WO2010057765A1 - Process for the preparation of iodinated contrast agent - Google Patents

Process for the preparation of iodinated contrast agent Download PDF

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Publication number
WO2010057765A1
WO2010057765A1 PCT/EP2009/064413 EP2009064413W WO2010057765A1 WO 2010057765 A1 WO2010057765 A1 WO 2010057765A1 EP 2009064413 W EP2009064413 W EP 2009064413W WO 2010057765 A1 WO2010057765 A1 WO 2010057765A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
reaction
hydroxide
amino
Prior art date
Application number
PCT/EP2009/064413
Other languages
English (en)
French (fr)
Inventor
Silvia Ceragioli
Giovanni Ciarciello
Salvatore Incandela
Pietro Minotti
Original Assignee
Bracco Imaging Spa
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to US13/127,804 priority Critical patent/US8624061B2/en
Priority to RU2011124888/04A priority patent/RU2493146C2/ru
Priority to SI200931735T priority patent/SI2365963T1/sl
Priority to CN200980145584.9A priority patent/CN102216259B/zh
Priority to MX2011005236A priority patent/MX2011005236A/es
Priority to ES09744402.0T priority patent/ES2637010T3/es
Priority to AU2009317450A priority patent/AU2009317450B2/en
Priority to JP2011536812A priority patent/JP5536087B2/ja
Application filed by Bracco Imaging Spa filed Critical Bracco Imaging Spa
Priority to BRPI0921464A priority patent/BRPI0921464B8/pt
Priority to CA2743079A priority patent/CA2743079C/en
Priority to DK09744402.0T priority patent/DK2365963T3/en
Priority to KR1020117011238A priority patent/KR101668042B1/ko
Priority to PL09744402T priority patent/PL2365963T3/pl
Priority to EP09744402.0A priority patent/EP2365963B1/en
Publication of WO2010057765A1 publication Critical patent/WO2010057765A1/en
Priority to IL212907A priority patent/IL212907A/en
Priority to HRP20171443TT priority patent/HRP20171443T1/hr

