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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Lutetium (177Lu) chloride


Lutetium (177Lu) chloride.png
LuCl3structure.jpg

Lutetium (177Lu) chloride

塩化ルテチウム (177Lu)

FormulaLu. 3Cl
CAS16434-14-3
Mol weight281.326

2022/9/15 EMA 2022, Illuzyce

EndolucinBeta

(177Lu)lutetium(3+) trichloride

Diagnostic aid, Radioactive agent

Lutetium 177 is an isotope of a rare-earth lanthanide metal lutetium. Radioactive decay of Lu 177 produces electrons with low energies making the isotope suitable for treatment of metastatic disease. A complex of Lu177 and somatostatin analog DOTA-TATE was approved by the FDA for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors, including foregut, midgut, and hindgut neuroendocrine tumors in adults. It is marketed under a tradename Lutathera. Lutetium in the complex with other carriers – phosphonates and monoclonal antibodies – was investigated in clinical trials as radiotherapy to prostate, ovarian, renal and other types of cancer.Lutetium (177Lu) chloride is a radioactive compound used for the radiolabeling of pharmaceutical molecules, aimed either as an anti-cancer therapy or for scintigraphy (medical imaging).[5][6] It is an isotopomer of lutetium(III) chloride containing the radioactive isotope 177Lu, which undergoes beta decay with a half-life of 6.65 days.

Medical uses

Lutetium (177Lu) chloride is a radiopharmaceutical precursor and is not intended for direct use in patients.[5] It is used for the radiolabeling of carrier molecules specifically developed for reaching certain target tissues or organs in the body. The molecules labeled in this way are used as cancer therapeutics or for scintigraphy, a form of medical imaging.[5] 177Lu has been used with both small molecule therapeutic agents (such as 177Lu-DOTATATE) and antibodies for targeted cancer therapy[8][9]

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Clinical data
Trade namesLumark, EndolucinBeta, Illuzyce
AHFS/Drugs.comLumark UK Drug Information
EndolucinBeta UK Drug Information
License dataEU EMAby INN
Pregnancy
category
AU: X (High risk)[1][2]
ATC codeNone
Legal status
Legal statusAU: Unscheduled [3][4]EU: Rx-only [5][6][7]In general: ℞ (Prescription only)
Identifiers
showIUPAC name
CAS Number16434-14-3
PubChem CID71587001
DrugBankDBSALT002634
ChemSpider32700269
UNII1U477369SN
KEGGD10828
CompTox Dashboard (EPA)DTXSID20167745 
Chemical and physical data
FormulaCl3Lu
Molar mass281.32 g·mol−1
3D model (JSmol)Interactive image
hideSMILES[Cl-].[Cl-].[Cl-].[177Lu+3]

Contraindications

Medicines radiolabeled with lutetium (177Lu) chloride must not be used in women unless pregnancy has been ruled out.[5]

Adverse effects

The most common side effects are anaemia (low red blood cell counts), thrombocytopenia (low blood platelet counts), leucopenia (low white blood cell counts), lymphopenia (low levels of lymphocytes, a particular type of white blood cell), nausea (feeling sick), vomiting and mild and temporary hair loss.[5]

Society and culture

Legal status

Lutetium (177Lu) chloride (Lumark) was approved for use in the European Union in June 2015.[5] Lutetium (177Lu) chloride (EndolucinBeta) was approved for use in the European Union in July 2016.[6]

On 21 July 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Illuzyce, a radiopharmaceutical precursor.[10] Illuzyce is not intended for direct use in patients and must be used only for the radiolabelling of carrier medicines that have been specifically developed and authorized for radiolabelling with lutetium (177Lu) chloride.[10] The applicant for this medicinal product is Billev Pharma ApS.[10] Illuzyce was approved for medical use in the European Union in September 2022.[7]

References

  1. ^ “Lutetium (177Lu) Chloride”Therapeutic Goods Administration (TGA). 21 January 2022. Archived from the original on 5 February 2022. Retrieved 5 February 2022.
  2. ^ “Updates to the Prescribing Medicines in Pregnancy database”Therapeutic Goods Administration (TGA). 12 May 2022. Archived from the original on 3 April 2022. Retrieved 13 May 2022.
  3. ^ “TGA eBS – Product and Consumer Medicine Information Licence”Archived from the original on 5 February 2022. Retrieved 5 February 2022.
  4. ^ http://www.ebs.tga.gov.au/servlet/xmlmillr6?dbid=ebs/PublicHTML/pdfStore.nsf&docid=1C7A40803A3A3F94CA2587D4003CE48A&agid=(PrintDetailsPublic)&actionid=1 Archived 30 July 2022 at the Wayback Machine[bare URL PDF]
  5. Jump up to:a b c d e f g “Lumark EPAR”European Medicines Agency (EMA)Archived from the original on 25 October 2020. Retrieved 7 May 2020. Text was copied from this source under the copyright of the European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  6. Jump up to:a b c “EndolucinBeta EPAR”European Medicines Agency (EMA)Archived from the original on 28 October 2020. Retrieved 7 May 2020. Text was copied from this source under the copyright of the European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  7. Jump up to:a b “Illuzyce EPAR”European Medicines Agency (EMA). 18 July 2022. Archived from the original on 22 September 2022. Retrieved 21 September 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  8. ^ Lundsten S, Spiegelberg D, Stenerlöw B, Nestor M (December 2019). “The HSP90 inhibitor onalespib potentiates 177Lu‑DOTATATE therapy in neuroendocrine tumor cells”International Journal of Oncology55 (6): 1287–1295. doi:10.3892/ijo.2019.4888PMC 6831206PMID 31638190.
  9. ^ Michel RB, Andrews PM, Rosario AV, Goldenberg DM, Mattes MJ (April 2005). “177Lu-antibody conjugates for single-cell kill of B-lymphoma cells in vitro and for therapy of micrometastases in vivo”. Nuclear Medicine and Biology32 (3): 269–78. doi:10.1016/j.nucmedbio.2005.01.003PMID 15820762.
  10. Jump up to:a b c “Illuzyce: Pending EC decision”European Medicines Agency. 21 July 2022. Archived from the original on 30 July 2022. Retrieved 30 July 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

External links

.///////////Lutetium (177Lu) chloride, EMA 2022, EU 2022, APPROVALS 2022,  Illuzyce, EndolucinBeta, 塩化ルテチウム (177Lu), 

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Gadopiclenol


STR1
Chemical structure of gadopiclenol [gadolinium chelate of 2,2′,2″-(3,6,9-triaza-1(2,6)-pyridinacyclodecaphane-3,6,9-triyl)tris(5-((2,3-dihydroxypropyl)amino)-5-oxopentanoic acid)]. The PCTA parent structure is shown in red. Two water molecules are included to show the coordination in solution.
Molecules 27 00058 g003 550

Gadopiclenol

ガドピクレノール;

FormulaC35H54N7O15. Gd
CAS933983-75-6
Mol weight970.0912

FDA APPROVED 2022/9/21, Elucirem

Diagnostic agent (MR imaging), WHO 10744, P 03277, UNII: S276568KOY

EluciremTM; G03277; P03277; VUEWAY

(alpha3,alpha6,alpha9-Tris(3-((2,3-dihydroxypropyl)amino)-3-oxopropyl)-3,6,9,15-tetraazabicyclo(9.3.1)pentadeca-1(15),11,13-triene-3,6,9-triacetato(3-)-kappaN3,kappaN6,kappaN9,kappaN15,kappaO3,kappaO6,kappaO9)gadolinium

Molecules 27 00058 g002 550
  • OriginatorGuerbet
  • ClassDiagnostic agents; Gadolinium-containing contrast agents; Macrocyclic compounds; Propylamines; Pyridines
  • Mechanism of ActionMagnetic resonance imaging enhancers
  • RegisteredCNS disorders
  • Phase IIIUnspecified
  • Phase IILiver cancer
  • 21 Sep 2022Registered for CNS disorders (Diagnosis) in USA (IV)
  • 13 Jun 2022Guerbet plans to launch Gadopiclenol in Europe
  • 13 Jun 2022The European Medicines Agency (EMA) accepts brand name EluciremTM for Gadopiclenol

PATENT

https://patents.google.com/patent/WO2020030618A1/en

MRI contrast agents used in daily diagnostic practice typically include gadolinium complex compounds characterized by high stability constants that guarantee against the in vivo release of the free metal ion (that is known to be extremely toxic for living organisms).

Another key parameter in the definition of the tolerability of a gadolinium-based contrast agent is the kinetic inertness (or kinetic stability) of Gd(III)-complex, that is estimated through the half-life (ti/2) of the dissociation (i.e. decomplexation) of the complex.

A high inertness becomes crucial in particular for those complex compounds having lower thermodynamic stability and/or longer retention time before excretion, in order to avoid or minimize possible decomplexation or transmetallation reactions.

EP1931673 (Guerbet) discloses PCTA derivatives of formula

Figure imgf000002_0001

and a synthetic route for their preparation.

EP 2988756 (same Applicant) discloses a pharmaceutical composition comprising the above derivatives together with a calcium complex of 1,4,7, 10-tetraazacyclododecane- 1,4,7, 10-tetraacetic acid. According to the EP 2988756, the calcium complex compensates the weak thermodynamic stability observed for PCTA-based gadolinium complexes, by forming, through transmetallation, a strong complex with free lanthanide ion, thereby increasing the tolerability of the contrast agent.

