CN106749323A - A kind of preparation method of Ioversol impurity - Google Patents
A kind of preparation method of Ioversol impurity Download PDFInfo
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- CN106749323A CN106749323A CN201610913905.7A CN201610913905A CN106749323A CN 106749323 A CN106749323 A CN 106749323A CN 201610913905 A CN201610913905 A CN 201610913905A CN 106749323 A CN106749323 A CN 106749323A
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- 0 C*1(C(C(OC2)=*CO)=C(C(C*)=*C)NCCC1)*2=* Chemical compound C*1(C(C(OC2)=*CO)=C(C(C*)=*C)NCCC1)*2=* 0.000 description 5
- BUJFTKPQXSIZFX-UHFFFAOYSA-N CCC(C)(C)NC Chemical compound CCC(C)(C)NC BUJFTKPQXSIZFX-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/06—Peri-condensed systems
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention provides a kind of preparation method of Ioversol impurity.Specifically, the invention provides the double oxos of 9 iodine of (2,3 dihydroxypropyl) 2,3,5,6 tetrahydrochysene 3 of Ioversol impurity N, N' [the Isosorbide-5-Nitrae] oxazines (preparation method of 4,3,2 d) diformamides of 4 benzoxazine 8,10.
Description
Technical field
The present invention relates to a kind of preparation method of Ioversol impurity.
Background technology
Ioversol, double (2,3 the dihydroxypropyl) -5- [N- (2- ethoxys)-hydroxyl acetamido] -2,4,6- of chemical name N, N'-
Three iodo- 1,3- benzenedicarboxamides.Because Ioversol has water solubility big, viscosity is small, and infiltration is forced down, and adverse reaction rate is low
Advantage, is clinically one of widely used contrast agent, specifically can be used as angiogram, vein Digital subtraction angiograph, closes
Section radiography, IVU, chest and cervical spine radiography and gastrointestinal examination etc..
The synthetic route of the disclosed a plurality of Ioversol of existing document, US4396598A reports double with 5- amidos-N, N'-
(2,3 dihydroxypropyl) -2,4,6- tri- iodo- 1,3- benzenedicarboxamides are raw material, with acetoxy acetyl chloride as acylating reagent, first acyl
Hydrolyzed after change, then the method that Ioversol is prepared with chlorethanol reaction.
US5648536 is reported with 5- amino-N, the N'- iodo- 1,3- phenyl-diformyls of double (2,3- dihydroxypropyls) -2,4,6- three
Amine is initiation material, first with chloracetyl chloride reaction, then is hydrolyzed through sodium acetate, then the method that Ioversol is prepared with chlorethanol reaction.
CN1477093A is then with 5- chloro acetylaminos-N, the N'- pair-iodo- 1,3- benzene of (2,3- dihydroxypropyls) -2,4,6- three
Diformamide and chlorethanol are raw material, the method that " one pot of two-step method " prepares Ioversol.
Double (2,3 dihydroxypropyl) -5- [N- (2- ethoxys)-hydroxyl acetamido] the iodo- 1,3- benzene two of -2,4,6- three of N, N'-
Fragrant hydrogen is replaced by iodine in formamide (Ioversol), it is prone to intramolecular coupling, generates hexa-member heterocycle structure, especially exists
During hydrolyzed under basic conditions, coupled product compound of formula I is inevitably produced in Ioversol.
For pharmaceuticals researcher, groundwork is not only only that how to obtain high-quality bulk drug (API), exploitation
Efficient synthesis technique, it is often more important that dopant species, the generation originated and how to control process contaminants in research bulk drug.
Generally, the impurity that research people first can be produced in controlled syntheses technique, secondly will then develop efficient impurity synthetic route, with
Just substantial amounts of impurity reference substance is obtained, it is ensured that every batch of development of bulk drug quality detection work (e.g., impurity HPLC positioning, impurity
Assay etc.).Therefore, the present invention is carried out on the premise of above-mentioned situation is considered, it is miscellaneous that the present invention provides a kind of new Ioversol
The preparation method of matter compound of formula I.
