-20 centreret saltsyre og omrøres så natten over ved omgivelsernes temperatur.After distillation, the residue is taken up in 6 ml of water and 5 ml of concentrated hydrochloric acid and then stirred overnight at ambient temperature.
Reaktionsblandingen koncentreres og renses så ved præparativ HPLC (RP 18, eluering med vand). Efter afdampning og tørring fås 0,1 g produkt i et samlet udbytte (alkylering - rensning) 25 på 27%.The reaction mixture is concentrated and then purified by preparative HPLC (RP 18, elution with water). After evaporation and drying, 0.1 g of product is obtained in a total yield (alkylation - purification) of 27%.
TLC (siliciumdioxid 60 F 254): CH2Cl2/methanol 7/3. Rf: 0,33.TLC (silica 60 F 254): CH 2 Cl 2 / methanol 7/3. Rf: 0.33.
HPLC, søjle af Hypersil C8, 5yu, 25 cm.HPLC, column of Hypersil C8, 5yu, 25 cm.
Stødpude: 0,01 M NaH2PC>4/MeOH 95/5.Cushion: 0.01 M NaH2PC> 4 / MeOH 95/5.
Renhed: 95%.Purity: 95%.
DK 175034 B1 20 EKSEMPEL 4.Example 17.
Fremstilling af 5-[3-hydroxy-2-(hydroxymethyl)-N-(2-hydroxy-ethyl)propionamido]-N-(2-hydroxyethyl)-Ν'-(2,3-dihydroxy-propyl)-2,4,6-trijod-isophthaiamid.Preparation of 5- [3-hydroxy-2- (hydroxymethyl) -N- (2-hydroxyethyl) propionamido] -N- (2-hydroxyethyl) -Ν '- (2,3-dihydroxy-propyl) -2 4,6-triiodo-isophthaiamid.
5 a) Fremstilling af 5-(2-isopropyl-l,3-dioxan-5-carboxamido)- 2.4.6- trijod-3-N'-(2-acetoxyethyl)carbamoyl-benzoylchlorid.5 a) Preparation of 5- (2-isopropyl-1,3-dioxane-5-carboxamido) -2,4,6-triiodo-3-N '- (2-acetoxyethyl) carbamoyl-benzoyl chloride.
5,36 g 2-isopropyl-l,3-dioxan-5-carboxylsyre (0,0308 mol) opløses i 18 ml DMAC. Reaktionsblandingen afkøles til 5°C, og 2,55 ml (0,0350 mol) SOClj tilsættes dråbevis, således at tem-10 peraturen forbliver under 15°C. Efter endt tilsætning henstilles reaktionsblandingen i 3 timer ved omgivelsernes temperatur.Dissolve 5.36 g of 2-isopropyl-1,3-dioxane-5-carboxylic acid (0.0308 mol) in 18 ml of DMAC. The reaction mixture is cooled to 5 ° C and 2.55 ml (0.0350 mole) of SOClj is added dropwise so that the temperature remains below 15 ° C. After the addition is complete, the reaction mixture is left for 3 hours at ambient temperature.
Derpå tilsættes 6,0 g (0,00906 mol) 5-amino-2,4,6-trijod-3-(N- 2-acetoxyethyl)carbamoyl-benzoylchlorid. Reaktionsblandingen holdes under argon i 4 dage ved omgivelsernes temperatur.Then 6.0 g (0.00906 mol) of 5-amino-2,4,6-triiodo-3- (N-2-acetoxyethyl) carbamoyl-benzoyl chloride is added. The reaction mixture is kept under argon for 4 days at ambient temperature.
15 DMAC fjernes i vakuum. Den fremkomne olie optages i ethylacetat. Den organiske fase vaskes med vand, tørres og koncentreres til tørhed. Produktet krystalliseres af 100 ml ether.DMAC is removed in vacuo. The resulting oil is taken up in ethyl acetate. The organic phase is washed with water, dried and concentrated to dryness. The product is crystallized from 100 ml of ether.
Efter frafiltrering og tørring fås 1,8 g produkt i et udbytte på 24%.After filtration and drying, 1.8 g of product is obtained in a yield of 24%.
20 TLC (silica 60 F 254): Ethylacetat/petroleumsether 80/20. Rf:0,83.TLC (silica 60 F 254): Ethyl acetate / petroleum ether 80/20. Rf: 0.83.
b) Fremstilling af 5-(2-isopropyl-l,3-dioxan-5-carboxamido)- 2.4.6- trijod-N-(2-acetoxyethyl)-Ν'-(2,3-dihydroxypropyl)iso-phthalamid.b) Preparation of 5- (2-isopropyl-1,3-dioxane-5-carboxamido) - 2,4,6-triiodo-N- (2-acetoxyethyl) -Ν '- (2,3-dihydroxypropyl) iso-phthalamide.