Both EP1931673 and EP 2988756 further refer to enantiomers or diastereoisomers of the claimed compounds, or mixture thereof, preferentially chosen from the RRS, RSR, and RSS diastereoisomers. Both the above patents disclose, among the specific derivatives, (a3, a6, a9)-tris(3- ((2,3-dihydroxypropyl)amino)-3-oxopropyl)-3,6,9,15-tetraazabicyclo(9.3.1)pentadeca- l(15),l l,13-triene-3,6,9-triacetato(3-)-(KN3,KN6,KN9,KN15,K03,K06,K09)gadolinium, more recently identified as gadolinium chelate of 2,2′,2″-(3,6,9-triaza-l(2,6)- pyridinacyclodecaphane-3,6,9-triyl)tris(5-((2,3-dihydroxypropyl)amino)-5-oxopentanoic acid), (CAS registry number: 933983-75-6), having the following formula

Figure imgf000003_0001

otherwise identified as P03277 or Gadopiclenol.

For Gadopiclenol, EP1931673 reports a relaxivity of 11 mM _1_1Gd 1 (in water, at 0.5 T, 37°C) while EP 2988756 reports a thermodynamic equilibrium constant of 10 14 9 (log Kterm

= 14.9).

Furthermore, for this same compound a relaxivity value of 12.8 mM _11 in human serum (37°C, 1.41 T), stability (log Kterm) of 18.7, and dissociation half-life of about 20 days (at pH 1.2; 37°C) have been reported by the proprietor (Investigative Radiology 2019, Vol 54, (8), 475-484).

The precursor for the preparation of the PCTA derivatives disclosed by EP1931673 (including Gadopiclenol) is the Gd complex of the 3,6,9,15-tetraazabicyclo- [9.3.1]pentadeca-l(15),l l,13-triene-tri(a-glutaric acid) having the following formula

Figure imgf000003_0002

Gd(PCTA-tris-glutaric acid)

herein identified as “Gd(PCTA-tris-glutaric acid)”. In particular, Gadopiclenol is obtained by amidation of the above compound with isoserinol.

As observed by the Applicant, Gd(PCTA-tris-qlutaric acid) has three stereocenters on the glutaric moieties (identified with an asterisk (*) in the above structure) that lead to a 23 = 8 possible stereoisomers. More particularly, the above structure can generate four pairs of enantiomers, schematized in the following Table 1

Table 1

Figure imgf000004_0002

Isomer RRR is the mirror image of isomer SSS and that is the reason why they are called enantiomers (or enantiomer pairs). As known, enantiomers display the same physicochemical properties and are distinguishable only using chiral methodologies, such as chiral chromatography or polarized light.

On the other hand, isomer RRR is neither equal to nor is it the mirror image of any of the other above six isomers; these other isomers are thus identified as diastereoisomers of the RRR (or SSS) isomer. Diastereoisomers may display different physicochemical properties, (e.g., melting point, water solubility, relaxivity, etc.).

Concerning Gadopiclenol, its chemical structure contains a total of six stereocenters, three on the glutaric moieties of the precursor as above discussed and one in each of the three isoserinol moieties attached thereto, identified in the following structure with an asterisk (*) and with an empty circle (°), respectively:

Figure imgf000004_0001

This leads to a total theoretical number of 26 = 64 stereoisomers for this compound. However, neither EP1931673 nor EP 2988756 describe the exact composition of the isomeric mixture obtained by following the reported synthetic route, nor does any of them provide any teaching for the separation and characterization of any of these isomers, or disclose any stereospecific synthesis of Gadopiclenol. Summary of the invention

The applicant has now found that specific isomers of the above precursor Gd(PCTA- tris-glutaric acid) and of its derivatives (in particular Gadopiclenol) possess improved physico-chemical properties, among other in terms of relaxivity and kinetic inertness.

An embodiment of the invention relates to a compound selected from the group consisting of:

the enantiomer [(aR,a’R,a”R)-a,a’,a”-tris(2-carboxyethyl)-3,6,9,15- tetraazabicyclo[9.3.1]pentadeca-l(15),l l,13-triene-3,6,9-triacetato(3-)- Kl\l3,Kl\l6,Kl\l9,Kl\ll5,K03,K06,K09]-gadolinium (RRR enantiomer) having the formula (la):

Figure imgf000005_0001

the enantiomer [(aS,a’S,a”S)-a,a’,a”-tris(2-carboxyethyl)-3,6,9,15-tetraazabicyclo- [9.3.1]pentadeca-l(15),ll,13-triene-3,6,9-triacetato(3-)KN3,KN6,KN9,KN15,K03,K06,K09]- gadolinium (SSS enantiomer) having the formula (lb):

Figure imgf000005_0002

the mixtures of such RRR and SSS enantiomers, and a pharmaceutically acceptable salt thereof.

Another embodiment of the invention relates to an isomeric mixture of Gd(PCTA-tris- glutaric acid) comprising at least 50% of the RRR isomer [(aR,a’R,a”R)-a,a’,a”-tris(2- carboxyethyl)-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-l(15),l l,13-triene-3,6,9- triacetato(3-)-KN3,KN6,KN9,KN15,K03,K06,K09]-gadolinium, of formula (la), or of the SSS isomer [(aS,a’S,a”S)-a,a’,a”-tris(2-carboxyethyl)-3,6,9,15- tetraazabicyclo[9.3.1]pentadeca-l(15),l l,13-triene-3,6,9-triacetato(3-)- Kl\l3,Kl\l6,Kl\l9,Kl\ll5,K03,K06,K09]-gadolinium of formula (lb), or of a mixture thereof, or a pharmaceutically acceptable salt thereof. Another aspect of the invention relates to the amides obtained by conjugation of one of the above compounds or isomeric mixture with an amino group, e.g. preferably, serinol or isoserinol.

An embodiment of the invention relates to an amide derivative of formula (II A)

F( N RI R2)3 (II A)

in which :

F is:

a RRR enantiomer residue of formula Ilia

Figure imgf000006_0001

a SSS enantiomer residue of formula Illb

Figure imgf000006_0002

or a mixture of such RRR and SSS enantiomer residues;

and each of the three -NRIR2 group is bound to an open bond of a respective carboxyl moiety of F, identified with a full circle (·) in the above structures;

Ri is H or a Ci-Ce alkyl, optionally substituted by 1-4 hydroxyl groups;

R2 is a Ci-Ce alkyl optionally substituted by 1-4 hydroxyl groups, and preferably a C1-C3 alkyl substituted by one or two hydroxyl groups.

Another embodiment of the invention relates to an isomeric mixture of an amide derivative of Gd(PCTA-tris-glutaric acid) having the formula (II B)

F'( N RI R2)3 (II B)

in which :

F’ is an isomeric mixture of Gd(PCTA-tris-glutaric acid) residue of formula (III)

Figure imgf000007_0001

said isomeric mixture of the Gd(PCTA-tris-glutaric acid) residue comprising at least 50 % of an enantiomer residue of the above formula (Ilia), of the enantiomer residue of the above formula (Illb), or of a mixture thereof; and each of the -NR1R2 groups is bound to an open bond of a respective carboxyl moiety of F’, identified with a full circle (·) in the above structure, and is as above defined for the compounds of formula (II A).

EXPERIMENTAL PART

HPLC characterization of the obtained compounds.

General procedures

Procedure 1: HPLC Characterization of Gd(PCTA-tris-glutaric acid) (isomeric mixture and individual/enriched isomers).

The HPLC characterization of the Gd(PCTA-tris-glutaric acid) obtained as isomeric mixture from Example 1 was performed with Agilent 1260 Infinity II system. The experimental setup of the HPLC measurements are summarized below.

Analytical conditions

HPLC system HPLC equipped with quaternary pump, degasser, autosampler,

PDA detector ( Agilent 1260 Infinity II system)

Stationary phase: Phenomenex Gemini® 5pm C18 lloA

Mobile phase: H2O/HCOOH 0.1% : Methanol

Elution : Gradient Time (min) H2O/HCOOH 0.1% Methanol

0 95 5

5 95 5

30 50 50

35 50 50

40 95 5

Flow 0.6 mL/min

Temperature 25 °C

Detection PDA scan wavelenght 190-800nm

Injection volume 50 pL

Sample Cone. 0.2 mM Gd(PCTA-tris-glutaric acid) complex

Stop time 40 min

Retention time GdL = 18-21 min.

Obtained HPLC chromatogram is shown in Figure 1

The HPLC chromatogram of the enriched enantiomers pair C is shown in Figure 2.

Procedure 2: HPLC Characterization of Gadopiclenol (isomeric mixture) and compounds obtained by coupling of enantiomers pair C with R, S, or racemic isoserinol.

The HPLC characterization of Gadopiclenol either as isomeric mixture obtained from Example 2, or as the compound obtained by conjugation of enantiomers pair C of the Gd(PCTA-tris-glutaric acid) with R, S, or racemic isoserinol was performed with Thermo Finnigan LCQ DECA XPPIus system. The experimental setup of the HPLC measurements are summarized below.

Analytical conditions

HPLC system HPLC equipped with quaternary pump, degasser, autosampler,

PDA and MS detector (LCQ Deca XP-Plus – Thermo Finnigan )

Stationary phase: Phenomenex Gemini 5u C18 110A

Mobile phase: H2O/TFA 0.1% : Acetonitrile/0.1%TFA

Elution : Gradient Time (min) H2O/TFA 0.1% Acetonitrile/0.1%TFA

0 100 0

5 100 0

22 90 10

26 90 10

Flow 0.5 mL/min

Temperature 25 °C

Detection PDA scan wavelenght 190-800nm

MS positive mode – Mass range 100-2000

Injection volume 50 pL

Sample cone. 0.2 mM Gd complex

Stop time 26 min

Retention time GdL = 20-22min.

Obtained HPLC chromatograms are shown in Figure 6.

Procedure 3: Chiral HPLC method for the separation of enantiomers of the compound C

A specific chiral HPLC method was set up in order to separate the RRR and SSS enantiomers of the enantiomers pair C (compound VI), prepared as described in Example 3. The separation and characterization of the enantiomers were performed with Agilent 1200 system or Waters Alliance 2695 system. The experimental setup of the HPLC measurements are summarized below.