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Classifications

    • 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 generally relates to a process for the preparation of non ionic iodinated contrast agents and, in more details, it relates to a process for the preparation of Iopamidol in high yields and with a high degree of purity.
  • Iopamidol, as well as others non ionic iodinated contrast agents, is employed in the diagnostic field in the X- ray imagine techniques.
  • N,N'-Bis[2-hydroxy- 1 -(hydroxymethyl)ethyl]-5-[[(2S)-2-hydroxy- 1 -oxopropyl]- amino]-2,4,6-triiodo-l,3-benzendicarboxamide (see the formula below), generally known as Iopamidol (The Merck Index, XIII Ed., 2001 , Nr. 5073), is a compound broadly used for diagnostic methodologies:
  • aliphatic tertiary amines such as, for instance, triethylamine, tripropylamine, tributylamine and diisopropylethylamine.
  • inorganic bases such as e.g. dimethylacetamide (DMA).
  • F-impurity is within the list of possible side-products generated from the synthesis of iopamidol (e.g. see European Pharmacopoeia 6.0 Ed. 01/2008:1115).
  • the process of the present invention enables for the preparation of iopamidol with a particularly low amount of F-impurity as well as others side-products, whilst using inorganic bases. All the above allows for the removal of such side products by ordinary purification steps, so to collect the final product within the imposed limitations, as previously indicated
  • alkaline or alkaline-rare earth metal oxide or hydroxide mean the lithium, potassium, magnesium or calcium oxides or hydroxides.
  • oxides particularly preferred are the calcium and magnesium oxides.
  • the reaction is performed in the presence of sodium or calcium hydroxide, and even more preferably, in the presence of calcium hydroxide.
  • hydroxide is carried out according to those techniques conventionally employed in industrial applications, i.e. by adding a suitable amount of the selected base, either in a solid form or as an aqueous solution.
  • Said addition is performed by a single addition or, alternatively, portion-wise, up to the achievement of the necessary amount of hydroxide.
  • the selected base is employed in a ratio of at least 2:1 (equivalents) compared to the amount of compound (II) [i.e. in a ratio of 1 :1 (equivalents), compared to the amount of 2-amino-l,3-propandiol] and more preferably in excess.
  • the base may be added to the solution of compound (II) either previously, or at the same time, or even after, the addition of 2- amino- 1 ,3-propandiol.
  • the mixture is conveniently stirred, according to the common procedures as industrially employed.
  • the addition of both the 2-amino-l,3- propandiol and the base is performed gradually, by monitoring the reaction mixture temperature, being said temperature kept under about 30 0 C.
  • reaction is carried out in the presence of an aprotic dipolar organic solvent, preferably dimethylacetamide (DMA).
  • DMA dimethylacetamide
  • the starting material i.e. compound of formula (II)
  • compound of formula (II) is a known compound, and, in case, it can be prepared according to the above scheme, starting from the corresponding 5-amino-2,4,6-triiodoisophtalic acid dichloride of formula (I).
  • the compound of formula (III) may be obtained according to the process object of the present invention, either starting from compound of formula (II) as such, or, optionally, starting from the corresponding compound of formula (I), without the needing of isolate the intermediate of formula (II), thus formed.
  • the condensation reaction between the 5-amino-2,4,6-triiodoisophtalic acid dichloride of formula (I) and (S)-[2-(acetyloxy)]propionic acid dichloride, as per step (a), is accomplished following methods known in the art, preferably in DMA as possible aprotic dipolar organic solvent.
  • reaction mixture is then directly added with the selected alkaline or alkaline rare-earth metal oxide or hydroxide along with the suitable amount of 2-amino- 1,3-propandiol, in a manner as previously reported.
  • the amount of base to be employed is remarkably higher.
  • the base is employed not only for the neutralization of the acid formed during the reaction of amidation between 5-amino-2,4,6-triiodoisophtalic acid dichloride (I) and (S)-[2-(acetyloxy)]propionic acid dichloride, but also for the neutralization of the acid that may arise from the possible excess of (S)-[2- (acetyloxy)]propionic acid dichloride, and, also, for the neutralization of the acid formed during the amidation reaction between compound (II) and 2-amino-l,3- propandiol.
  • the selected base when the present process is carried out without isolation of the intermediate(II), is employed in a ratio of at least 3:1 (equivalents) respect to the amount of 5-amino-2,4,6- triiodoisophtalic acid dichloride of formula (I), and more preferably in excess.
  • the addition of the base to the reaction system is performed before the addition of 2-amino-l,3-propandiol actually occurs.
  • the addition of the reactives e.g. the addition of the hydroxide or oxide, either in a solid form or as aqueous solution, and the 2-amino-l,3-propandiol, is preferably effected slowly or portion-wise, under stirring and keeping the temperature below about 30 0 C.
  • the addition of the base to the crude reaction material, which contains the intermediate of formula (II), is conducted at a temperature between about 5°C and about 20 0 C.
  • the thus obtained compound of formula (III), either starting from the isolated compound of formula (II) or starting from the corresponding precursor of formula (I), is afterwards converted in iopamidol (IV), by operating according to the methods known in literature.
  • compound of formula (III) is first isolated from the crude reaction material, purified, optionally by a passage through ionic exchange resins, and then hydrolyzed under basic conditions for the cleavage of the acetyl group.
  • a further object of the present invention a process for the preparation of iopamidol (IV) comprising the basic hydrolysis of the corresponding acetyl iopamidol of formula (III), being said compound of formula (III) prepared as previously indicated, i.e.
  • the process in object leads to the desired product in high yield and with a high degree of purity.
  • the amount of the existing impurities, and among them the F-impurity as mentioned above, is particularly low so that said impurities may be removed, by conventional purification methodologies.
  • the present process may have a general industrial applicability and may be advantageously applied in the preparation of other iodinated non ionic contrast agents, which synthesis contemplate the condensation reaction between a suitable derivative of the dichloride of the 5-amino-2,4,6-triiodoisophtalic acid and an aminoalcohol. It is therefore an additional object of the present invention a process for the preparation of a compound of formula (VII) comprising the condensation reaction between the acid dichloride of formula (V) with an aminoalcohol of formula (VI), being said reaction carried out in an aprotic dipolar solvent and in the presence of an alkaline or rare-earth alkaline metal oxide or hydroxide
  • R is a linear or branched alkyl group with 1 to 6 carbon atoms, optionally substituted by one or more hydroxy groups optionally in a protected form, being said alkyl group optionally interrupted by one or more hetero atoms selected from -O- and -NH-;
  • Ri is a hydrogen atom or it has one of the meanings of R;
  • R 2 is a linear or branched alkyl group with 1 to 4 carbon atoms, substituted by at least one hydroxy group;
