CN106316878B - A kind of preparation method of iomeprol impurity - Google Patents
A kind of preparation method of iomeprol impurity Download PDFInfo
- Publication number
- CN106316878B CN106316878B CN201510326397.8A CN201510326397A CN106316878B CN 106316878 B CN106316878 B CN 106316878B CN 201510326397 A CN201510326397 A CN 201510326397A CN 106316878 B CN106316878 B CN 106316878B
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- methylamino
- iodo
- tri
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Detergent Compositions (AREA)
Abstract
The present invention relates to a kind of formula（1）Iomeprol impurity N（1,3 dihydroxypropyl）‑N’‑（2,3 dihydroxypropyls）‑5‑[（Hydroxyacetyl）Methylamino] 2,4,6 triiodo 1,3 benzenedicarboxamide preparation method.Structural formula is as follows：
Description
Technical field
The invention belongs to medicinal chemistry art, more particularly to caused miscellaneous in a kind of iomeprol preparation process
Matter N-（1,3- dihydroxypropyl）-N’-（2,3- dihydroxypropyls）-5-[（Hydroxyacetyl）Methylamino] -2,4,6- tri- is iodo-
The preparation method of 1,3- benzenedicarboxamide.
Background technology
Iomeprol is a kind of non-ionic X-ray contrast agent developed by Italian Bracco companies, can be extensive
Ground is applied under intravascular, arachnoid and body cavity interimage, respectively in May, 1993 in Italy and in December, 1992 in Britain
Go through to list, the approval of import in 2006, clinically obtained relatively broad application.It is same on iomeprol and market today
The non-ionic contrast agent of type（Such as Iohexol, Iopamidol and Ioversol）Compare, under same concentration, there is minimum ooze
Pressure and relatively low viscosity thoroughly, can be made into up to 400mg（I）/ ml high concentrate formulation, there are more excellent contrasting effects, because
This, iomeprol has wide application market.
However, iomeprol and its similar contrast agent use as the big transfusion of high concentration, micro impurity can all gather
Collection zooms into a relatively large amount, may cause serious adverse reaction.So specification carry out impurity research, and by its
Control will be directly connected to the quality and application safety of iomeprol in a safety, rational limits.Therefore, it is right
Significant in the synthesis of iomeprol impurity, impurity is qualitative during it can be produced as impurity reference substance for iomeprol
And quantitative analysis, so as to improve the quality standard of iomeprol, important guidance is provided for the safe medication of the people.
The content of the invention
The invention provides a kind of iomeprol impurity N-（1,3- dihydroxypropyl）-N-（2,3- dihydroxypropyls）-5-
[（Hydroxyacetyl）Methylamino] -2,4,6- tri- iodo- 1,3- benzenedicarboxamides preparation method.
The present invention is based in iomeprol preparation process, a kind of impurity compound isolated, i.e. N-（1,3- dihydroxy
Propyl group）-N-（2,3- dihydroxypropyls）-5-[（Hydroxyacetyl）Methylamino] -2,4,6- tri- iodo- 1,3- benzenedicarboxamides,
Isomers of the impurity as iomeprol, it is defined as the system suitability of assay in iomeprol import quality standard
Impurity.The impurity and iomeprol structure are very close, it is difficult to enough high-purity impurity reference substances are directly isolated to obtain, and so far
The present yet there are no the synthetically prepared report of the impurity, therefore, the invention provides a kind of synthetic method for preparing the impurity, the present invention
The formula of preparation（1）The structural formula of compound is as follows：
The impurity be by isomers 2- amino -1 of raw material 3- amino -1,2-PD in iomeprol building-up process,
Caused by ammediol.The preparation of 3- amino -1,2-PD is using epoxychloropropane as raw material, is obtained through hydrolysis, ammonification, because
For the difference of open ring position, there is a small amount of 2- amino-1,3-propanediols generation, introduced in iomeprol amidation process, then
Impurity formula has been ultimately generated through subsequent reactions（1）Compound.The preparation process of iomeprol（Referenced patent US4352788）Such as
Under：
The present invention is with iomeprol synthetic intermediate formula（2）Compound is initiation material, by respectively with 3- amino -1,2-
Propane diols and 2- amino-1,3-propanediols react to obtain iomeprol impurity formula（1）Compound.The synthetic route of the present invention is not yet
Appear in the newspapers, formula（2）Compound generates the formula of single acylation with 3- amino -1,2-PD reaction（3）Compound and hydroxyl
Full esterification is the key of this synthetic route.