Analytical conditions

HPLC System HPLC equipped with quaternary pump, degasser, autosampler,

PDA detector

Stationary phase SUPELCO Astec CHIROBIOTIC 5 pm 4.6x250mm

Mobile phase H2O/HCOOH 0.025% : Acetonitrile

Elution : isocratic 2% Acetonitrile for 30 minutes

Flow 1 mL/min

Column Temperature 40°C

Detection 210-270 nm. Obtained HPLC chromatogram is shown in Figure 5a) compared to the chromatograms of the pure RRR enantiomer (compound XII of Example 5, Tr. 7.5 min.) and the pure SSS enantiomer (Compound XVII of Example 6, Tr. 8.0 min), shown in figure 5b) and 5c), respectively.

Example 1: Synthesis of Gd(PCTA-tris-glutaric acid) (isomeric mixture)

Gd(PCTA-tris-glutaric acid) as an indiscriminate mixture of stereoisomers has been prepared by using the procedure reported in above mentioned prior-art, according to the following synthetic Scheme 1 :

Scheme 1

Figure imgf000030_0001

a) Preparation of Compound II

Racemic glutamic acid (33.0 g, 0.224 mol) and sodium bromide (79.7 g, 0.782 mol) were suspended in 2M HBr (225 ml_). The suspension was cooled to -5°C and NaN02 (28.0 g, 0.403 mol) was slowly added in small portions over 2.5 hours, maintaining the inner temperature lower than 0 °C. The yellow mixture was stirred for additional 20 minutes at a temperature of -5°C; then concentrated sulfuric acid (29 ml.) was dropped in the mixture. The obtained dark brown mixture was warmed to RT and then extracted with diethyl ether (4×150 ml_). The combined organic phases were washed with brine, dried over Na2S04 and concentrated to a brown oil (21.2 g), used in the following step without further purification. The oil was dissolved in ethanol (240 ml_), the resulting solution was cooled in ice and thionyl chloride (14.5 ml_, 0.199 mol) was slowly added. The slightly yellow solution was stirred at RT for 2 days. Then the solvent was removed in vacuum and the crude oil was dissolved in dichloromethane (200 ml.) and washed with 5% aq. NaHCC>3 (4×50 ml_), water (1×50 ml.) and brine (1×50 ml_). The organic phase was concentrated and purified on silica eluting with petroleum ether-ethyl acetate 3: 1, obtaining 19.5 g of pure product. (Yield 33%).

b) Preparation of Compound IV

A solution of Compound II (17.2 g, 0.0645 mol) in acetonitrile (40 ml.) was added to a suspension of 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-l(15),l l,13-triene (pyclen) Compound (III) (3.80 g, 0.018 mol) and K2CO3 (11.2 g, 0.0808 mol) in acetonitrile (150 ml_). The yellow suspension was heated at 65 °C for 24 h, then the salts were filtered out and the organic solution was concentrated. The orange oil was dissolved in dichloromethane and the product was extracted with 1M HCI (4 x 50 ml_). The aqueous phases were combined, cooled in ice and brought to pH 7-8 with 30% aq. NaOH. The product was then extracted with dichloromethane (4 x 50 ml.) and concentrated to give a brown oil (10.1 g, yield 73%). The compound was used in the following step without further purification.

c) Preparation of compound V

Compound IV (9.99 g, 0.013 mol) was dissolved in Ethanol (40 ml.) and 5M NaOH (40 ml_). The brown solution was heated at 80 °C for 23 h. Ethanol was concentrated; the solution was cooled in ice and brought to pH 2 with cone HCI. The ligand was purified on resin Amberlite XAD 1600, eluting with water-acetonitrile mixture, obtaining after freeze- drying 5.7 g as white solid (yield 73%). The product was characterized in HPLC by several peaks.

d) Preparation of compound VI

Compound V (5.25 g, 0.0088 mol) was dissolved in deionized water (100 ml.) and the solution was brought to pH 7 with 2M NaOH (20 ml_). A GdCh solution (0.0087 mol) was slowly added at RT, adjusting the pH at 7 with 2M NaOH and checking the complexation with xylenol orange. Once the complexation was completed, the solution was concentrated and purified on resin Amberlite XAD 1600 eluting with water-acetonitrile gradient, in order to remove salts and impurities. After freeze-drying the pure compound was obtained as white solid (6.79 g, yield 94%). The product was characterized in HPLC; the obtained HPLC chromatogram, characterized by several peaks, is shown in Figure 1 A compound totally equivalent to compound VI, consisting of an isomeric mixture with a HPLC chromatogram substantially superimposable to that of Figure 1 is obtained even by using (S)-methyl a-bromoglutarate obtained starting from L-glutamic acid.

Example 2: Synthesis of Gadopiclenol (isomeric mixture)

Gadopiclenol as an indiscriminate mixture of stereoisomers has been prepared as disclosed in EP11931673 B1 by coupling the isomeric mixture of Gd(PCTA-tris-glutaric acid) obtained from Example 1 with racemic isoserinol according to the following synthetic Scheme 2:

Scheme 2

Figure imgf000032_0001

Preparation of compound VII

Compound VI (0.90 g, 0.0011 mol) obtained from Example 1 was added to a solution of racemic isoserinol (0.40 g, 0.0044 mol) in water adjusted to pH 6 with cone. HCI. Then N- ethyl-N’-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI-HCI) (1.0 g, 0.0055 mol) and hydroxybenzotriazole (HOBT) (0.12 g, 0.00088 mol) were added and the resulting solution was stirred at pH 6 and RT for 24 h. The product was then purified on preparative HPLC on silica C18, eluting with water/acetonitrile gradient. Fractions containing the pure compound were concentrated and freeze-dried, obtaining a white solid (0.83 g, yield 78%). The product was characterized in HPLC; the obtained HPLC chromatogram is shown in Figure 4a.

Example 3: Isolation of the enantiomers pair related to the peak C.

Compound VI obtained as described in Example 1 (step d) (1.0 g, 0.0013 mol) was dissolved in water (4 ml.) and the solution was acidified to pH 2-3 with cone. HCI. The obtained solution was loaded into a pre-packed column of silica C18 (Biotage® SNAP ULTRA C18 120 g, HP-sphere C18 25 pm) and purified with an automated flash chromatography system eluting with deionized water (4 CV) and then a very slow gradient of acetonitrile. Fractions enriched of the enantiomers pair related to the peak C were combined, concentrated and freeze-dried obtaining a white solid (200 mg).

The HPLC chromatogram of the obtained enriched enantiomers pair C is shown in Figure 2.

Corresponding MS spectrum (Gd(H4L)+:752.14 m/z) is provided in Figure 3

Example 4: Coupling of the enantiomers pair C with isoserinol.

a) Coupling of the enantiomers pair C with R-isoserinol.

Enriched enantiomers pair C collected e.g. as in Example 3 (34 mg, titer 90%, 0.040 mmol) was dissolved in deionized water (5 ml_), and R-isoserinol (16 mg, 0.17 mmol) was added adjusting the pH at 6 with HCI 1M. Then, EDCI-HCI (39 mg, 0.20 mmol) and HOBT (3 mg, 0.02 mmol) were added and the solution was stirred at RT at pH 6 for 48 h. The solution was concentrated and loaded to pre-packed silica C18 column (Biotage® SNAP ULTRA C18 12 g, HP-sphere C18 25 pm), eluting with water/acetonitrile gradient using an automated flash chromatography system. Fractions containing the pure product, or showing a major peak at the HPLC with area greater than 90%, were combined, concentrated and freeze-dried giving a white solid (21 mg, yield 54%).

The HPLC chromatogram of the obtained product is shown in Figure 6b.

b) Coupling of the enantiomers pair C with S-isoserinol

Enriched enantiomers pair C collected e.g. as in Example 3 (55 mg, titer 90%, 0.066 mmol) was dissolved in deionized water (5 mL), and S-isoserinol (34 mg, 0.29 mmol) was added adjusting the pH at 6 with 1M HCI. Then, EDCI-HCI (64 mg, 0.33 mmol) and HOBT (4.5 mg, 0.033 mmol) were added and the solution was stirred at RT at pH 6 for 48 h. The solution was concentrated and loaded to pre-packed silica C18 column (Biotage® SNAP ULTRA C18 12 g, HP-sphere C18 25 pm), eluting with water/acetonitrile gradient using an automated flash chromatography system. Fractions containing the pure product, or showing a major peak at the HPLC with area greater than 90%, were combined, concentrated and freeze-dried giving a white solid (52 mg, yield 81%).

HPLC chromatogram of the obtained product is shown in Figure 6c.

c) Coupling of the enantiomers pair C with racemic isoserinol.

The enriched enantiomers pair C collected e.g. as in Example 3 (54 mg, titer 90%, 0.065 mmol) was dissolved in deionized water (5 mL), and racemic isoserinol (27 mg, 0.29 mmol) was added adjusting the pH at 6 with 1M HCI. Then, EDCI-HCI (62 mg, 0.32 mmol) and HOBT (4.3 mg, 0.032 mmol) were added and the solution was stirred at RT at pH 6 for 24 h. The solution was concentrated and loaded to pre-packed silica C18 column (Biotage® SNAP ULTRA C18 12 g, HP-sphere C18 25 pm), eluting with water/acetonitrile gradient using an automated flash chromatography system. Fractions containing the pure product, or showing a major peak at the HPLC with area greater than 90%, were combined, concentrated and freeze-dried giving a white solid (60 mg, yield 95%).

HPLC chromatogram of the obtained product is shown in Figure 6d. Example 5: Stereoselective synthesis of the RRR Gd(PCTA-tris-glutaric acid) (compound XII).