  • R 3 is a hydrogen atom or has one of the meanings of R 2 .
  • linear or branched alkyl group with 1 to 6 carbon atoms means those groups such as, for instance, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like.
  • Said alkyl group is optionally substituted by one or more hydroxy groups as such, or preferably, in a protected form.
  • protected form we intend that the hydroxy group is conveniently protected by a suitable moiety which is responsible for the preservation of the subjected group, during the course of the reaction, to be subsequently removed according to known methods, so to cleave the hydroxy group back to the original form.
  • the hydroxy group is preferably protected by an acyl group, e.g. acetyl (-COCH3), so that the corresponding acetoxy moiety (-OCOCH 3 ) is thus formed.
  • an acyl group e.g. acetyl (-COCH3)
  • the aminoalcohol of formula (VI) is preferably selected from 2- amino-l,3-propandiol or 3-amino-l,2-propandiol, so that the group R 2 corresponds to [- CH(CH 2 OH) 2 or -CH 2 CHOHCH 2 OH], respectively.
  • the aprotic dipolar organic solvent the proper oxide or hydroxide, as well as the major process parameters, see what previously described.
  • reaction mixture On completion of the reaction, the reaction mixture is properly diluted with a supplementary amount of solvent and optionally cooled, e.g. at about 15°C.
  • a suitable amount of selected base for instance powdered calcium hydroxide, along with a proper amount of 2-amino-l,3-propandiol are thus added.
  • the mixture is finally kept under stirring overnight at the selected temperature, e.g. at about 30 0 C, up to the completion of the reaction.
  • the obtained raw material is distilled under vacuum to remove the most of the solvent, and the residual crude is diluted with water and purified by means of a cationic resin, according to conventional techniques.
  • the eluted material, containing the product of formula (III), is then hydrolyzed under basic conditions and, at the completion of the reaction, the mixture is adjusted to a pH substantially neutral (i.e. around 7).
  • the resulting mixture which contains iopamidol (IV) is finally purified by known methods, comprising, for instance, purification through resins, nano- filtration and crystallization in the presence of a suitable alcohol, such as, e.g., 2-butanol.
  • a suitable alcohol such as, e.g., 2-butanol.
  • the crude reaction material containing the derivative of formula (III) may be purified and hydro lyzed according to the procedure of the following Example 3.
  • the crude reaction mixture was then distilled under vacuum (95°C, 10 mbar, 7.5 mmHg) to remove the most of the solvent, up to the obtainment of a viscous residue.
  • the hot residue was then treated with deionised water (1455 g) and the pH was adjusted to 1.7 by addition of hydrochloric acid (33 g, 34% w/w).
  • the resulting solution was eluted through 1500 mL of a strong cationic exchange resin (Dowex C350TM by DOW) in the Na + form, to remove the Ca 2+ ions, along with the excess of 2-amino-l,3-propandiol.
  • the eluted solution was afterward treated with a solution of sodium hydroxide (250 g, 30%) and kept at about 35°C for 7 hours, in order to hydro lyse the acetic ester.
  • the pH was then adjusted at a value of about 7 by addition of hydrochloric acid and the resulting solution was treated with sodium sulphite (0.25 g), purified on a PS-DVB resin (1300 mL, Amberlite XAD 100TM by Rohm and Haas) and then desalted by nano- filtration.
  • the final desalting step was performed by a series of two resin plates comprising 425 mL of a strong cationic exchange resin in the H + form (Dowex C350TM) and 500 mL of weak anionic exchange resin (Re lite MG1 ® by Mitsubishi).
  • the resulting solution was then concentrated under vacuum, obtaining by that a water content of 30% w/w, and the residue was crystallized from 2-butanol (1250 g).
  • the crystallization was completed by adding a suitable aliquot of 2-butanol and by simultaneously distilling off the azeotrope at atmospheric pressure, up to a water content in the suspension close to 3% w/w.
  • the product was filtered and dried under vacuum at about 50 0 C, to obtain iopamidol (591 g, 90.0% of yield, starting from compound (II).
  • the thus obtained iopamidol satisfied the purity specifications as required.
  • Example 5 The procedure of the Example 5 was modified by operating at a lower temperature, as described herein below.
  • the crude reaction material was then distilled under vacuum (95°C, 10 mbar, 7,5 mmHg) to remove the most of the solvent, until the formation of a viscous residue.
  • the hot residue was hence treated with deionised water (1460 g) and the pH was adjusted to 2 by addition of hydrochloric acid (108 g, 34% w/w).
  • the eluted was then treated with a solution of sodium hydroxide (260 g, 30%) and maintained at 35°C for 7 hours to hydrolyze the acetic ester.
  • the pH was adjusted to 7 by addition of hydrochloric acid and the resulting solution was treated with sodium sulphite (0,25 g), purified on a PS-DVB resin (1300 mL, Amberlite XAD1600TM by Rohm and Haas) and therefore desalted by nano-filtration.
  • the final desalting step was performed by a series of two resin plates comprising 425 mL of a strong cationic exchange resin in the H + form (Dowex C350TM) and 500 mL of a week anionic exchange resin (Relite MG1 ® by Mitsubishi).
  • the resulting solution was then concentrated under vacuum until the obtainment of a water content of about 30% w/w, and the residue was then crystallized from 2-butanol (1250 g).
  • the crystallization was completed by adding 2-butanol and simultaneously distilling off the azeotrope at atmospheric pressure until the water content in the suspension was about 3% w/w.
  • the product was filtered and dried under vacuum at about 50 0 C, to obtain iopamidol (576 g, 87.3% yield starting from compound II ).
  • the iopamidol thus obtained satisfies the purity specifications as required.
  • Example 8 The same procedure as the previous Example 7 was followed, with the exception that calcium hydroxide was replaced by a same molar amount of calcium oxide. Iopamidol was obtained with 83.0% yield starting from compound II and satisfies the purity specifications as required.
  • Example 8
  • Example 5 The same procedure as the previous Example 5 was modified by using sodium carbonate in place of calcium hydroxide, as follow. 423 g of the crude reaction material in DMA as per Example 4 (0.25 theoretical mol of compound II) was diluted with DMA (200 g) and the mixture was cooled at -5°C.
  • Example 5 The procedure as per Example 5 was modified by using trietilamine in place of calcium hydroxide as follow. 423 g of the crude reaction material in DMA as per Example 4 (0.25 theoretical mol of compound II) was diluted with DMA (199 g) and the mixture was cooled at a temperature of about -5°C. Triethylamine (114 g, 1.13 mol) was then slowly added to the reaction mixture, under stirring and keeping the temperature lower than 5 0 C. After that, a solution of 2-amino-l,3-propandiol in DMA (231 g, 24% w/w, 0.61 mol) was added over 1 hour. The mixture was then heated at 70 0 C and maintained in such conditions for 3 hours until the completion of the reaction. By operating in an analogue manner as Example 3, iopamidol (IV) was thus obtained by purification and hydrolysis of the compound of formula (III).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
PCT/EP2009/064413 2008-11-18 2009-11-02 Process for the preparation of iodinated contrast agent WO2010057765A1 (en)