The synthetic route of the present invention is as follows：
The synthetic method of the present invention, comprises the following steps：
The first step：Using formula（2）Compound 5- [（Acetoxyacetyl）Methylamino] -2,4,6- tri- iodo- 1,3- benzene
Dimethyl chloride and 3- amino -1,2-PD react, then with acetic acid anhydride reactant, by isolating and purifying, obtain formula（3）Compound 3-
N-（2,3- diacetoxy propyl group carbamyls）-5-[（Acetoxyacetyl）Methylamino] -2,4,6- triiodo benzoyls
Chlorine；
Second step：Formula（3）Compound and 2- amino-1,3-propanediols react, then with acetic acid anhydride reactant, obtain formula（4）Change
Compound N-（1,3- diacetoxy propyl group base）-N’-（2,3- diacetoxy propyl group）-5-[（Acetoxyacetyl）Methyl
Amino] -2,4,6- tri- iodo- 1,3- benzenedicarboxamides；
3rd step：Formula（4）Compound alcoholysis in methanol solution of sodium methylate obtains formula（1）Compound N-（1,3- dihydroxy
Propyl group）-N’-（2,3- dihydroxypropyls）-5-[（Hydroxyacetyl）Methylamino] -2,4,6- tri- iodo- 1,3- benzenedicarboxamides
Crude product；
4th step：Formula（1）Crude compound obtains formula by purifying（1）Compound iomeprol impurity sterling.
In said synthesis route, formula（2）Compound can be easily synthesized by the preparation process of iomeprol.
Preferably, the present invention includes following synthesis step：
The first step：Acylated and esterification：Formula（2）Compound 5- [（Acetoxyacetyl）Methylamino] -2,4,6-
Three iodo- 1,3- phthalyl chlorides and 3- amino -1,2-PD are subsequently added into aceticanhydride, in 25-30 in 0-5 DEG C of insulation reaction 1h
DEG C insulation reaction 2h, TLC are monitored to raw material reaction and finished.Water and dichloromethane are added, layering, washes dichloromethane layer, then subtract
Pressure is evaporated dichloromethane and obtains formula（3）Compound 3-N-（2,3- diacetoxy propyl group carbamyls）-5-[（Acetoxyl group second
Acyl group）Methylamino] -2,4,6- triiodo chlorobenzoyl chloride crude products.Formula（3）Crude compound purifies by silica gel column chromatography（Elution
Agent：Dichloromethane：Ethyl acetate=3：1）, obtain formula（3）Compound highly finished product.
Second step：Acylated and esterification：Formula（3）Compound 3-N-（2,3- diacetoxy propyl group carbamyls）-5-
[（Acetoxyacetyl）Methylamino] -2,4,6- triiodo chlorobenzoyl chlorides and 2- amino-1,3-propanediols be in 20-25 DEG C of insulation
1h is reacted, is subsequently added into aceticanhydride, in 25-30 DEG C of insulation reaction 2h, TLC is monitored to raw material reaction and finished.Add water and dichloromethane
Alkane, layering, dichloromethane layer is washed, then evaporated under reduced pressure dichloromethane obtains formula（4）Compound N-（1,3- diacetoxy third
Base）-N’-（2,3- diacetoxy propyl group）-5-[（Acetoxyacetyl）Methylamino] -2,4,6- tri- iodo- 1,3- benzene two
Formamide.
3rd step：Alcoholysis reaction：Formula（4）Compound N-（1,3- diacetoxy propyl group）-N’-（2,3- diacetoxies
Propyl group）-5-[（Acetoxyacetyl）Methylamino] -2,4,6- tri- iodo- 1,3- benzenedicarboxamides are dissolved in methanol, add 30%
Methanol solution of sodium methylate, adjust pH 8-9, in 20-30 DEG C of stirring reaction 1h, reaction finishes, and pH is to neutrality for regulation, filters, filter
Liquid evaporated under reduced pressure, obtain target product formula（1）Compound N-（1,3- dihydroxypropyl）-N’-（2,3- dihydroxypropyls）-5-
[（Hydroxyacetyl）Methylamino] -2,4,6- tri- iodo- 1,3- benzenedicarboxamides crude products.
4th step：Purification：By above-mentioned formula（1）Crude compound is dissolved with water, adds resin agitating 0.5h, is filtered, filtrate
Evaporated under reduced pressure obtains formula（1）Compound N-（1,3- dihydroxypropyl）-N’-（2,3- dihydroxypropyls）-5-[（Hydroxyacetyl）
Methylamino] -2,4,6- tri- iodo- 1,3- benzenedicarboxamides highly finished product.
The present invention has following technical characterstic：
1. because formula（1）Compound is close with iomeprol structure, is directly separated difficulty, of the invention from formula（1）Compound
Synthetic intermediate start to purify.Specifically, silica gel column chromatography is used to formula in the first step（3）Compound is purified, and is obtained
To the formula of the single acylation of high-purity（3）Compound, it ensure that second step reacts to obtain the higher formula of purity（4）Compound, formula
（4）Almost without the generation of iomeprol after compound alcoholysis.