The content of the invention
The present invention provides a kind of preparation method of Ioversol impurity compound of formula I,
The method includes：The compound of Formulas I -2 issues raw intramolecular coupling reaction in metallic catalyst catalysis, forms Formulas I -3
The step of compound,
Removing R1And R2Hydroxyl protecting group, to form compound of formula I,
Wherein, the R1And R2Hydroxyl protecting group each is stood alone as, the hydroxyl protecting group preferably is selected from alkyl, cycloalkyl, acyl
Base, silylation, aryl or heteroaryl, or R1And R2A heterocyclic group is formed together.
Specifically, the metallic catalyst is selected from least one of Metal Palladium or metal copper catalyst, the Metal Palladium
Catalyst is selected from PdCl2、Pd(OAc)2、PdCl2[dtbpf]、PdCl2[dppf]、PdCl2[dcypf]、(CH3CN)2PdCl2、
PdCl2[xantphos]、PdCl2[P(t-Bu)3)]2, preferably Pd (OAc)2、PdCl2[dppf]、PdCl2[dcypf]；The gold
Category copper catalyst is selected from CuCl2、CuI2、Cu(OAc)2, at least one in CuI.
The transition metal palladium catalyst amount be 0.01~2mol% (relative to starting material compound of formula I mole
For amount), preferably 0.05~1mol%, more preferably 0.1~0.8mol%, specific embodiment consumption can be：0.1、0.2、
0.3rd, 0.4,0.5,0.6,0.7,0.8mol%.
The transition metal copper catalyst amount be 0.01~2mol% (relative to starting material compound of formula I mole
For amount), preferably 0.05~1.5mol%.
Further, alkali is also contained in the reaction, described alkali is alkali alcoholate, alkali metal or alkaline-earth metal carbon
Hydrochlorate or hydroxide, preferably are selected from sodium tert-butoxide, caustic alcohol, potassium carbonate, sodium carbonate, cesium carbonate, potassium fluoride, cesium fluoride, phosphoric acid
At least one of at least one of potassium, more preferably sodium tert-butoxide, caustic alcohol, cesium fluoride, cesium carbonate.
Present invention reaction solvent for use is at least one in methyl tertiary butyl ether(MTBE), tetrahydrofuran, 2- methyltetrahydrofurans, acetonitrile
Kind, it preferably is selected from least one of acetonitrile, tetrahydrofuran；
It is 0.05~0.3M (mol/L), specific implementation that the Ioversol occurs reaction solution concentration when intramolecular coupling reacts
In example, numerical value can for 0.05,0.06,0.07,0.08,0.09,0.1,0.12,0.14,0.16,0.18,0.2,0.22,0.24,
0.26th, 0.28,0.3M, preferably 0.08~0.2M.
The amount of alkali used by coupling reaction of the present invention is 1~5 times of mole of compound of formula I, preferably 2~4 times amounts
(equiv), in instantiation, its consumption can for 2,2.5,3,3.5,4eq；More preferably 2.5~3.5equiv.
Coupling reaction temperature of the present invention is 0~100 DEG C, more preferably preferably 30~90 DEG C, 50~80 DEG C.And it is real
The mode of existing its temperature is by the mode of heating of routine or by microwave condition realization, in a particular embodiment, microwave condition
There is preferably influence on reaction yield, conversion ratio or its product quality, beneficial to the product for obtaining better quality and yield.
The microwave condition is：Reaction time is 5~20min, 50~250W of microwave power, furthermore, described anti-
5~15min, more preferably 5~10min are preferably between seasonable；The microwave power is preferably 50~200W, more preferably 80~
150W。
It is acid condition that the present invention implements Deprotection condition, preferably is selected from hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-methyl benzenesulfonic acid
At least one of.
The compound of Formulas I -2 of the present invention is by N, N'- couples of (2,3 dihydroxypropyl) -5- [N- (2- ethoxys)-hydroxyl acetyl
Amido] -2,4,6- tri- iodo- 1,3- benzenedicarboxamides carry out hydroxyl protection be obtained,
Wherein, the R1And R2As previously described.
Detailed description of the invention
Unless stated to the contrary, otherwise following term in the specification and in the claims has following implications.