Priority Applications (16)

Application Number Priority Date Filing Date Title
BRPI0921464A BRPI0921464B8 (pt) 2008-11-18 2009-11-02 processo para preparação de agente de contraste iodado
RU2011124888/04A RU2493146C2 (ru) 2008-11-18 2009-11-02 Способ получения йодированного контрастного агента
CA2743079A CA2743079C (en) 2008-11-18 2009-11-02 Process for the preparation of iodinated contrast agent
MX2011005236A MX2011005236A (es) 2008-11-18 2009-11-02 Proceso para la preparacion de agente de contraste yodado.
ES09744402.0T ES2637010T3 (es) 2008-11-18 2009-11-02 Proceso para la preparación de agente de contraste yodado
AU2009317450A AU2009317450B2 (en) 2008-11-18 2009-11-02 Process for the preparation of iodinated contrast agent
JP2011536812A JP5536087B2 (ja) 2008-11-18 2009-11-02 ヨウ化造影剤の製造方法
US13/127,804 US8624061B2 (en) 2008-11-18 2009-11-02 Process for the preparation of iodinated contrast agent
SI200931735T SI2365963T1 (sl) 2008-11-18 2009-11-02 Postopek priprave jodiranih kontrastnih sredstev
CN200980145584.9A CN102216259B (zh) 2008-11-18 2009-11-02 制备碘化的造影剂的方法
DK09744402.0T DK2365963T3 (en) 2008-11-18 2009-11-02 PROCEDURE FOR THE PREPARATION OF IODATED CONTRACTOR
KR1020117011238A KR101668042B1 (ko) 2008-11-18 2009-11-02 요오드화된 조영제의 제조방법
PL09744402T PL2365963T3 (pl) 2008-11-18 2009-11-02 Sposób przygotowywania jodowanych środków kontrastowych
EP09744402.0A EP2365963B1 (en) 2008-11-18 2009-11-02 Process for the preparation of iodinated contrast agent
IL212907A IL212907A (en) 2008-11-18 2011-05-16 A method of producing contrast material containing iodine
HRP20171443TT HRP20171443T1 (hr) 2008-11-18 2017-09-26 Postupak za pripremanje jodiranog kontrastnog sredstva

