CN104661995B - The preparation of x-ray contrast agent IOFORMINOL - Google Patents
The preparation of x-ray contrast agent IOFORMINOL Download PDFInfo
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- CN104661995B CN104661995B CN201380050408.3A CN201380050408A CN104661995B CN 104661995 B CN104661995 B CN 104661995B CN 201380050408 A CN201380050408 A CN 201380050408A CN 104661995 B CN104661995 B CN 104661995B
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- ioforminol
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- contrast agent
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- 239000002872 contrast media Substances 0.000 title abstract description 24
- BFVVDRUCXCIALU-UHFFFAOYSA-N 5-[[3-[3,5-bis(2,3-dihydroxypropylcarbamoyl)-N-formyl-2,4,6-triiodoanilino]-2-hydroxypropyl]-formylamino]-1-N,3-N-bis(2,3-dihydroxypropyl)-2,4,6-triiodobenzene-1,3-dicarboxamide Chemical compound OCC(O)CNC(=O)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(N(CC(O)CN(C=O)C=2C(=C(C(=O)NCC(O)CO)C(I)=C(C(=O)NCC(O)CO)C=2I)I)C=O)=C1I BFVVDRUCXCIALU-UHFFFAOYSA-N 0.000 title abstract description 22
- 229950004332 Ioforminol Drugs 0.000 title abstract description 21
- 238000002360 preparation method Methods 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 76
- 238000005804 alkylation reaction Methods 0.000 claims abstract description 15
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 10
- 238000011065 in-situ storage Methods 0.000 claims abstract description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- BRLQWZUYTZBJKN-UHFFFAOYSA-N epichlorohydrin Chemical group ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 claims description 5
- 239000000463 material Substances 0.000 claims description 5
- 239000000843 powder Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atoms Chemical class [H]* 0.000 claims description 2
- 239000000203 mixture Substances 0.000 abstract description 19
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 abstract description 2
- 238000003384 imaging method Methods 0.000 abstract description 2
- RIWAPWDHHMWTRA-UHFFFAOYSA-N 1,2,3-triiodobenzene Chemical class IC1=CC=CC(I)=C1I RIWAPWDHHMWTRA-UHFFFAOYSA-N 0.000 abstract 1
- KFNNIILCVOLYIR-UHFFFAOYSA-N propyl formate Chemical compound CCCOC=O KFNNIILCVOLYIR-UHFFFAOYSA-N 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- -1 formyloxy Chemical group 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- 229940039231 CONTRAST MEDIA Drugs 0.000 description 7
- 238000006471 dimerization reaction Methods 0.000 description 7
- 239000003513 alkali Substances 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000008186 active pharmaceutical agent Substances 0.000 description 5
- 238000007792 addition Methods 0.000 description 4
- 239000000539 dimer Substances 0.000 description 4
- 239000000193 iodinated contrast media Substances 0.000 description 4
- NBQNWMBBSKPBAY-UHFFFAOYSA-N iodixanol Chemical compound IC=1C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C(I)C=1N(C(=O)C)CC(O)CN(C(C)=O)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NBQNWMBBSKPBAY-UHFFFAOYSA-N 0.000 description 4
- 229960004359 iodixanol Drugs 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000005457 optimization Methods 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 238000002601 radiography Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000002194 synthesizing Effects 0.000 description 3
- KGBXLFKZBHKPEV-UHFFFAOYSA-N Boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- NTHXOOBQLCIOLC-UHFFFAOYSA-N Iohexol Chemical compound OCC(O)CN(C(=O)C)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NTHXOOBQLCIOLC-UHFFFAOYSA-N 0.000 description 2
- TYYBFXNZMFNZJT-UHFFFAOYSA-N Ioxaglic acid Chemical compound CNC(=O)C1=C(I)C(N(C)C(C)=O)=C(I)C(C(=O)NCC(=O)NC=2C(=C(C(=O)NCCO)C(I)=C(C(O)=O)C=2I)I)=C1I TYYBFXNZMFNZJT-UHFFFAOYSA-N 0.000 description 2
- 208000003663 Ventricular Fibrillation Diseases 0.000 description 2
- 238000002583 angiography Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical class [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 description 2
- 229960001025 iohexol Drugs 0.000 description 2