1 g (0,00122 mol) af produktet fremkommet i a opløses i 100 ml 25 DMAC, og derefter tilsættes 0,26 ml triethylamin (0,00189 mol). 0,18 g (0,00196 mol) 3-amino-l,2-propandiol sættes dråbevis til reaktionsblandingen. Efter endt tilsætning omrøres reaktionsblandingen under argon ved omgivelsernes temperatur i 24 timer.Dissolve 1 g (0.00122 mol) of the product obtained in a in 100 ml of DMAC and then add 0.26 ml of triethylamine (0.00189 mol). 0.18 g (0.00196 mole) of 3-amino-1,2-propanediol is added dropwise to the reaction mixture. Upon completion of the addition, the reaction mixture is stirred under argon at ambient temperature for 24 hours.
21 DK 175034 B121 DK 175034 B1
Triethylamin-hydrochloridet frafiltreres, og derpå afdampes DMAC. Den fremkomne olie krystalliseres af 20 ml ether.The triethylamine hydrochloride is filtered off and then DMAC is evaporated. The resulting oil is crystallized from 20 ml of ether.
Efter frafiltrering og tørring fås 0,8 g produkt i et udbytte på 75,5%.After filtration and drying, 0.8 g of product is obtained in 75.5% yield.
5 TLC (siliciumdioxid 60 F 254): CHCl3/MeOH/NH4OH 53/30/10.TLC (silica 60 F 254): CHCl 3 / MeOH / NH 4 OH 53/30/10.
Rf: 0,77.Rf: 0.77.
c) Fremstilling af 5-[3-hydroxy-2-(hydroxymethyl)-N-(2-hydroxyethyl)propionamido]-N-(2-hydroxyethyl)-Ν' -(2,3-dihydroxy-propyl)-2,4,6-trijodisophthaiamid.c) Preparation of 5- [3-hydroxy-2- (hydroxymethyl) -N- (2-hydroxyethyl) propionamido] -N- (2-hydroxyethyl) -Ν '- (2,3-dihydroxy-propyl) -2 4,6-trijodisophthaiamid.
10 0,4 g (0,000458 mol) af produktet fremkommet i b opløses i 0,7 ml ethylenglycol og 0,69 ml (0,00275 mol) af en 4 N ppløs-ning af natriummethylat. Til denne opløsning sættes 0,18 ml (0,00275 mol) chlorethanol. Reaktionsblandingen opvarmes til 40°C i 5 timer. 0,34 ml 4 N natriummethylat og 0,1 ml chlor-15 ethanol tilsættes. Blandingen holdes ved 40°C natten over.Dissolve 0.4 g (0.000458 mol) of the product obtained in b in 0.7 ml of ethylene glycol and 0.69 ml (0.00275 mol) of a 4 N solution of sodium methylate. To this solution is added 0.18 ml (0.00275 mol) of chloroethanol. The reaction mixture is heated to 40 ° C for 5 hours. 0.34 ml of 4 N sodium methylate and 0.1 ml of chloro-ethanol are added. The mixture is kept at 40 ° C overnight.
Reaktionsblandingens pH-værdi bringes til 7,00 ved tilsætning af fortyndet saltsyre.The pH of the reaction mixture is brought to 7.00 by the addition of dilute hydrochloric acid.
Ethylenglycolen afdampes i vakuum.The ethylene glycol is evaporated in vacuo.
Efter destillation optages remanensen i 6 ml vand og 5 ml kon-20 centreret saltsyre og omrøres så natten over ved omgivelsernes temperatur.After distillation, the residue is taken up in 6 ml of water and 5 ml of concentrated hydrochloric acid and then stirred overnight at ambient temperature.
Reaktionsblandingen koncentreres og renses så ved præparativ HPLC (RP 18, eluering med vand). Efter afdampning og tørring fås 0,1 g produkt i et samlet udbytte (alkylering - rensning) 25 på 271.The reaction mixture is concentrated and then purified by preparative HPLC (RP 18, elution with water). After evaporation and drying, 0.1 g of product is obtained in a total yield (alkylation - purification) of 271.
TLC (siliciumdioxid 60 F 254): Ci^C^/methanol 7/3. Rf: 0,33.TLC (silica 60 F 254): C) CC ^ / methanol 7/3. Rf: 0.33.
HPLC, søjle af Hypersil C8, 5yu, 25 cm.HPLC, column of Hypersil C8, 5yu, 25 cm.
Stødpude: 0,01 M NaH2P04/Me0H 95/5.Cushion: 0.01 M NaH2 PO4 / Me0H 95/5.
Renhed: 95%.Purity: 95%.
22 DK 175034 B1 •^H NMR (Bruker - 200 MHz) i DMSO: i overensstemmelse med den forventede struktur.22 DK 175034 B1 • 1 H NMR (User - 200 MHz) in DMSO: in accordance with expected structure.