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI20082042 2008-11-18
ITMI2008A002042 2008-11-18

Publications (1)

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WO2010057765A1 true WO2010057765A1 (en) 2010-05-27

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PCT/EP2009/064413 WO2010057765A1 (en) 2008-11-18 2009-11-02 Process for the preparation of iodinated contrast agent

Country Status (19)

Country Link
US (1) US8624061B2 (pt)
EP (1) EP2365963B1 (pt)
JP (1) JP5536087B2 (pt)
KR (1) KR101668042B1 (pt)
CN (1) CN102216259B (pt)
AU (1) AU2009317450B2 (pt)
BR (1) BRPI0921464B8 (pt)
CA (1) CA2743079C (pt)
DK (1) DK2365963T3 (pt)
ES (1) ES2637010T3 (pt)
HR (1) HRP20171443T1 (pt)
HU (1) HUE034436T2 (pt)
IL (1) IL212907A (pt)
MX (1) MX2011005236A (pt)
PL (1) PL2365963T3 (pt)
PT (1) PT2365963T (pt)
RU (1) RU2493146C2 (pt)
SI (1) SI2365963T1 (pt)
WO (1) WO2010057765A1 (pt)

Cited By (4)

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RU2481325C2 (ru) * 2008-12-05 2013-05-10 Даевунг Фармасьютикал Ко., Лтд. Способ селективной кристаллизации z-изомера иопромида
GB2496971A (en) * 2011-11-25 2013-05-29 Ge Healthcare As Preparation of X-ray contrast agents
US9950991B2 (en) 2013-11-05 2018-04-24 Bracco Imaging S.P.A. Process for the preparation of iopamidol
WO2018104228A1 (en) 2016-12-05 2018-06-14 Bracco Imaging Spa Mechanochemical synthesis of radiographic agents intermediates

Families Citing this family (2)

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PT108524B (pt) * 2015-06-02 2017-12-15 Hovione Farmaciência S A Processo para a preparação de intermediários úteis na preparação de agentes de contraste não-iónicos
CN106831480B (zh) * 2015-12-07 2019-01-15 北京大学 基于碘帕醇脂质衍生物的造影剂及其制备方法与用途

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2481325C2 (ru) * 2008-12-05 2013-05-10 Даевунг Фармасьютикал Ко., Лтд. Способ селективной кристаллизации z-изомера иопромида
GB2496971A (en) * 2011-11-25 2013-05-29 Ge Healthcare As Preparation of X-ray contrast agents
US9950991B2 (en) 2013-11-05 2018-04-24 Bracco Imaging S.P.A. Process for the preparation of iopamidol
US10377700B2 (en) 2013-11-05 2019-08-13 Bracco Imaging S.P.A. Process for the recovery of a boronic acid
WO2018104228A1 (en) 2016-12-05 2018-06-14 Bracco Imaging Spa Mechanochemical synthesis of radiographic agents intermediates
US10836710B2 (en) 2016-12-05 2020-11-17 Bracco Imaging Spa Mechanochemical synthesis of radiographic agents intermediates

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US20110207960A1 (en) 2011-08-25
JP5536087B2 (ja) 2014-07-02
IL212907A (en) 2015-03-31
BRPI0921464B8 (pt) 2021-05-25
BRPI0921464A2 (pt) 2016-01-12
IL212907A0 (en) 2011-07-31
CA2743079A1 (en) 2010-05-27
EP2365963A1 (en) 2011-09-21
HUE034436T2 (en) 2018-02-28
KR101668042B1 (ko) 2016-10-20
US8624061B2 (en) 2014-01-07
RU2011124888A (ru) 2012-12-27
DK2365963T3 (en) 2017-10-09
HRP20171443T1 (hr) 2017-11-03
ES2637010T3 (es) 2017-10-10
RU2493146C2 (ru) 2013-09-20
AU2009317450B2 (en) 2015-05-07
PT2365963T (pt) 2017-08-22
BRPI0921464B1 (pt) 2020-10-06
MX2011005236A (es) 2011-06-16
CA2743079C (en) 2014-03-25
KR20110093805A (ko) 2011-08-18
AU2009317450A1 (en) 2010-05-27
EP2365963B1 (en) 2017-06-28
PL2365963T3 (pl) 2017-12-29
SI2365963T1 (sl) 2017-11-30
CN102216259A (zh) 2011-10-12
JP2012509290A (ja) 2012-04-19
CN102216259B (zh) 2016-01-20

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