- 230000002045 lasting Effects 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- KIHQZLPHVZKELA-UHFFFAOYSA-N 1,3-dibromopropan-2-ol Chemical compound BrCC(O)CBr KIHQZLPHVZKELA-UHFFFAOYSA-N 0.000 description 1
- 206010048610 Cardiotoxicity Diseases 0.000 description 1
- YVPYQUNUQOZFHG-UHFFFAOYSA-N Diatrizoic acid Chemical compound CC(=O)NC1=C(I)C(NC(C)=O)=C(I)C(C(O)=O)=C1I YVPYQUNUQOZFHG-UHFFFAOYSA-N 0.000 description 1
- NJKDOADNQSYQEV-UHFFFAOYSA-N Iomeprol Chemical compound OCC(=O)N(C)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NJKDOADNQSYQEV-UHFFFAOYSA-N 0.000 description 1
- 229960004647 Iopamidol Drugs 0.000 description 1
- 229940029407 Ioxaglate Drugs 0.000 description 1
- 229960001707 Ioxaglic Acid Drugs 0.000 description 1
- 229940063718 Lodine Drugs 0.000 description 1
- 206010029155 Nephropathy toxic Diseases 0.000 description 1
- 210000002381 Plasma Anatomy 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 125000001821 azanediyl group Chemical group [H]N(*)* 0.000 description 1
- 230000000903 blocking Effects 0.000 description 1
- 150000007516 brønsted-lowry acids Chemical class 0.000 description 1
- 150000007528 brønsted-lowry bases Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atoms Chemical group C* 0.000 description 1
- 231100000259 cardiotoxicity Toxicity 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 230000003247 decreasing Effects 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- NNYBQONXHNTVIJ-UHFFFAOYSA-N etodolac Chemical compound C1COC(CC)(CC(O)=O)C2=C1C(C=CC=C1CC)=C1N2 NNYBQONXHNTVIJ-UHFFFAOYSA-N 0.000 description 1
- 238000006170 formylation reaction Methods 0.000 description 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000003301 hydrolyzing Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002497 iodine compounds Chemical class 0.000 description 1
- 229960000780 iomeprol Drugs 0.000 description 1
- XQZXYNRDCRIARQ-LURJTMIESA-N iopamidol Chemical compound C[C@H](O)C(=O)NC1=C(I)C(C(=O)NC(CO)CO)=C(I)C(C(=O)NC(CO)CO)=C1I XQZXYNRDCRIARQ-LURJTMIESA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000000051 modifying Effects 0.000 description 1
- 238000001728 nano-filtration Methods 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 230000003287 optical Effects 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000002459 sustained Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Abstract
A kind of method that the present invention relates to contrast agent Ioforminol preparing and can be used for X radial imaging.More particularly; the present invention relates to and is prepared Ioforminol by a kind of compound mixture by the method including in-situ hydrolysis and double alkylation; described compound mixture includes 1 Formylamino 3; 5 pairs (2; 3 pairs of (formyloxy) propane 1 base carbamoyls) 2; 4,6 triiodo-benzenes.
Description
The present invention relates to a kind of method preparing iodinated X-ray contrast agent, prepare particularly to one and can be used for X-ray
The method of the contrast agent Ioforminol of imaging.More particularly, it relates to prepared by a kind of compound mixture
Ioforminol, described compound mixture includes 1-Formylamino-3, double (2,3-double (formyloxy) propane-1-bases of 5-
Carbamoyl)-2,4,6-triiodo-benzene (a kind of key intermediate during preparing Ioforminol).
In 50 years of past, x-ray contrast agent field is accounted for leading by solubility containing iodine compound always.Generally by city
Sell the available contrast media containing iodinated contrast media and classify as ion monomer such as cardiografin (GastrografenTM), ion
Dimer such as Ioxaglic Acid (ioxaglate) (HexabrixTM), non-ionic monomer such as iohexol (OmnipaqueTM), iopamidol
(IsovueTM), iomeprol (IomeronTM) and nonionic dimer iodixanol (VisipaqueTM).The most extensively make
Commercially available nonionic X-ray contrast agent (as described above those) be considered as safe.Containing iodinated contrast media
Contrast media is used for the X-ray inspection more than 2,000 ten thousand times in the U.S. every year, and the number of times of untoward reaction is considered as can
Accept.But, the X-ray inspection strengthened due to radiography will may require that the contrast media giving accumulated dose most about 200ml,
So for providing the contrast media improved to there is lasting power.