Claims (8)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8807369A FR2632304B1 (en) | 1988-06-02 | 1988-06-02 | NON-IONIC TRIODOBENZENIC COMPOUNDS, PROCESS FOR THEIR PREPARATION AND CONTRAST PRODUCTS CONTAINING THEM |
| FR8807369 | 1988-06-02 | ||
| FR8900762A FR2643077B1 (en) | 1989-01-23 | 1989-01-23 | NOVEL IODIC NON-IONIC COMPOUNDS AND CONTRAST PRODUCTS CONTAINING THEM |
| FR8900762 | 1989-01-23 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK259589D0 DK259589D0 (en) | 1989-05-26 |
| DK259589A DK259589A (en) | 1989-12-03 |
| DK175034B1 true DK175034B1 (en) | 2004-05-03 |
Family
ID=26226693
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK198902595A DK175034B1 (en) | 1988-06-02 | 1989-05-26 | Iodized, nonionic triiodobenzene compounds and contrast agent containing them |
Country Status (25)
| Country | Link |
|---|---|
| EP (1) | EP0357467B1 (en) |
| JP (1) | JPH07100684B2 (en) |
| KR (1) | KR0148358B1 (en) |
| CN (1) | CN1021440C (en) |
| AT (1) | ATE98220T1 (en) |
| AU (1) | AU617810B2 (en) |
| CA (1) | CA1339665C (en) |
| CZ (1) | CZ277984B6 (en) |
| DE (1) | DE68911237T2 (en) |
| DK (1) | DK175034B1 (en) |
| DZ (1) | DZ1341A1 (en) |
| EG (1) | EG19008A (en) |
| ES (1) | ES2060800T3 (en) |
| FI (1) | FI102745B (en) |
| GE (1) | GEP19960460B (en) |
| HR (1) | HRP920498B1 (en) |
| HU (1) | HU201732B (en) |
| IL (1) | IL90326A (en) |
| LV (1) | LV10234B (en) |
| MA (1) | MA21565A1 (en) |
| NO (1) | NO177461C (en) |
| PT (1) | PT90696B (en) |
| RU (1) | RU1833365C (en) |
| SI (1) | SI8911042A (en) |
| YU (1) | YU48318B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2656865B1 (en) * | 1990-01-05 | 1993-03-26 | Guerbet Sa | NON-IONIC IODINE COMPOUND, PROCESS FOR PREPARING THE SAME, AND CONTRAST PRODUCT CONTAINING THE SAME. |
| FR2673180B1 (en) * | 1991-02-25 | 1994-03-04 | Guerbet Sa | NOVEL POLY-IODIC NON-IONIC COMPOUNDS, PREPARATION METHOD, CONTRAST PRODUCT CONTAINING THE SAME. |
| DE4109169A1 (en) * | 1991-03-20 | 1992-09-24 | Koehler Chemie Dr Franz | WATER-SOLUBLE NON-IONIC X-RAY CONTRASTING AGENTS AND AGENTS AND METHOD FOR THE PRODUCTION THEREOF |
| FR2695125B1 (en) * | 1992-08-25 | 1994-12-23 | Guerbet Sa | New polyiodinated compounds, preparation process, contrast medium containing them. |
| US6310243B1 (en) * | 1994-09-23 | 2001-10-30 | Nycomed Imaging As | Iodinated x-ray contrast media |
| PT101720A (en) * | 1995-06-08 | 1997-01-31 | Hovione Sociedade Quimica S A | PROCESS FOR THE PURIFICATION AND CRYSTALLIZATION OF IOPAMIDOL |
| US5705692A (en) * | 1996-09-27 | 1998-01-06 | Abbott Laboratories | Process for the preparation of iohexol |
| CN110903275A (en) * | 2018-09-14 | 2020-03-24 | 苏州科伦药物研究有限公司 | Process for producing iobitridol, intermediate therefor, and process for producing the same |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2909439A1 (en) * | 1979-03-08 | 1980-09-18 | Schering Ag | NEW NON-ionic x-ray contrast agents |
| US4396598A (en) * | 1982-01-11 | 1983-08-02 | Mallinckrodt, Inc. | Triiodoisophthalamide X-ray contrast agent |
| DE3429949A1 (en) * | 1984-08-10 | 1986-02-20 | Schering AG, 1000 Berlin und 4709 Bergkamen | Novel non-ionic 2,4,6-triiodoisophthalic acid bisamides, process for the preparation thereof and the use thereof as X-ray contrast media |
| WO1988009328A1 (en) * | 1987-05-22 | 1988-12-01 | Bracco Industria Chimica S.P.A. | Preparation of 5-acylamino-2,4,6-triiodo- or tribromo-benzoic acid derivatives |
| FR2632304B1 (en) * | 1988-06-02 | 1991-05-17 | Guerbert Sa | NON-IONIC TRIODOBENZENIC COMPOUNDS, PROCESS FOR THEIR PREPARATION AND CONTRAST PRODUCTS CONTAINING THEM |
-
1989
- 1989-05-17 IL IL90326A patent/IL90326A/en not_active IP Right Cessation