RRR enriched Gd(PCTA-tris-glutaric acid) acid has been prepared by following the synthetic Scheme 3 below

Scheme 3

Figure imgf000034_0001

comprising :

a) Preparation of Compound VIII

The preparation was carried out as reported in Tetrahedron 2009, 65, 4671-4680.

In particular: 37% aq. HCI (50 pL) was added to a solution of (S)-(+)-5- oxotetrahydrofuran-2-carboxylic acid (2.48 g, 0.019 mol) (commercially available) in anhydrous methanol (20 ml_). The solution was refluxed under N2 atmosphere for 24 h. After cooling in ice, NaHCC>3 was added, the suspension was filtered, concentrated and purified on silica gel with hexanes/ethyl acetate 1 : 1. Fractions containing the pure product were combined and concentrated, giving a colorless oil (2.97 g, yield 89%).

b) Preparation of Compounds IX and X

Compound VIII (445 mg, 2.52 mmol) obtained at step a) was dissolved in anhydrous dichloromethane (6 ml.) and triethylamine (0.87 ml_, 6.31 mmol) was added. The solution was cooled at -40°C and then (triflic) trifluoromethansulfonic anhydride (0.49 ml_,2.91 mmol) was slowly added. The dark solution was stirred at -40°C for 1 h, then a solution of Compound III (104 mg, 0.506 mmol) in anhydrous dichloromethane (3 ml.) and triethylamine (1 ml_, 7.56 mmol) were added and the solution was slowly brought to RT and stirred at RT overnight. The organic solution was then washed with 2M HCI (4x 10 ml_), the aqueous phase was extracted again with dichloromethane (3 x 10 ml_). The organic phases were combined and concentrated in vacuum, obtaining 400 mg of a brown oil that was used in the following step with no further purification.

c) Preparation of Compound XI

Compound X (400 mg, 0.59 mmol) was dissolved in methanol (2.5 ml.) and 5M NaOH (2.5 ml_). The brown solution was heated at 80°C for 22 h to ensure complete hydrolysis. Methanol was concentrated, the solution was brought to pH 1 with concentrated HCI and purified through an automated flash chromatography system with a silica C18 pre-packed column (Biotage® SNAP ULTRA C18 12 g, HP-sphere C18 25 pm), eluting with deionized water/acetonitrile gradient. Fractions containing the pure product were combined, concentrated and freeze-dried (64 mg, yield 18 %). The HPLC showed a major peak.

d) Compound XII

Compound XI (32 mg, 0.054 mmol) was dissolved in deionized water (4 mL) and the pH was adjusted to 7 with 1M NaOH. GdCl3-6H20 (20 mg, 0.054 mmol) was added and the pH was adjusted to 7 with 0.1 M NaOH. The clear solution was stirred at RT overnight and the end of the complexation was checked by xylenol orange and HPLC. The HPLC of the crude showed the desired RRR isomer as major peak: about 80% in area %. The mixture was brought to pH 2 with concentrated HCI and purified through an automated flash chromatography system with a silica C18 pre-packed column (Biotage® SNAP ULTRA C18 12 g, HP-sphere C18 25 pm), eluting with deionized water/acetonitrile gradient. Fractions containing the pure product were combined, concentrated and freeze-dried (36 mg, yield 90%).

By reaction of the collected compound with isoserinol e.g. by using the procedure of the Example 2, the corresponding RRR amide derivative can then be obtained.

Example 6: stereoselective synthesis of the SSS Gd(PCTA-tris-glutaric acid) (compound XVII).

SSS enriched Gd(PCTA-tris-glutaric acid) acid has been similarly prepared by following the synthetic Scheme 4 below Scheme 4

Figure imgf000036_0001

comprising :

a) Preparation of Compound XIII

37% aq. HCI (100 pl_) was added to a solution of (R)-(-)-5-oxotetrahydrofuran-2- carboxylic acid (5.0 g, 0.038 mol) (commercially available) in anhydrous methanol (45 ml_). The solution was refluxed under N2 atmosphere for 24 h. After cooling in ice, NaHC03 was added, the suspension was filtered, concentrated and purified on silica gel with hexanes/ethyl acetate 1 : 1. Fractions containing the pure product were combined and concentrated, giving a colorless oil (6.7 g, yield 99%).

b) Preparation of Compounds XIV and XV

Compound XIII (470 mg, 2.67 mmol) was dissolved in anhydrous dichloromethane (6 ml.) and trimethylamine (0.93 ml_, 6.67 mmol) was added. The solution was cooled down at -40°C and then trifluoromethanesulfonic anhydride (0.50 ml_, 3.07 mmol) was slowly dropped. The dark solution was stirred at -40°C for 1 h, then Compound III (140 mg, 0.679 mmol) and trimethylamine (0.93 ml_, 6.67 mmol) were added and the solution was slowly brought to RT overnight. The organic solution was then washed with water (3 x 5 ml.) and 2M HCI (4 x 5 ml_). The aqueous phase was extracted again with dichloromethane (3 x 10 ml_). the organic phases were combined and concentrated in vacuum, obtaining 350 mg of a brown oil that was used in the following step with no further purification. c) Preparation of Compound XVI

Compound XV (350 mg, 0.514 mmol) was dissolved in methanol (4.5 ml.) and 5M NaOH (4.5 ml_). The obtained brown solution was heated at 80°C for 16 h to ensure complete hydrolysis. Methanol was concentrated, the solution was brought to pH 2 with concentrated HCI and purified through an automated flash chromatography system with a silica C18 pre-packed column (Biotage® SNAP ULTRA C18 12 g, HP-SPHERE C18 25 pm), eluting with a water/acetonitrile gradient. Fractions containing the pure product were combined, concentrated and freeze-dried (52 mg, yield 17%). The HPLC showed a major peak.

d) Preparation of Compound XVII

Compound XVI (34 mg, 0.057 mmol) was dissolved in deionized water (5 mL) and the pH was adjusted to 7 with 1 M HCI. GdCl3-6H20 (20 mg, 0.0538 mmol) was added and the pH was adjusted to 7 with 0.1 M NaOH. The solution was stirred at RT overnight and the end of complexation was checked by xylenol orange and HPLC. The HPLC of the crude showed the desired SSS isomer as major peak: about 85% in area %. The solution was brought to pH 2.5 with concentrated HCI and purified through an automated flash chromatography system with a silica C18 pre-packed column (Biotage® SNAP ULTRA C18 12 g, HP-SPHERE C18 25 pm), eluting with a water/acetonitrile gradient. Fractions containing the pure product SSS were combined, concentrated and freeze-dried (39 mg, yield 87%).

Example 7: Kinetic studies of the dissociation reactions of Gd(PCTA-tris- glutaric acid) (isomeric mixture) in 1.0 M HCI solution (25°C)

The kinetic inertness of a Gd(III)-complex is characterized either by the rate of dissociation measured in 0.1-1.0 M HCI or by the rate of the transmetallation reaction, occurring in solutions with Zn(II) and Cu(II) or Eu(III) ions. However, the dissociation of lanthanide(III)-complexes formed with macrocyclic ligands is very slow and generally proceeds through a proton-assisted pathway without the involvement of endogenous metal ions like Zn2+ and Cu2+.

We characterized the kinetic inertness of the complex Gd(PCTA-tris-glutaric acid) by the rates of the dissociation reactions taking place in 1.0 M HCI solution. The complex (isomeric mixture from Example 1) (0.3 mg) was dissolved in 2.0 mL of 1.0 M HCI solution and the evolution of the solution kept at 25 °C was followed over time by HPLC. The HPLC measurements were performed with an Agilent 1260 Infinity II system by use of the analytical Procedure 1.

The presence of a large excess of H+ ([HCI] = 1.0 M), guarantees the pseudo-first order kinetic conditions.

GdL + yH÷ ^ Gd3+ + HyL y=7 and 8 (Eg. 1) where L is the protonated PCTA-tri-glutaric acid, free ligand, and y is the number of protons attached to the ligand.

The HPLC chromatogram of Gd(PCTA-tris-glutaric acid) is characterized by the presence of four signals (A, B, C and D) having the same m/z ratio (Gd(H4L)+ :752.14 m/z) in the MS spectrum. Each of these peaks is reasonably ascribable to one of the 4 pairs of enantiomers generated by the three stereocenters on the three glutaric arms of the molecule, formerly identified in Table 1. The HPLC chromatogram of this complex in the presence of 1.0 M HCI changes over time: in particular, the areas of peaks A, B, C, and D decrease, although not in the same way for the different peaks, while new signals corresponding to non-complexed diastereoisomers are formed and grow over time. Differences in the decrease of the integral areas of the peaks can be interpreted by a different dissociation rate of the enantiomer pairs associated to the different peaks.

In the presence of [H + ] excess the dissociation reaction of enantiomer pairs of Gd(PCTA-tris-glutaric acid) can be treated as a pseudo-first-order process, and the rate of the reactions can be expressed with the following Eq. 2, where kA, kB, kc and kD are the pseudo-first-order rate constants that are calculated by fitting the area-time data pair, and [A]t, [B]t, [C]t and [D]t are the total concentration of A, B, C and D compounds at time t.

Figure imgf000038_0001

The decrease of the area values of signals of A, B, C, and D has been assessed and plotted over time. Area values of A, B, C and D signals as a function of time are shown in Figure 7.