PATIENT POPULATION is considered as the part of high-risk patient is in increase.In order to meet sustained improvement for whole patient population
The demand of the internal X-ray diagnostic agent of body, for finding the x-ray contrast agent with improved property and about contrast agent
There is lasting power in the nephrotoxicity (CIN) of induction.
X-containing the compound with two triiodide phenyl (being connected by linker) as active pharmaceutical ingredient
Ray contrast medium is typically considered dimerization contrast agent or dimer.In period these years, there has been proposed diversified
Iodate dimer.At present, market exists a kind of containing iodinated nonionic dimer as active pharmaceutical ingredient radiography be situated between
Matter contains the product Visipaque of compound iodixanol.
A kind of novel dimerization contrast agent, named Ioforminol is disclosed in the WO2009/008734 of applicant.
Its character is described in greater detail in following publication: Chai et al., " Predicting cardiotoxicity propensity
of the novel iodinated contrast medium GE-145: ventricular fibrillation
During left coronary arteriography in pigs " (predict the heart of novel iodinated contrast medium GE-145
Toxicity is inclined to: the ventricular fibrillation during pig left-side tubular angiography), Acta Radiol, 2010 and Wistrand, L.G. etc.
People, " GE-145, a new low-osmolar dimeric radiographic contrast medium " (GE-145,
A kind of new hyposmosis dimerization radiography contrast media), Acta Radiol, 2010.Ioforminol (GE-145) herein
Named compound 1 also has a structure that
Compound 1:
5,5'-(2-hydroxy propane-1,3-diyl) double (formoxyl azane diyl) double (N1,N3-bis-(2,3-dihydroxy third
Base)-2,4,6-triiodoisophthal amide).
Manufacture ionic X-ray contrast media relate to produce chemicals, active pharmaceutical ingredient (API), i.e. contrast agent,
It is configured to drug products subsequently, context means that X-ray compositions.The WO2009/008734 of applicant provides use
In prepare API Ioforminol synthetic route.Total preparation description and embodiment 1 such as WO2009/008734 carry
Confession, Ioforminol can be such as by commercially available 5-amino-N, N'-pair-(2,3-dihydroxy-propyl group)-2, and 4,6-tri-is iodo-
(compound (4) synthesizes isophthaloyl amine.The preparation of this compound by iohexol and the synthesis of iodixanol it is known that also
And can also be prepared by such as 5-nitro isophathalic acid, as described in WO2006/016815, including hydrogenation and iodate (example subsequently
As, by lodine chloride, ICl).Or, it is possible to use 5-amino-2,4,6-tri-triiodoisophthalic acids, it is commercially available precursor, example
As derived from Sigma-Aldrich.Subsequently the free amino group of isophthaloyl amines (compound (4)) is acylated, and substituent group
In hydroxyl also can be by acylated protection.N can be produced by this protection group by such as hydrolyzing removing1,N3-bis-(2,3-dihydroxies
Base propyl group)-5-Formylamino-2,4,6-triiodoisophthal amide.In dimerization step, by its in the double alkylation of chloropropylene oxide anti-
Should be to provide Ioforminol contrast agent compound.
The synthesis of the state of the art of Ioforminol, as disclosed in the embodiment 1 and 2 of WO2009/008734,
It is shown in scheme 1 below.
Flow process 1.
As described in WO2009/008734, compound 3 is that one includes 1-Formylamino-3, double (2, the 3-double (formyls of 5-
Epoxide) propane-1-base carbamoyl)-2, the mixture of 4,6-triiodo-benzenes, and X is then formyl group.