- 1989-05-21 DZ DZ890079A patent/DZ1341A1/en active
- 1989-05-22 SI SI8911042A patent/SI8911042A/en not_active IP Right Cessation
- 1989-05-22 YU YU104289A patent/YU48318B/en unknown
- 1989-05-23 KR KR1019890006875A patent/KR0148358B1/en not_active IP Right Cessation
- 1989-05-26 AU AU35235/89A patent/AU617810B2/en not_active Ceased
- 1989-05-26 DK DK198902595A patent/DK175034B1/en not_active IP Right Cessation
- 1989-05-30 RU SU894614183A patent/RU1833365C/en not_active IP Right Cessation
- 1989-05-31 CZ CS893291A patent/CZ277984B6/en not_active IP Right Cessation
- 1989-05-31 NO NO892189A patent/NO177461C/en not_active Application Discontinuation
- 1989-06-01 EG EG26789A patent/EG19008A/en active
- 1989-06-01 FI FI892681A patent/FI102745B/en not_active IP Right Cessation
- 1989-06-01 MA MA21817A patent/MA21565A1/en unknown
- 1989-06-01 JP JP1140222A patent/JPH07100684B2/en not_active Expired - Fee Related
- 1989-06-01 ES ES89401509T patent/ES2060800T3/en not_active Expired - Lifetime
- 1989-06-01 EP EP89401509A patent/EP0357467B1/en not_active Expired - Lifetime
- 1989-06-01 DE DE89401509T patent/DE68911237T2/en not_active Expired - Fee Related
- 1989-06-01 CN CN89103735A patent/CN1021440C/en not_active Expired - Lifetime
- 1989-06-01 CA CA000601412A patent/CA1339665C/en not_active Expired - Fee Related
- 1989-06-01 AT AT89401509T patent/ATE98220T1/en not_active IP Right Cessation
- 1989-06-01 PT PT90696A patent/PT90696B/en not_active IP Right Cessation
- 1989-06-02 HU HU892826A patent/HU201732B/en not_active IP Right Cessation
-
1992
- 1992-09-25 HR HRP-1042/89A patent/HRP920498B1/en not_active IP Right Cessation
-
1993
- 1993-03-11 GE GEAP1993599A patent/GEP19960460B/en unknown
- 1993-05-25 LV LVP-93-404A patent/LV10234B/en unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5043152A (en) | Novel iodinated non-ionic triiodobenzene compounds and contrast media containing them | |
| US5066823A (en) | Preparation of 5-acylamino-2,4,6-triiodo- or tribromo-benzoic acid derivatives | |
| DK175034B1 (en) | Iodized, nonionic triiodobenzene compounds and contrast agent containing them | |
| AU654341B2 (en) | New polyiodated compounds, method of preparation, contrast product containing them | |
| DE2508045A1 (en) | SUBSTITUTED N- (1-BENZYLPYRROLIDINYL-2-ALKYL) BENZAMIDES, METHOD FOR THE PREPARATION AND MEDICINAL PRODUCTS CONTAINING THESE | |
| US5191119A (en) | Process for producing non-ionic radiographic contrast media utilizing N-allylation | |
| US3914294A (en) | 3,5-Disubstituted-2,4,6-triiodobenzoic acids | |
| CS277109B6 (en) | Nonionic contrast means and process for preparing thereof | |
| JPS6058742B2 (en) | Novel iodinated isophthalamic acid derivative, its production method and X-ray contrast agent containing the derivative | |
| NO853953L (en) | R¯NTGENKONTRASTMIDLER. | |
| CA2142986A1 (en) | New polyiodinated compounds, process of preparation, and contrast agent containing them | |
| JPS59193857A (en) | Nonionic iodo- or bromo-benzene compounds and x ray contrastagent containing them | |
| FI67078C (en) | NYA ROENTGENKONTRASTMEDEL OCH FOERFARANDE FOER DERAS FRAMSTAELLNING | |
| KR100194506B1 (en) | Nonionic iodide compound, preparation method thereof and contrast agent containing the same | |
| US3666800A (en) | Substituted triiodoisophthalamic acids | |
| LT3251B (en) | Process for preparing trijodobenzene compounds | |
| IE63861B1 (en) | Novel iodinated non-ionic triiodobenzene compounds and contrast media containing them | |
| EP0196910B1 (en) | Benzo[a]phenazine derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PBP | Patent lapsed |
Country of ref document: DK |