" hydroxyl protecting group " of the present invention is the group for hydroxyl protection that can be appropriate known in the art, referring to text
In offering (" Protective Groups in Organic Synthesis ", 5Th.Ed.T.W.Greene＆P.G.M.Wuts)
Monohydroxy protection or the protection of 1,2- glycol, it is preferable that the monohydroxy protection can be alkyl, cycloalkyl, acyl group, silane
Base, aryl or heteroaryl, described acyl group can be but not limited to acetyl group (Ac), benzoyl (Bz) or valeryl
(Piv), described silylation can be but not limited to t-Butyldimethylsilyl (TBDMS), tert-butyl diphenyl silicon substrate
(TBDPS), triisopropylsilyl epoxide methyl (TOM) or triisopropylsilyl (TIPS)；Described 1,2- glycol
Protection can (e.g., acetone solvate, cyclopenta subunit ketal, cyclohexyl subunit ketal, suberyl be sub- using cyclic acetal and ketal
Base ketal and benzyl subunit acetal) protected.
The number of the atom in length or alkyl group, the aromatic yl group of alkyl be not limited specifically and should be ability
The those of ordinary skill in domain is known or can be determined.In a particular embodiment, the alkyl group is a C1-6Alkyl.Another
In one embodiment, the aryl groups are a C6-14Aryl.
" alkyl " refers to the aliphatic hydrocarbon group of saturation, and choosing (can be expressed as C containing 1 to 6 alkyl of carbon atom1-6Alkyl).It is non-
Restricted embodiment includes methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, sec-butyl, n-pentyl, 1,
1- dimethyl propyls, 1,2- dimethyl propyls, 2,2- dimethyl propyls, 1- ethyl propyls, 2- methyl butyls, 3- methyl butyls,
N-hexyl, 1- Ethyl-2-Methyls propyl group, 1,1,2- thmethylpropyls, 1,1- dimethylbutyls, 1,2- dimethylbutyls, 2,2-
Dimethylbutyl, 1,3- dimethylbutyls, 2- ethyl-butyls, 2- methyl amyls, 3- methyl amyls.
" heterocyclic radical " refers to that saturation or part are undersaturated containing one or more heteroatomic cyclic alkyls, and it includes
4 to 12 annular atoms, preferably comprise 5 to 8 annular atoms, and most preferably 5 to 6 annular atoms, wherein hetero atom are oxygen, sulphur or nitrogen.
Non-limiting example includes heterocycle amyl group, Polymorphs alkenyl, piperidyl, heterocycle hexenyl, heterocycle hexadienyl etc..It is described
Heterocyclic radical can be optionally substituted, preferred substitution base is including alkyl, alkoxy, halogen, hydroxyl etc..
" aryl " refers to the aromatic group with least one conjugated pi-Electron Ring, and including isocyclic aryl, heterocycle
Aryl (also referred to as heteroaryl groups) and biaryl group, these groups can be all optionally substituted.Aromatic yl group
6 to 14 carbon atoms can be included, preferably 6 to 10 carbon atoms, non-limiting example includes phenyl, pyridine radicals or naphthyl.
Specific embodiment
The present invention is explained in greater detail below with reference to embodiment, embodiments of the invention are merely to illustrate skill of the invention
Art scheme, the spirit and scope of the invention are not limited thereto.
Embodiment 1
Under argon atmosphere, to addition Ioversol (8.1g, 10mmol), 2,2- dimethoxys third in the reaction bulb of 100ml
Alkane (4.2g, 40mmol) and 50mL acetone, add p-methyl benzenesulfonic acid monohydrate (0.19g, 1mmol), and reaction is stirred at room temperature
5-8h, TLC detection raw material Ioversol after completion of the reaction, are concentrated to dryness, and add 50ml ethyl acetate, 10ml water process concentration residual
Thing, point liquid is dried, and is concentrated to give target compound 7.9g, the yield 89%, (M+Na of ESI (+) MS m/z 910+)。
Embodiment 2：
Under argon atmosphere, in the reaction bulb of 50ml add compound 1a (4.4g, 5mmol), palladium (112mg),
Iodate Asia ketone (950mg), caustic alcohol (850mg) and 25mL anhydrous tetrahydro furans, are warming up to 75~80 DEG C of 3~4h of stirring reaction,
TLC detection starting compound 1a reactions are finished, and are concentrated to dryness, and add 50ml ethyl acetate, 10ml water process concentration residues, point
Liquid, dries, and concentration, column chromatography purifies to obtain target compound 2.87g, the yield 91%, (M+H of ESI (+) MS m/z 631+)。
Embodiment 3：
Under argon atmosphere, to 20mL tetrahydrofurans are added in 2.5g compounds 2a (4mmol), stir it is molten it is clear after, be added dropwise 2
~3ml 6M (mol/L) HCl, 2~3h of stirring reaction, is concentrated to dryness, and adds ethyl acetate 20ml dissolution residual substances and 10ml
Neutrality is washed to, point liquid is concentrated to dryness after drying, column chromatography purifying (methylene chloride/methanol/triethylamine 10:1:0.1) target is obtained
Compound 2.1g, yield 95.4%.