In each synthesis step, it is important that but by productivity optimization, the generation of impurity being minimized also will be by
Spent time and cost minimization.The problem solved by the present invention is it is believed that be to provide by the compound (3) of flow process 1
(i.e. comprising 1-Formylamino-3,5-double (double (formyloxy) propane-1-base carbamoyl of 2,3-)-2,4,6-triiodo-benzene)
Prepare the optimization of the method for Ioforminol.Therefore, the present invention relates to one and include hydrolysis and the dimerization reaction of compound (3)
The method that Ioforminol is provided.
In the method for the state of the art, as disclosed in WO2009/008734 embodiment 2 program B, by 1-formoxyl ammonia
Base-3, double (2,3-double (formyloxy) propane-1-base carbamoyls)-2 of 5-, 4,6-phenyl triiodides (compound (3), wherein X
For formoxyl) prepare compound (1) (Ioforminol) and carry out in following methods, wherein compound (3) is dissolved in Shui Hejia
In the mixture of alcohol, this mixture is possibly together with boric acid, and makes pH be positioned at 11.6-11.7 by adding potassium hydroxide.Molten when becoming
During liquid, chloropropylene oxide divide several part add.This mixture is kept stirring for, and repeatedly adjusts pH by adding potassium hydroxide
Value, meanwhile regulates temperature.The whole process being prepared compound (1) by compound (3) it is reported to be at least 48 hours.
Explore and had more cost-benefit method to prepare Ioforminol (compound (1)), wherein decreased reaction
Time and wherein improve the productivity of compound (1).We have found that compound (1) preparation can with have cost benefit and
Eco-friendly method completes, and described method relates to the in-situ hydrolysis of the blocking group of compound (3), double alkylation subsequently, also
It is expressed as dimerization, uses water as unique solvent.The method spending notable shorter time than the state of the art method is able to
Determine.
Therefore, in first aspect, the present invention provides the method being prepared compound (1) by compound (3)
Compound (1)
Compound (3)
The most each X individually represents hydrogen, formoxyl (-CO-H) or acetyl group (-CO-CH3)；
The method includes the step of the protection group (-OX) in-situ hydrolysis of compound (3), and wherein compound (3) is only suspended in
In water.
Compound (3) is the mixture of the different compounds with formoxyl and acetyl protecting group.This is to make
For the result of early stage formylation step, described step is prepared compound (3) by compound (4), the acid of mixing is preferably used
Acid anhydride.In one embodiment, compound 3 includes that the most all X group are individually for the mixed of the compound of formoxyl or acetyl group
Compound.The key component of compound (3) is double (double (formyloxy) propane-1-Ji Anjijia of 2,3-of 1-Formylamino-3,5-
Acyl group)-2,4,6-triiodo-benzene.Therefore, in one embodiment, all of X group all represents formoxyl.
In one embodiment of the invention, described method includes following sequential steps before double alkylation reacts:
I) compound (3) is suspended in water；
Ii) pH of the solution of step i) is adjusted to 10.0-12.5.
When compound (3) has suspended, and modulated whole pH value, the formoxyl of compound (3) and acetyl protecting group
In-situ hydrolysis occur.It is prepared for compound (2) in this reaction, but it does not separates.Meanwhile generate formyl-and
Acetyl salt is as by-product.The generation of salt can have the impact of acceleration to the double alkylation reaction rate occurred after in-situ hydrolysis, thus
Quick and complete double alkylation is provided.When parent material compound (3) only suspends in water and uses this in-situ hydrolysis
During program, it was observed that the beyond thought raising of reaction rate of double alkylation.It is believed that produced salt is by using with double alkylation
Dialkylating agent is coordinated and/or the transitive state of stable reaction improves reaction rate.Meanwhile, this process provides high yield.
Have been found that and can carry out in less than 24 hours from compound (3) to the reaction of compound (1), such as less than 20 hours, and carry
For 90% or higher productivity, such as 93% or up to or more than 95%.It was unexpected that " the only step of water " of the inventive method carries
Supply about 20% higher productivity and saved production time of about one day (embodiment 2 compared to WO2009/008734 is retouched
The art methods stated).
In step i), use water as single solvent, and have been surprisingly found that and need not add other solvents or additive
(such as boric acid).In the method for the present invention, parent material compound (3) preferably has the fine powder of low acid content.At one
In embodiment, the mixture of compound (3) can include the residue of some solvent resistant, such as alcohol, but need not add alcohol.?