Area value at time t can be expressed by the following equation:

A. = A + (A0 – A )e kxt

(Eg. 3)

where At, A0 and Ae are the area values at time t, at the beginning and at the end of the reactions, respectively, kx pseudo-first-order rate constants (/fX=/fA, kB, kc and kD) characterizing the dissociation rate of the different enantiomer pairs of Gd(PCTA-tris-glutaric acid) complex were calculated by fitting the area – time data pairs of Figure 7 to the above equation 3. kx rate constants and half-lives (ti/2= In2/ x) are thus obtained, as well as the average the half-life value for the isomeric mixture of Gd(PCTA-tris-glutaric acid), calculated by considering the percentage composition of the mixture. Obtained values are summarized in the following Table 2, and compared with corresponding values referred in the literature for some reference contrast agents. (Gd-DOTA or DOTAREM™). Table 2. Rate constants ( kx ) and half-lives (ti/2= In2/ x) characterizing the acid catalyzed dissociation of the different stereoisomers of Gd(PCTA-tris-glutaric acid), Dotarem® and Eu(PCTA) in 1.0 M HCI (pH 0) ( 25°C)

A B C D

Ms 1) (4.5±0.1) x105 (1.1±0.1)x104 (1.6±0.1)x10-6 (1.2±0.1)x10-5 fi/2 (hour) 4.28 ± 0.03 1.76 ± 0.02 120 ± 3 15.8 ± 0.5

fi/2 (hour)

Figure imgf000039_0001

average

Dotarem a

k, (S‘1) 8.0×10-6

fi/2 (hour) 23 hour

Eu(PCTA) b

*1 (s·1) 5.08X10·4

fi/2 (hour) 0.38 hour

a) Inorg. Chem. 1992, 31 ,1095-1099.

b) Tircso, G. et al. Inorg Chem 2006, 45 (23), 9269-80.

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A gadolinium-based paramagnetic contrast agent, with potential imaging enhancing activity upon magnetic resonance imaging (MRI). Upon administration of gadopiclenol and placement in a magnetic field, this agent produces a large magnetic moment and creates a large local magnetic field, which can enhance the relaxation rate of nearby protons. This change in proton relaxation dynamics, increases the MRI signal intensity of tissues in which this agent has accumulated; therefore, contrast and visualization of those tissues is enhanced compared to unenhanced MRI.

FDA Approves New MRI Contrast Agent Gadopiclenol

September 22, 2022

https://www.diagnosticimaging.com/view/fda-approves-new-mri-contrast-agent-gadopiclenol

Requiring only half of the gadolinium dose of current non-specific gadolinium-based contrast agents (GBCAs), gadopiclenol can be utilized with magnetic resonance imaging (MRI) to help detect lesions with abnormal vascularity in the central nervous system and other areas of the body.

Gadopiclenol, a new magnetic resonance imaging (MRI) contrast agent that offers high relaxivity and reduced dosing of gadolinium, has been approved by the Food and Drug Administration (FDA).1

Approved for use with MRI in adults and pediatric patients two years of age or older, gadopiclenol is a macrocyclic gadolinium-based contrast agent that aids in the diagnosis of lesions with abnormal vascularity in the brain, spine, abdomen, and other areas of the body.

Recently published research demonstrated that gadopiclenol provides contrast enhancement and diagnostic efficacy at half of the gadolinium dosing of other gadolinium-based contrast agents (GBCAs) such as gadobutrol and gadobenate dimeglumine.2

Co-developed by Bracco Diagnostics and Guerbet, gadopiclenol will be manufactured and marketed as Vueway™ (Bracco Diagnostics) and Elucirem™ (Guerbet).1,3

Alberto Spinazzi, M.D., the chief medical and regulatory officer at Bracco Diagnostics, said gadopiclenol is “a first of its kind MRI agent that delivers the highest relaxivity and highest kinetic stability of all GBCAs on the market today.”

Reference

1. Bracco Diagnostics. Bracco announces FDA approval of gadopiclenol injection, a new macrocyclic high-relaxivity gadolinium-based contrast agent which will be commercialized as VUEWAY™ (gadopiclenol) injection and VUEWAY™ (gadopiclenol) phamarcy bulk package by Bracco. Cision PR Newswire. Available at: https://www.prnewswire.com/news-releases/bracco-announces-fda-approval-of-gadopiclenol-injection-a-new-macrocyclic-high-relaxivity-gadolinium-based-contrast-agent-which-will-be-commercialized-as-vueway-gadopiclenol-injection-and-vueway-gadopiclenol-pharmacy-bulk-p-301630124.html . Published September 21, 2022. Accessed September 21, 2022.

2. Bendszus M, Roberts D, Kolumban B, et al. Dose finding study of gadopiclenol, a new macrocyclic contrast agent, in MRI of central nervous system. Invest Radiol. 2020;55(3):129-137.

3. Guerbet. Guerbet announces U.S. Food and Drug Administration (FDA) approval of Elucirem™ (gadopiclenol) injection for use in contrast-enhanced MRI. Cision PR Newswire. Available at: https://www.prnewswire.com/news-releases/guerbet-announces-us-food-and-drug-administration-fda-approval-of-elucirem-gadopiclenol-injection-for-use-in-contrast-enhanced-mri-301630085.html . Published September 21, 2022. Accessed September 21, 2022.

////Gadopiclenol, FDA 2022, APPROVALS 2022, ガドピクレノール, WHO 10744, P 03277,  EluciremTM, G03277; P03277, VUEWAY, Guerbet

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IOHEXOL


Iohexol
Iohexol.svg
Iohexol.png

IOHEXOLCAS Registry Number: 66108-95-0N1,N3-bis(2,3-dihydroxypropyl)-5-[N-(2,3-dihydroxypropyl)acetamido]-2,4,6-triiodobenzene-1,3-dicarboxamide 
CAS Name: 5-[Acetyl(2,3-dihydroxypropyl)amino]-N,N¢-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamideAdditional Names:N,N¢-bis(2,3-dihydroxypropyl)-5-[N-(2,3-dihydroxypropyl)acetamido]-2,4,6-triiodoisophthalamide 
Manufacturers’ Codes: Win-39424; Compd 545Trademarks: Omnipaque (GE Healthcare) 
Molecular Formula: C19H26I3N3O9Molecular Weight: 821.14Percent Composition: C 27.79%, H 3.19%, I 46.36%, N 5.12%, O 17.54% 
Literature References: Nonionic radio-contrast medium. Prepn: V. Nordal, H. Holtermann, DE2726196eidem,US4250113 (1977, 1981 both to Nyegaard). HPLC-UV determn in plasma: R. S. Soman et al.J. Chromatogr. B816, 339 (2005). 
Pharmacology and toxicology: Acta Radiol.Suppl. 362, 1-134 (1980). Acute toxicity: S. Salvesen, ibid. 73. Fibrillatory potential in dogs: G. L. Wolf et al.,Invest. Radiol.16, 320 (1981).Comparative clinical studies in coronary angiography: G. B. J. Mancini et al.,Am. J. Cardiol.51, 1218 (1983); I. D. Sullivan et al.,Br. Heart J.51, 643 (1984); M. A. Bettmann et al.,Radiology153, 583 (1984). Review: T. Almén, Acta Radiol.Suppl. 366, 9-19 (1983). 
Properties: Crystals from butanol, mp 174-180°. Sol in water. Stable in aqueous solutions. Viscosity (cP): 6.2 at 37°; 12.6 at 20° (c = 200 mg Iodine/ml). LD50 in male, female rats, mice (g Iodine/kg): 15.0, 12.3, 24.3, 25.1 i.v. (Salvesen). 
Melting point: mp 174-180° 
Toxicity data: LD50 in male, female rats, mice (g Iodine/kg): 15.0, 12.3, 24.3, 25.1 i.v. (Salvesen)Therap-Cat: Diagnostic aid (radiopaque medium).Keywords: Diagnostic Aid (Radiopaque Medium). 

Synthesis ReferenceXiu C. Wang, Steve A. Chamberlin, Ashok V. Bhatia, Gregg E. Robinson, John Hufnagel, “Process for the preparation of iohexol.” U.S. Patent US5705692, issued December, 1985.

US5705692

Iohexol, sold under the trade name Omnipaque among others, is a contrast agent used for X-ray imaging.[1] This includes when visualizing arteriesveinsventricles of the brain, the urinary system, and joints, as well as during computed tomography (CT scan).[1] It is given by mouth, injection into a vein, or into a body cavity.[2]

Iohexol is a contrast agent for intrathecal administration used in myelography and contrast enhancement for computerized tomography.

Side effects include vomitingskin flushing, headache, itchiness, kidney problems, and low blood pressure.[1] Less commonly allergic reactions or seizures may occur.[1] Allergies to povidone-iodine or shellfish do not affect the risk of side effects more than other allergies.[3] Use in the later part of pregnancy may cause hypothyroidism in the baby.[4] Iohexol is an iodinated non-ionic radiocontrast agent.[1] It is in the low osmolar family.[5]

Iohexol was approved for medical use in 1985.[6] It is on the World Health Organization’s List of Essential Medicines.[7][2]

Chemistry

The osmolality of iohexol ranges from 322 mOsm/kg—approximately 1.1 times that of blood plasma—to 844 mOsm/kg, almost three times that of blood.[8] Despite this difference, iohexol is still considered a low-osmolality contrast agent; the osmolality of older agents, such as diatrizoate, may be more than twice as high.[9]

Society and culture

Names

It is sold under the brand names Omnipaque[10] and Hexopaque. It is also sold as a density gradient medium under the names Accudenz, Histodenz and Nycodenz.[11][12]

Formulations

It is available in various concentrations, from 140[citation needed] to 350[13] milligrams of iodine per milliliter.