ESI(+)MS m/z 574(M+Na+)；13C NMR(DMSO-d6)δ(ppm)：37.4,42.5,63.7,64.5,
67.1,70.2,85.9,114.4,125.2,127.1,140.5,141.1,161.3,165.9,166.3。
Embodiment 4：
Under argon atmosphere, to addition Ioversol (4g, 5mmol), triethyl orthoformate in the reaction bulb of 100ml
(2.96g, 20mmol) and 10mL acetone, adds p-methyl benzenesulfonic acid monohydrate (0.19g, 1mmol), and reaction 6 is stirred at room temperature
~8h, TLC detection raw material Ioversol after completion of the reaction, are concentrated to dryness, and add 25ml ethyl acetate and 5ml water process concentration residual
Thing, point liquid is dried, and is concentrated to give target compound 4.2g, the yield 93%, (M+H of ESI (+) MS m/z 919+)。
Embodiment 5：
Under argon atmosphere, in the reaction bulb of 50ml add compound 1b (9.2g, 10mmol), 200mg palladiums,
1.9g iodate Asia ketone, 1.9g caustic alcohols and 60mL anhydrous tetrahydro furans, are warming up to 75~80 DEG C of stirring reaction 3~4h, TLC detections
Starting compound 1b reactions are finished, and are concentrated to dryness, and add 150ml ethyl acetate, 20ml water process concentration residues, and point liquid is done
Dry, concentration, column chromatography purifies to obtain target compound 5.76g, the yield 87%, (M+H of ESI (+) MS m/z 663+)。
Embodiment 6：
Under argon atmosphere, to 20mL tetrahydrofurans are added in 2.6g compounds 2b (4mmol), stir it is molten it is clear after, be added dropwise 2
~3ml 6M (mol/L) HCl, 2~3h of stirring reaction, is concentrated to dryness, and adds ethyl acetate 20ml dissolution residual substances, 10ml water
Neutrality is washed till, point liquid is concentrated to dryness after drying, column chromatography purifying (methylene chloride/methanol/triethylamine 10:1:0.1) targeted is obtained
Compound 2.0g, yield 90.1%, ESI (+) MS m/z574 (M+Na+)。
Embodiment 7：
Under argon atmosphere, in the reaction bulb of 50ml add compound 1a (4.4g, 5mmol), palladium (112mg),
Iodate Asia ketone (950mg), caustic alcohol (850mg) and 25mL anhydrous tetrahydro furans, microwave reaction 8min (microwave power is 150W),
TLC detection starting compound 1a reactions are finished, and are concentrated to dryness, and add 50ml ethyl acetate, 10ml water process concentration residues, point
Liquid, dries, and concentration, column chromatography purifies to obtain target compound 2.9g, the yield 92%, (M+H of ESI (+) MS m/z 631+)。
Process conditions are groped
The condition with reference to described in embodiment 2, selects different types of catalyst, solvent and alkali to investigate coupling reaction bar respectively
Part, enumerates but is not limited to such as the experimental data of table 1：
Table 1
Experimental example 1-9 as shown by data method of the present invention can effectively synthesize in Ioversol impurity compound of formula I
Catalyst combination used in mesosome, especially experimental example 1,4 and 5；Meanwhile, the intermediate only needs simple deprotection base
Compound of formula I is obtained, whole synthetic route is simple and easy to do and efficient.
Claims (7)
1. a kind of preparation method of Ioversol impurity compound of formula I,
The method includes：The compound of Formulas I -2 issues raw intramolecular coupling reaction in metallic catalyst catalysis, to form the change of Formulas I -3
Compound,
Removing R1And R2Hydroxyl protecting group, to form compound of formula I,
Wherein, the R1And R2Each stand alone as hydroxyl protecting group, the hydroxyl protecting group preferably be selected from alkyl, cycloalkyl, acyl group,
Silylation, aryl or heteroaryl, or R1And R2Heterocyclic group is formed together.