During manufacturing compound (3), short chain alcohol can be used to carry out optimization and to prepare the compound (3) of powder type, find useful
It is that the compound (3) being used as parent material in the method for current request protection is not completely dried, but the alcohol containing 0-15%, with
And residue alcohol content is 0-7%, and most preferably 2-5%, for appropriate.Residue alcohol in compound (3) is typically short chain alcohol,
Described short chain alcohol is straight chain or branched C1-C6 alcohol, or these mixture.This alcohol can be monohydroxylated or dihydroxy
's.Methanol, ethanol and propanol are preferred alcohol, and propanol, particularly isopropanol are preferred.The water yield needed for optimum reaction condition
Depend on the factor such as remaining alcohol content and temperature.Find that the suitable water yield is about 0.5-2.0 and rises water/kg compound (3), as
About 1 liter of water/kg compound (3).
Therefore, in step ii, by addition alkali in compound (3) suspension, pH is adjusted to before double alkylation reacts
10.0-12.5, more preferably 11.0-1.8, most preferably 11.0-11.2.This pH adjusts and is preferably gradually completing to neutralize also acid
And avoid the most unexpected heat to produce.This alkali is selected from strong water-soluble alkali such as sodium hydroxide and potassium hydroxide, wherein, preferably hydrogen-oxygen
Change sodium solution (such as 50%).The hydrolysis that the alkali of the protection ester group that the addition of alkali provides compound (3) drives, wherein generates first
Acyl group-and acetyl group salt as side-product, such as formoxyl sodium salt and acetyl group sodium salt.Carry it addition, this pH is adjusted to double alkylation
For Optimal pH condition.In one embodiment, this pH adjusts and uses pH-stat system to carry out, to ensure that pH value keeps constant.
Such pH system includes both bronsted lowry acids and bases bronsted lowries, such as HCl and NaOH solution.
Should be via the double alkylation (dimerization step) of 2-hydroxy propane bridge preferably by appropriate dialkylating agent be joined
Alkaline solution in step (ii) occurs.This dose is selected from dihalo alkanol or halogenated heterocycloalkyl, such as 1, the chloro-2-of 3-bis-third
Alcohol, 1-chloro-2,3-propanol, 1,3-bis-bromo-2-hydroxy propane and chloropropylene oxide (EPI), wherein particularly preferably EPI.Therefore, at this
In another bright embodiment, the method farther includes dialkylating agent is joined step ii) alkaline solution in
Step.Dialkylating agent is joined in alkaline aqueous solution with one or more parts, as with 1 to 5 part, preferably 3 phases
Etc. part.The dialkylating agent of the compound (3) of about 2 molar equivalents with a molar equivalent is reacted and bridges.Owing to alkali is to two
The trace consumption of alkylating agent, therefore can use the dialkylating agent of trace molar excess.During and after adding, should
Reactant mixture is kept stirring for making double alkylation reaction carry out required a period of time.This can spend 5-20 hour, preferably 10-
15 hours.
Before hydrolysis, period and/or afterwards, it is possible to regulation temperature, as being cool below room temperature, such as arrive 12-16 DEG C or
Lower.In a preferred embodiment, before adding dialkylating agent, temperature is adjusted to about 15 DEG C.Particularly preferably
Ground, by pH regulator to 11.0-11.2, and is adjusted to about 15 DEG C before addition by temperature, and these conditions is remained to double
Alkanisation completes.
The compound prepared, such as compound (1), can be purified by any convenient method, such as, by washing, leads to
Cross preparative chromatography, by recrystallization or ultrafiltration/nanofiltration.Therefore, optional other step is for purifying and being dried.
Compound mixture (3) and the compound (1) prepared according to the method being claimed include optically active isomer
And will exist with various isomeric forms due to chiral carbon atom.In addition, described compound due to large volume iodine former
Being obstructed of N-CO key in the neighbouring formoxyl official's energy caused of son rotates and presents outward turning/rotational isomer.Enantiomer-pure is produced
The preparation of both thing and optical isomer intermixture is included in the inventive method.