PATENT

https://patents.google.com/patent/WO2005003080A1/en#:~:text=Primary%20production%20of%20iohexol%20involves,and%20a%20thorough%20purification%20stage.&text=The%20solvent%20is%20then%20evaporated,and%20recrystallised%20twice%20from%20butanol.The present invention relates to a process for the manufacture of iohexol, 5-[N- (2,3- dihydroxypropyl) -acetamido]-N,N’-bis(2,3 -dihydroxypropyl)-2,4,6- triiodoisophtalamide.Iohexol is the non-proprietory name of the chemical drug substance of a non-ionic iodinated X-ray contrast agent marketed under the trade name OMNIPAQUE®. OMNIPAQUE® is one of the most used agents in diagnostic X-ray procedures.The manufacture of such non-ionic contrast agents involves the production of the chemical drug substance (referred to as primary production) followed by formulation into the drug product (referred to as secondary production). Primary production of iohexol involves a multistep chemical synthesis and a thorough purification stage. For a commercial drug product it is important for the primary production to be efficient and economical and to provide a drug substance fulfilling the specifications.The final step in the synthesis of iohexol is a N-alkylation step in which 5-(acetamido)-N,N’-bis(2,3-dihydroxypropyl)-2,4,6 triiodoisophtalamide (hereinafter 5- Acetamide) is reacted in the liquid phase with an alkylating agent to introduce the 2,3-dihydroxypropyl group at the nitrogen of the 5-acetamido group. Following this reaction, iohexol is isolated from the reaction mixture and purified by crystallisation and treatment with ion exchange resins.The manufacture of iohexol is disclosed for example in US-4,250,113 which is hereby incorporated by reference. In the last step of the multistep chemical synthesis crude iohexol is obtained from the reaction between 5-Acetamide and 1-chloro-2,3- propandiol at ambient temperature in propylene glycoi and in the presence of sodium methoxide. The solvent is then evaporated and crude iohexol is obtained. The crude product is evaporated to dryness and recrystallised twice from butanol.Several suggestions to improve the N-alkylation and the purification steps have been published. WO-A-98/08804 discloses the use of 2-methoxy-ethanol and optionally isopropanol both in the alkylation step of 5-Acetamide and in the purification of crude iohexol. WO-A-02/083623 discloses the purification of crude iohexol using 1- methoxy-2-propanol as the solvent optionally in a mixture with other solvents.The N-alkylation step where 5-Acetamide in solution is reacted with an alkylation agent such as e.g. 1-chloro-2,3-propandiol to introduce the 2,3-dihydroxypropyl group at the nitrogen of the 5-acetamido group is illustrated in Scheme 1 :

Figure imgf000003_0001

5-Acetamide Iohexol5-acatamido-N,N’-bis(2,3-dihydroxypropyl)- 5-[N-(2,3-dihydroxypropyl)acetamido]- 2,4,6-triiodoisophtalamide N,N’-bis(2,3-dihydroxypropyl)- 2,4,6-triiodoisophtalamideScheme 1.The N-alkylation step is challenging because O-alkylated by-products can also be formed when the alkylation occurs at the oxygen atoms of the hydroxy groups. It is therefore a desire to limit the formation of these O-alkylated by-products and thereby to limit their presence in the final purified iohexol. The upper limit for values for O- alkylated by-products in the end product is fixed by the European Pharmacopea to 0.6% (HPLC by area).The O-alkylated by-products are removed to the degree desired or necessary by recrystallisation steps. Further unidentified by-products also referred to as impurities are also formed during the alkylation reaction and must be reduced to a tolerable level. In addition the solvents used should be easily available, be environmentally friendly and be of low toxicity.There is therefore a need to identify a solvent that can be used in the N-alkylation reaction and that fulfil the desiderata mentioned above. It is further desired to improve the overall process including the N-alkylation step and the purification step in the manufacture of iohexol. If the crude product obtained by the N-alkylation step is to be re-crystallised from a solvent that is different from the solvent used in the N- alkylation step, then the reaction solvent must first be removed e.g. by evaporation to dryness. It is known from crystallisation theory and experience that even small quantities of residual solvents from previous steps may cause a crystallisation process to get out of control due to changes in its supersaturation conditions, and thorough removal of the reaction solvent is an important step. Solvent removal is an energy consuming operation which also risks degradation of the product due to exposure to elevated temperature.Example 1 : Synthesis of iohexol in 1-methoxy-2-propanol/methanol1-methoxy-2-propanol (44 ml), methanol (19 ml) and sodium hydroxide (4.87 g) was added to a jacketed glass reactor and stirred for about 15 minutes at 25°C. 5-Acetamide (70 g) was added to the reactor, and the mixture stirred overnight at 45°C, before it was allowed to cool to 25°C. 1-chloro-2,3-propanediol (12.43 g) was added to the solution. After 1.5 hours, more 1-chloro-2,3-propanediol (0.83 g) was added, and the reaction was allowed to proceed for 24 hours. HPLC analysis (water/acetonitrile) of the reaction mixture gave the following results:Iohexol 98.1 %5-Acetamide 1.17 % O-alkylated substances 0.58 %Other impurities 0.1 %Example 2: Synthesis of iohexol in 1 -methoxy-2-propanol/water1-methoxy-2-propanol (63 ml), water (7 ml) and sodium hydroxide (4.50 g) was added to a jacketed glass reactor and stirred for about 15 minutes at 25°C. 5-Acetamide (70 g) was added to the reactor, and the mixture stirred overnight at 45°C, before it was allowed to cool to 35°C. 1-chloro-2,3-propanediol (11.39 g) was added to the solution. After 3 hours, more 1-chloro-2,3-propanediol (0.83 g) was added, and the reaction was allowed to proceed for 24 hours. HPLC analysis (water/acetonitrile) of the reaction mixture gave the following results:Iohexol 98.3 % 5-Acetamide 0.68 %O-alkylated substances 0.81 %Other impurities 0.3 % Example 3: Alkylation and crystallisation in solutions containing 1-methoxy-2- propanol1-methoxy-2-propanol (63 L), methanol (27 L) and sodium hydroxide (6.96 kg) was added to a 500 L reactor and stirred until all solids were dissolved and the temperature was below 30°C. 5-Acetamide (100 kg) was added to the reactor, and the mixture stirred overnight at 45°C before it was allowed to cool to 25°C. 1-chloro- 2,3-propanediol (16.76 kg) was added to the clear solution. After 1.5 hours, more 1- chloro-2,3-propanediol (1.18 kg) was added, and the reaction was allowed to proceed for 30 hours. HPLC analysis (water/acetonitrile) of the reaction mixture gave the following results:Iohexol 97.9 % 5-Acetamide 0.9 %O-alkylated substances 0.83 %Other impurities 0.4 %The reaction was stopped by addition of hydrochloric acid (650 ml), and the reaction mixture diluted with a mixture of 1-methoxy-2-propanol (53 L) and methanol (13 L). The mixture was filtered, and the salts on the filter washed with methanol (3×10 L). The combined filtrate and wash was diluted with water (22 L) and treated with cationic ion exchange resin (AMB 200C, 80 L) and anionic ion exchange resin (IRA 67, 80 L) to a salt content of 0.006 w/w %. The solution was filtered, and the ion exchange resins washed in several stages with a mixture of water (160 L) and methanol (85 L). The combined filtrate and wash was concentrated under reduced pressure to a volume of 155 L. One half of this was taken further to crystallisation as described below.Water was removed from the solution by azeotropic distillation. The volume was held at a constant level by replacing the distillate by 1-methoxy-2-propanol (80 L). At water content of 0.16 Ukg iohexol, further 1-methoxy-2-propanol (159 L) was added, and the solution seeded with iohexol crystals (0.26 kg). After stirring at reflux overnight, the volume of the solution was reduced by 42 L by distillation under reduced pressure (300-600 mbar). The temperature was set to 90°C, which was held for 3 hours before cooling to 60°C over 3 hours. The crystallisation mixture was stirred overnight at 60°C, filtered and washed with isopropanol (90 L, 6 portions). The yield was 48.4 kg (as dry powder), corresponding to 88-weight % corrected for seeding material and samples. HPLC analysis (water/acetonitrile) of the crystals gave the following results:Iohexol 99.3 %5-Acetamide 0.15 %O-alkylated substances 0.45 %Other impurities 0.11 % 
PAPERhttps://www.quickcompany.in/patents/a-new-process-for-the-synthesis-of-high-pure-iohexol-and-its-intermediatesPATENThttps://patents.google.com/patent/WO2005003080A1/enThe present invention relates to a process for the manufacture of iohexol, 5-[N- (2,3- dihydroxypropyl) -acetamido]-N,N’-bis(2,3 -dihydroxypropyl)-2,4,6- triiodoisophtalamide.Iohexol is the non-proprietory name of the chemical drug substance of a non-ionic iodinated X-ray contrast agent marketed under the trade name OMNIPAQUE®. OMNIPAQUE® is one of the most used agents in diagnostic X-ray procedures.The manufacture of such non-ionic contrast agents involves the production of the chemical drug substance (referred to as primary production) followed by formulation into the drug product (referred to as secondary production). Primary production of iohexol involves a multistep chemical synthesis and a thorough purification stage. For a commercial drug product it is important for the primary production to be efficient and economical and to provide a drug substance fulfilling the specifications.The final step in the synthesis of iohexol is a N-alkylation step in which 5-(acetamido)-N,N’-bis(2,3-dihydroxypropyl)-2,4,6 triiodoisophtalamide (hereinafter 5- Acetamide) is reacted in the liquid phase with an alkylating agent to introduce the 2,3-dihydroxypropyl group at the nitrogen of the 5-acetamido group. Following this reaction, iohexol is isolated from the reaction mixture and purified by crystallisation and treatment with ion exchange resins.The manufacture of iohexol is disclosed for example in US-4,250,113 which is hereby incorporated by reference. In the last step of the multistep chemical synthesis crude iohexol is obtained from the reaction between 5-Acetamide and 1-chloro-2,3- propandiol at ambient temperature in propylene glycoi and in the presence of sodium methoxide. The solvent is then evaporated and crude iohexol is obtained. The crude product is evaporated to dryness and recrystallised twice from butanol.Several suggestions to improve the N-alkylation and the purification steps have been published. WO-A-98/08804 discloses the use of 2-methoxy-ethanol and optionally isopropanol both in the alkylation step of 5-Acetamide and in the purification of crude iohexol. WO-A-02/083623 discloses the purification of crude iohexol using 1- methoxy-2-propanol as the solvent optionally in a mixture with other solvents.The N-alkylation step where 5-Acetamide in solution is reacted with an alkylation agent such as e.g. 1-chloro-2,3-propandiol to introduce the 2,3-dihydroxypropyl group at the nitrogen of the 5-acetamido group is illustrated in Scheme 1 :