2. method according to claim 1, it is characterised in that the metallic catalyst is selected from Metal Palladium or metal copper catalysis
At least one of agent, the metal palladium catalyst is selected from PdCl2、Pd(OAc)2、PdCl2[dtbpf]、PdCl2[dppf]、PdCl2
[dcypf]、PdCl2[xantphos]、PdCl2[P(t-Bu)3)]2、(CH3CN)2PdCl2At least one of, it preferably is selected from Pd
(OAc)2、PdCl2[dppf]、PdCl2[dcypf]；The metal copper catalyst is selected from CuCl2、CuI2、Cu(OAc)2, in CuI
It is at least one.
3. method according to claim 1 and 2, it is characterised in that also contain alkali in the reaction, described alkali is alkali gold
Category alcoholates, alkali metal or alkaline earth metal carbonate or hydroxide, preferably are selected from sodium tert-butoxide, caustic alcohol, potassium carbonate, carbonic acid
At least one of sodium, cesium carbonate, potassium fluoride, cesium fluoride, potassium phosphate, preferably sodium tert-butoxide, caustic alcohol, cesium fluoride, cesium carbonate
At least one of.
4. method according to claim 1 and 2, it is characterised in that reaction solvent for use is methyl tertiary butyl ether(MTBE), tetrahydrochysene furan
Mutter, at least one of 2- methyltetrahydrofurans, acetonitrile, preferably be selected from least one of acetonitrile, tetrahydrofuran.
5. method according to claim 1 and 2, it is characterised in that reaction temperature is 0~100 DEG C, preferably 10~80 DEG C,
More preferably 20~70 DEG C.
6. method according to claim 1 and 2, it is characterised in that reaction solution concentration is 0.05~0.3M, preferably
0.08~0.2M.
7. method according to claim 1 and 2, it is characterised in that described Deprotection condition is acid condition, preferably
From at least one of hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-methyl benzenesulfonic acid.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4396598A (en) * | 1982-01-11 | 1983-08-02 | Mallinckrodt, Inc. | Triiodoisophthalamide X-ray contrast agent |
| US5648536A (en) * | 1995-06-07 | 1997-07-15 | Dunn; Thomas Jeffrey | Process for producing ioversol |
| CN1477093A (en) * | 2003-07-10 | 2004-02-25 | 江苏省原子医学研究所 | Preparation method of ioversol |
| CN1884257A (en) * | 2006-06-30 | 2006-12-27 | 江苏省原子医学研究所 | Improved process for synthesizing ioversol |
| CN101307010A (en) * | 2008-07-12 | 2008-11-19 | 厦门大学 | Method for synthesizing Ioversol |
| CN101337907A (en) * | 2007-07-06 | 2009-01-07 | 江苏恒瑞医药股份有限公司 | Process for purifying ioversol |
-
2016
- 2016-10-19 CN CN201610913905.7A patent/CN106749323B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4396598A (en) * | 1982-01-11 | 1983-08-02 | Mallinckrodt, Inc. | Triiodoisophthalamide X-ray contrast agent |
| US5648536A (en) * | 1995-06-07 | 1997-07-15 | Dunn; Thomas Jeffrey | Process for producing ioversol |
| CN1477093A (en) * | 2003-07-10 | 2004-02-25 | 江苏省原子医学研究所 | Preparation method of ioversol |
| CN1884257A (en) * | 2006-06-30 | 2006-12-27 | 江苏省原子医学研究所 | Improved process for synthesizing ioversol |
| CN101337907A (en) * | 2007-07-06 | 2009-01-07 | 江苏恒瑞医药股份有限公司 | Process for purifying ioversol |
| CN101307010A (en) * | 2008-07-12 | 2008-11-19 | 厦门大学 | Method for synthesizing Ioversol |
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| Title |
|---|
| KARCN E.TORRACA ET AL.: "A high-yield, general method for the catalytic formation of oxygen heterocycles", 《J.AM.CHEM.SOC》 * |
| PIER LUCIO ANELLI ET AL.: "Smiles rearrangement as a tool for the preparation of 5-[(2-hydroxyacyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamides: main pathway and side reactions", 《TETRAHEDRON》 * |
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| 李婕等: "碘佛醇主成分异构体及其有关物质同时分离检测和结构确证", 《中国药学杂志》 * |
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