Can serve as contrast agent according to the compound prepared by the present invention and can join with conventional carrier and excipient
System, to produce diagnosis contrast media.Therefore, from other side, the present invention provides Ioforminol (compound (1)), and
Including the diagnosis composition of Ioforminol prepared according to the methods of the invention, wherein said composition includes at least one physiology
Upper permissible carrier or excipient, such as, the aqueous solution being used for injecting is (optionally with the plasma ion added or dissolved oxygen one
Rise).The contrast agent composition of the present invention can be before administration instant concentration maybe can be for dilution conc forms.
Therefore, the present invention farther includes according to the Ioforminol prepared by described preparation process and containing this Ioforminol
Diagnostic compositions purposes in X-ray contrast examination.
The present invention illustrates with reference to following non-limiting example.
Embodiment
Embodiment 1: prepare compound (1) from compound (3)
Use the reactor with top mechanism stirring that compound (3) (1103kg, 890mol) is suspended in water (1213L)
In, this suspension is cooled to 10 degree and aqueous NaOH (50%) was added through 12 hours, pH and temperature are kept at low
In 12.5 and 20 degree.This solution is cooled to 16 degree and uses the pH stat system equipped with HCl (30%) and NaOH (50%) to incite somebody to action
PH is set as 11.1.As long as temperature is less than 18 degree, run this system the most always.By EPI (41kg, 445mol) through 2.5 little constantly
Between be continuously added to, maintain the temperature between 15-18 degree.By using HCl (30%) to adjust pH to 7 after stirring 38 hours
This reactant mixture of cancellation.HPLC shows compound (1) ~ 95.5% UV productivity.
Extend the double alkylation response time in this embodiment to have ensured and to have maximized productivity.Can the most earlier
Ground cancellation reaction, such as 10-12 hour, and does not produce significant loss of yield.
Claims (7)
1. the method being prepared compound (1) by compound (3),
Compound (1)
Compound (3)
The most each X individually represents hydrogen, formoxyl (-CO-H) or acetyl group (-CO-CH3)；Described method includes compound (3)
The step of protection group (-OX) in-situ hydrolysis, wherein compound (3) only suspends in water, and the change that wherein will only suspend in water
The pH of compound (3) is adjusted to 10.0-12.5.
2. the method for claim 1, described method includes following sequential steps before double alkylation reacts:
I) compound (3) is suspended in water；
Ii) pH of the solution of step i) is adjusted to 10.0-12.5.
3. method as claimed in claim 1 or 2, wherein said parent material compound (3) is the fine powder with low acid content
End.
4. method as claimed any one in claims 1 to 3, wherein said parent material compound (3) comprises 0-15% alcohol.
5. the method as according to any one of claim 2 to 4, described method farther includes by by appropriate di
Agent joins the double alkylation reaction in the alkaline solution of step (ii).
6. method as claimed in claim 5, wherein said dialkylating agent is chloropropylene oxide.
7. the method as according to any one of claim 2 to 6, described method includes from step i) or ii) solution
Temperature is adjusted to 12-16 DEG C.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NO20121103 | 2012-09-27 | ||
| NO20121103 | 2012-09-27 | ||
| PCT/US2013/060092 WO2014052092A1 (en) | 2012-09-27 | 2013-09-17 | Preparation of ioforminol, an x-ray contrast agent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104661995A CN104661995A (en) | 2015-05-27 |
| CN104661995B true CN104661995B (en) | 2016-11-30 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012007456A1 (en) * | 2010-07-12 | 2012-01-19 | Ge Healthcare As | X-ray imaging at low contrast agent concentrations and/or low dose radiation |
| WO2012084926A1 (en) * | 2010-12-21 | 2012-06-28 | Ge Healthcare As | Desalination of a composition comprising a contrast agent |
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012007456A1 (en) * | 2010-07-12 | 2012-01-19 | Ge Healthcare As | X-ray imaging at low contrast agent concentrations and/or low dose radiation |
| WO2012084926A1 (en) * | 2010-12-21 | 2012-06-28 | Ge Healthcare As | Desalination of a composition comprising a contrast agent |
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