Figure imgf000003_0001

5-Acetamide Iohexol5-acatamido-N,N’-bis(2,3-dihydroxypropyl)- 5-[N-(2,3-dihydroxypropyl)acetamido]- 2,4,6-triiodoisophtalamide N,N’-bis(2,3-dihydroxypropyl)- 2,4,6-triiodoisophtalamideScheme 1.The N-alkylation step is challenging because O-alkylated by-products can also be formed when the alkylation occurs at the oxygen atoms of the hydroxy groups. It is therefore a desire to limit the formation of these O-alkylated by-products and thereby to limit their presence in the final purified iohexol. The upper limit for values for O- alkylated by-products in the end product is fixed by the European Pharmacopea to 0.6% (HPLC by area).The O-alkylated by-products are removed to the degree desired or necessary by recrystallisation steps. Further unidentified by-products also referred to as impurities are also formed during the alkylation reaction and must be reduced to a tolerable level. In addition the solvents used should be easily available, be environmentally friendly and be of low toxicity.There is therefore a need to identify a solvent that can be used in the N-alkylation reaction and that fulfil the desiderata mentioned above. It is further desired to improve the overall process including the N-alkylation step and the purification step in the manufacture of iohexol. If the crude product obtained by the N-alkylation step is to be re-crystallised from a solvent that is different from the solvent used in the N- alkylation step, then the reaction solvent must first be removed e.g. by evaporation to dryness. It is known from crystallisation theory and experience that even small quantities of residual solvents from previous steps may cause a crystallisation process to get out of control due to changes in its supersaturation conditions, and thorough removal of the reaction solvent is an important step. Solvent removal is an energy consuming operation which also risks degradation of the product due to exposure to elevated temperature.Example 1 : Synthesis of iohexol in 1-methoxy-2-propanol/methanol1-methoxy-2-propanol (44 ml), methanol (19 ml) and sodium hydroxide (4.87 g) was added to a jacketed glass reactor and stirred for about 15 minutes at 25°C. 5-Acetamide (70 g) was added to the reactor, and the mixture stirred overnight at 45°C, before it was allowed to cool to 25°C. 1-chloro-2,3-propanediol (12.43 g) was added to the solution. After 1.5 hours, more 1-chloro-2,3-propanediol (0.83 g) was added, and the reaction was allowed to proceed for 24 hours. HPLC analysis (water/acetonitrile) of the reaction mixture gave the following results:Iohexol 98.1 %5-Acetamide 1.17 % O-alkylated substances 0.58 %Other impurities 0.1 %Example 2: Synthesis of iohexol in 1 -methoxy-2-propanol/water1-methoxy-2-propanol (63 ml), water (7 ml) and sodium hydroxide (4.50 g) was added to a jacketed glass reactor and stirred for about 15 minutes at 25°C. 5-Acetamide (70 g) was added to the reactor, and the mixture stirred overnight at 45°C, before it was allowed to cool to 35°C. 1-chloro-2,3-propanediol (11.39 g) was added to the solution. After 3 hours, more 1-chloro-2,3-propanediol (0.83 g) was added, and the reaction was allowed to proceed for 24 hours. HPLC analysis (water/acetonitrile) of the reaction mixture gave the following results:Iohexol 98.3 % 5-Acetamide 0.68 %O-alkylated substances 0.81 %Other impurities 0.3 % Example 3: Alkylation and crystallisation in solutions containing 1-methoxy-2- propanol1-methoxy-2-propanol (63 L), methanol (27 L) and sodium hydroxide (6.96 kg) was added to a 500 L reactor and stirred until all solids were dissolved and the temperature was below 30°C. 5-Acetamide (100 kg) was added to the reactor, and the mixture stirred overnight at 45°C before it was allowed to cool to 25°C. 1-chloro- 2,3-propanediol (16.76 kg) was added to the clear solution. After 1.5 hours, more 1- chloro-2,3-propanediol (1.18 kg) was added, and the reaction was allowed to proceed for 30 hours. HPLC analysis (water/acetonitrile) of the reaction mixture gave the following results:Iohexol 97.9 % 5-Acetamide 0.9 %O-alkylated substances 0.83 %Other impurities 0.4 %The reaction was stopped by addition of hydrochloric acid (650 ml), and the reaction mixture diluted with a mixture of 1-methoxy-2-propanol (53 L) and methanol (13 L). The mixture was filtered, and the salts on the filter washed with methanol (3×10 L). The combined filtrate and wash was diluted with water (22 L) and treated with cationic ion exchange resin (AMB 200C, 80 L) and anionic ion exchange resin (IRA 67, 80 L) to a salt content of 0.006 w/w %. The solution was filtered, and the ion exchange resins washed in several stages with a mixture of water (160 L) and methanol (85 L). The combined filtrate and wash was concentrated under reduced pressure to a volume of 155 L. One half of this was taken further to crystallisation as described below.Water was removed from the solution by azeotropic distillation. The volume was held at a constant level by replacing the distillate by 1-methoxy-2-propanol (80 L). At water content of 0.16 Ukg iohexol, further 1-methoxy-2-propanol (159 L) was added, and the solution seeded with iohexol crystals (0.26 kg). After stirring at reflux overnight, the volume of the solution was reduced by 42 L by distillation under reduced pressure (300-600 mbar). The temperature was set to 90°C, which was held for 3 hours before cooling to 60°C over 3 hours. The crystallisation mixture was stirred overnight at 60°C, filtered and washed with isopropanol (90 L, 6 portions). The yield was 48.4 kg (as dry powder), corresponding to 88-weight % corrected for seeding material and samples. HPLC analysis (water/acetonitrile) of the crystals gave the following results:Iohexol 99.3 %5-Acetamide 0.15 %O-alkylated substances 0.45 %Other impurities 0.11 % 

PatentCN109134289https://patents.google.com/patent/CN109134289A/en

N-Acylation of 5-amino-N,N’-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (1) with acetic anhydride (2) in the presence of p-TsOH gives 5-(acetylamino)-N,N’-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (3) , which upon condensation with glycidol  using NaOMe in 2-methoxyethanol at 90 °C  or epichlorohydrin  by means of NaHCO3 in propylene glycol at 85 °C  or 3-chloropropane-1,2-diol (5) using aqueous NaOH furnishes the  iohexol .(7) synthesis of IodixanolModus ponens (I) compound (200g, 0.28mol) be added 1L there-necked flask in, thereto be added acetic anhydride (207g, 2.03mol), acetic acid (103.3mL), p-methyl benzenesulfonic acid monohydrate (1g, 5.42mmol), finishes reaction solution being heated to 60 DEG C Start to react, keep the temperature 30 minutes after reacting liquid temperature reaches 120-125 DEG C, cooling is concentrated into after can just stirring thereto It is added 50%v/v (600mL), is slowly added dropwise thereto into 50%w/v sodium hydrate aqueous solution, by adding in reaction process The mode of 50%w/v sodium hydrate aqueous solution keeps the pH of reaction solution between 11~12, and reaction temperature is maintained at 40-45 DEG C, Reaction is finished, and concentrated hydrochloric acid is added into reaction solution and adjusts pH3-4, and stirring filters after 3.0 hours, and filter cake is washed with water to neutrality, dries It is dry, obtain white solid 187g, yield 88.2%, HPLC98.14%.Go step obtained solid (150g, 0.2mol) be added there-necked flask in, thereto be added sodium hydroxide (14.4g, 0.36mol), purified water (300mL), epoxychloropropane (27.9g, 0.30mol) finish 30-35 DEG C of reaction 72.0 hours, instead It should finish, adjust pH3-4, Iodixanol HPLC purity 72.5%, Iohexol HPLC11.3% with concentrated hydrochloric acid.(4) synthesis of IohexolModus ponens (I) compound (200g, 0.28mol) be added 1L there-necked flask in, thereto be added acetic anhydride (432g, 4.23mol) flows back 3.0 hours, be then concentrated under reduced pressure into p-methyl benzenesulfonic acid monohydrate (1g, 5.42mmol), agitating and heating It can just stir, be added portionwise into reaction solution methanol (25g), methanol is added after 1.0 hours in stirring thereto again (140g) is finished and is stirred to react 1.0 hours, and being concentrated under reduced pressure into can just stir, and purified water (20g) then is added thereto, 60 DEG C are finished to be stirred overnight.Reaction solution is cooled to 30 DEG C hereinafter, extracting reaction solution 200mL, stirring is lower will with 50%w/v sodium hydrate aqueous solution Reaction solution pH is adjusted to 12, the addition 1- chloro- 2 into reaction solution, 3-propanediol (20g, 0.18mol), passes through benefit in reaction process The mode of 50%w/v sodium hydrate aqueous solution is added to keep the pH of reaction solution between 11~12, after reaction 12.0 hours thereto Add 1- chloro- 2,3-propanediol (3g, 29.29mmol) finishes that the reaction was continued 48.0 hours, and reaction solution samples HPLC detection, iodine Mykol purity is 89.9%.(5) synthesis of IoversolModus ponens (I) compound (200g, 0.28mol) is added in 1L there-necked flask, and N-Methyl pyrrolidone is added thereto Chloracetyl chloride (200mL) is added in (200mL) thereto under stirring, finish 50-53 DEG C and react 3.0 hours, and reaction is finished, and is cooled to 20 DEG C, reaction solution is slowly added in methanol (2000mL).It finishing, flows back 9.0 hours, reaction is finished, and is cooled to 25 DEG C, it filters, Filter cake is washed with methanol, and drying obtains white solid 177g, yield 79.8%, HPLC purity 98.3%.It takes previous step obtained solid (150g, 0.19mol) to be added in 1L there-necked flask, purified water 300mL is added thereto, Acetic acid sodium trihydrate (183g, 1.34mol) finishes back flow reaction, by adding 50%w/v sodium hydroxide water in reaction process The mode of solution keeps the pH of reaction solution between 5-6, and reaction is finished, and concentrated hydrochloric acid is added into reaction solution, adjusts pH3-4, stirring It being filtered after 3.0 hours, filter cake is with purifying water washing to neutrality, and drying obtains white solid 127g, yield 86.7%, HPLC98.4%.It takes step obtained solid (100g, 0.13mol), is added in 1L there-necked flask, purified water 300mL, chlorine are added thereto Change sodium (46.5g, 0.796mol), finish, be warming up to 50 DEG C, 10N sodium hydrate aqueous solution (39.3mL) and 2- are added thereto Chlorethanol (63.5g, 0.79mol) finishes 48-52 DEG C of heat preservation and reacts 5.0 hours, and reaction is finished, and concentrated hydrochloric acid is added thereto and adjusts PH6.5, reaction solution HPLC detection, Iohexol purity 89.7%.(6) synthesis of IopentolModus ponens (I) compound (200g, 0.28mol) be added 1L there-necked flask in, thereto be added acetic anhydride (432g, 4.23mol) flows back 3.0 hours, be then concentrated under reduced pressure into p-methyl benzenesulfonic acid monohydrate (1g, 5.42mmol), agitating and heating It can just stir, be added portionwise into reaction solution methanol (25g), methanol (140g) is added thereto again after stirring 1.0 hours, It finishes and is stirred to react 1.0 hours, being concentrated under reduced pressure into can just stir, and purified water (20g) then is added thereto, finishes 60 DEG C It is stirred overnight.Reaction solution is cooled to 30 DEG C hereinafter, extracting reaction solution 200mL, stirring is lower will with 50%w/v sodium hydrate aqueous solution Reaction solution pH is adjusted to 12, and the chloro- 3- methoxy-2-propanol (22.5g, 0.18mol) of 1-, reaction process are added into reaction solution In keep the pH of reaction solution between 11~12 by way of adding 50%w/v sodium hydrate aqueous solution, react 12.0 hours Add 1- chloro- 2 thereto afterwards, 3-propanediol (3.4g, 29.29mmol) finishes that the reaction was continued 48.0 hours, reaction solution sampling HPLC detection, Iopentol purity are 91.3%.(7) synthesis of IodixanolModus ponens (I) compound (200g, 0.28mol) be added 1L there-necked flask in, thereto be added acetic anhydride (207g, 2.03mol), acetic acid (103.3mL), p-methyl benzenesulfonic acid monohydrate (1g, 5.42mmol), finishes reaction solution being heated to 60 DEG C Start to react, keep the temperature 30 minutes after reacting liquid temperature reaches 120-125 DEG C, cooling is concentrated into after can just stirring thereto It is added 50%v/v (600mL), is slowly added dropwise thereto into 50%w/v sodium hydrate aqueous solution, by adding in reaction process The mode of 50%w/v sodium hydrate aqueous solution keeps the pH of reaction solution between 11~12, and reaction temperature is maintained at 40-45 DEG C, Reaction is finished, and concentrated hydrochloric acid is added into reaction solution and adjusts pH3-4, and stirring filters after 3.0 hours, and filter cake is washed with water to neutrality, dries It is dry, obtain white solid 187g, yield 88.2%, HPLC98.14%.Go step obtained solid (150g, 0.2mol) be added there-necked flask in, thereto be added sodium hydroxide (14.4g, 0.36mol), purified water (300mL), epoxychloropropane (27.9g, 0.30mol) finish 30-35 DEG C of reaction 72.0 hours, instead It should finish, adjust pH3-4, Iodixanol HPLC purity 72.5%, Iohexol HPLC11.3% with concentrated hydrochloric acid.To sum up, method of the invention is easy to operate, and (III) three obtained formula (I), formula (II) or formula intermediate can be made For the raw material for synthesizing diodone, not by-product truly;Importantly, general sieve of synthesis iodine that can be convenient Amine does not have the generation of two acylated by-products, and compared with original grinds the production technology of medicine, process route is entirely different, high income, cost It is low, a kind of very effective, completely new approach is provided for industrialized production Iopromide, is had a extensive future.

Patent

Publication numberPriority datePublication dateAssigneeTitleWO1998008804A1 *1996-08-291998-03-05Nycomed Imaging AsProcess for iohexol manufactureUS5847212A *1997-04-211998-12-08Abbott LaboratoriesProcess for the preparation of iohexolWO1999026916A1 *1997-11-261999-06-03Nycomed Imaging AsN-alkylation of 5-amino-2,4,6-triiodo-isophthalamidesFamily To Family CitationsITMI20010773A1 *2001-04-112002-10-11Chemi SpaProcess for the production of high purity iohexole

Non-Patent

TitleHAAVALDSEN J ET AL: “X-RAY CONTRAST AGENTS. I. SYNTHESIS OF SOME DERIVATIVES OF 5-AMINO-2, 4, 6-TRIIODOISOPHTHLAMIDE”, ACTA PHARMACEUTICA SUECICA, XX, XX, vol. 20, no. 3, 1983, pages 219 – 232, XP002052827, ISSN: 0001-6675 * 

 

Publication numberPriority datePublication dateAssigneeTitleWO2007013816A1 *2005-07-292007-02-01Ge Healthcare AsContinuous crystallisation process of iodinated phenyl derivativesWO2007060380A1 *2005-11-242007-05-31Hovione Inter LtdProcess for the manufacture of iohexolJP2009502910A *2005-07-292009-01-29ジーイー・ヘルスケア・アクスイェ・セルスカプMethod for continuous crystallization of iodinated phenyl derivativesCN101195587B *2006-12-192010-07-21浙江尖峰海洲制药有限公司Production method for lodixanol hydrolysateUS8766002B22009-11-262014-07-01Imax Diagnostic Imaging Holding LimitedPreparation and purification of iodixanolNO342021B1 *2005-07-292018-03-12Ge Healthcare AsContinuous crystallization processFamily To Family CitationsWO2011041275A1 *2009-09-302011-04-07Mallinckrodt Inc.Alkylation of triiodo-substituted arylamides in an aqueous mixed solvent systemES2680019T3 *2010-12-212018-09-03Ge Healthcare AsDesalination of a composition comprising a contrast agentUS20140065076A1 *2012-08-302014-03-06Otsuka Pharmaceutical Co. Ltd.Container with concentrated substance and method of using the same* Cited by examiner, † Cited by third party, ‡ Family to family citation

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References

  1. Jump up to:a b c d e World Health Organization (2009). Stuart MC, Kouimtzi M, Hill SR (eds.). WHO Model Formulary 2008. World Health Organization. pp. 317–8. hdl:10665/44053ISBN 9789241547659.
  2. Jump up to:a b Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 171. ISBN 9781284057560.
  3. ^ ACR Manual on Contrast Media v10.3. 2017 (PDF). American College of Radiology. 2017. p. 6. ISBN 9781559030120Archived (PDF) from the original on 1 January 2018. Retrieved 1 January 2018.
  4. ^ Briggs, Gerald G.; Freeman, Roger K.; Yaffe, Sumner J. (2011). Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk. Lippincott Williams & Wilkins. p. 761. ISBN 9781608317080Archived from the original on 1 January 2017.
  5. ^ Sutton, David; Young, Jeremy W. R. (2012). A Short Textbook of Clinical Imaging. Springer Science & Business Media. p. 235. ISBN 9781447117551Archived from the original on 1 January 2017.
  6. ^ Broe, Marc E. de; Porter, George A.; Bennett, William M.; Verpooten, G. A. (2013). Clinical Nephrotoxins: Renal Injury from Drugs and Chemicals. Springer Science & Business Media. p. 325. ISBN 9789401590884Archived from the original on 1 January 2017.
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External links

Clinical data
Trade namesOmnipaque, Hexopaque, Oraltag, others
Other names5-[N-(2,3-Dihydroxypropyl)acetamido]-2,4,6-triiodo-N,N’-bis(2,3-dihydroxypropyl)isophthalamide
AHFS/Drugs.comMicromedex Detailed Consumer Information
License dataUS DailyMedIohexol
Routes of
administration
intrathecalintravascularby mouth, intracavital, rectal
ATC codeV08AB02 (WHO)
Legal status
Legal statusUS: ℞-onlyIn general: ℞ (Prescription only)
Pharmacokinetic data
Protein bindingLow
MetabolismNil
Elimination half-lifeVariable
ExcretionKidney, unchanged
Identifiers
showIUPAC name
CAS Number66108-95-0 
PubChem CID3730
DrugBankDB01362 
ChemSpider3599 
UNII4419T9MX03
KEGGD01817 
ChEBICHEBI:31709 
ChEMBLChEMBL1200455 
CompTox Dashboard (EPA)DTXSID6023157 
ECHA InfoCard100.060.130 
Chemical and physical data
FormulaC19H26I3N3O9
Molar mass821.142 g·mol−1
3D model (JSmol)Interactive image
Melting point174 to 180 °C (345 to 356 °F)
showSMILES
showInChI
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////////////IOHEXOL, Win-39424, Compd 545, Omnipaque, Oraltag, GE Healthcare, X RAY CONTRAST AGENTS, WIN 39424

CC(=O)N(CC(O)CO)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I

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