2. formula（2）Compound and 3- amino -1,2-PD or the reacted product of 2- amino-1,3-propanediols are water-soluble
Property it is very big, therefore the first step and second step reaction all employ excessive acetic anhydride and are esterified hydroxyl entirely, make formula（3）And formula（4）
Compound is all in strong-hydrophobicity, then by extracting and washing, removes solvent and water-solubility impurity, beneficial to separation and purifying.
3. after the alcoholysis reaction of the 3rd step use resin cation in and sodium methoxide, avoid using inorganic acid produce with
Formula（1）The salt that compound is not readily separated；
4. easily employing resin anion (R.A.) in the purification step of the 4th step, formula is eliminated（1）In account for it is main it is cloudy from
Sub- impurity, directly obtains formula（1）Pure compounds（HPLC purity is more than 99%）, without further solvent refining.
The synthetic route reaction condition that the present invention designs is gentle, simple to operate, obtained formula（1）Compound quality stabilization,
Purity is high, can be as the impurity reference substance in iomeprol detection process, quality control and drug safety to iomeprol
It is significant.
Embodiment：
Embodiment 1：Formula（3）Compound 3-N-（2,3- diacetoxy propyl group carbamyls）-5-[（Acetoxyl group acetyl
Base）Methylamino] -2,4,6- triiodo chlorobenzoyl chlorides synthesis
By formula（2）Compound 5- [（Acetoxyacetyl）Methylamino] -2,4,6- tri- iodo- 1,3- phthalyl chlorides
（10g）It is dissolved in DMA（20ml）In, instill 3- amino -1,2-PD（1.3g, it is dissolved in 6ml N, N- diformazans
Yl acetamide and 2.3ml triethylamines）In, it is 0-5 DEG C to control reaction temperature when being added dropwise, and drips and finishes insulation reaction 1h.Reaction finishes
Afterwards, DMAP is added（0.1g）, aceticanhydride is added dropwise（3.4ml）, less than 30 DEG C, drop finishes in 25-30 control thermotonus
DEG C reaction 2h.After completion of the reaction, water is added（20ml）, dichloromethane is added after stirring 10min（45ml）, divide after stirring 30min
Layer, water layer dichloromethane（45ml）Extraction once, merges organic layer, adds water（45ml）Stirring, uses saturated sodium bicarbonate water
Solution regulation pH is 7-8, agitator treating 20min, separates dichloromethane layer.Dichloromethane layer adds water（45ml）, with 10% salt
Acid for adjusting pH is 3, agitator treating 20min, separates dichloromethane layer.Dichloromethane layer water（45ml*4）Washing is done to neutrality
Dry, evaporated under reduced pressure dichloromethane layer obtains formula（3）Crude compound（10.5-12.7g HPLC purity 76%）.By formula（3）Compound
Crude product is dissolved with q. s. methylene chloride, is loaded on the silica gel column chromatography of 200-300 mesh, and eluant, eluent uses dichloromethane：Acetic acid
Ethyl ester=3:1, product point is collected, is evaporated to obtain formula（3）Compound highly finished product（7.5g, HPLC purity 95%）.
Embodiment 2：Formula（4）Compound N-（1,3- diacetoxy propyl group）-N’-（2,3- diacetoxy propyl group）-5-
[（Acetoxyacetyl）Methylamino] -2,4,6- tri- iodo- 1,3- benzenedicarboxamides synthesis
By formula（3）Compound 3-N-（2,3- diacetoxy propyl group carbamyls）-5-[（Acetoxyacetyl）Methyl
Amino] -2,4,6- triiodo chlorobenzoyl chloride highly finished product（6.5g）It is dissolved in DMA（13ml）, be added dropwise to 2- amino-
1,3-PD（It is dissolved in 7ml DMAs and 1.5ml triethylamines）In, drop finishes in 20-25 DEG C of insulation reaction
1.5h.After completion of the reaction, DMAP is added（0.07g）, aceticanhydride is added dropwise（2.2ml）, control temperature is less than 30 DEG C, drop
Finish and react 2h in 25-30 DEG C.After completion of the reaction, water is added（13ml）, dichloromethane is added after stirring 10min（25ml）, stirring
It is layered after 30min, water layer dichloromethane（25ml）Extraction once, merges organic layer, adds water（13ml）Stirring, uses saturated carbon
Sour hydrogen sodium water solution regulation pH is 7-8, agitator treating 20min, separates dichloromethane layer.Water 13ml is added in dichloromethane layer,
It is 3 with 10% salt acid for adjusting pH, agitator treating 20min, separates dichloromethane layer.Dichloromethane layer water（13ml*4）Washing
To neutrality, anhydrous sodium sulfate drying, evaporated under reduced pressure dichloromethane obtains formula（4）Compound（5.7g, HPLC purity 94%）.Need not
Purifying, directly carry out next step reaction.
Embodiment 3：Formula（1）Compound N-（1,3- dihydroxypropyl）-N’-（2,3- dihydroxypropyls）-5-[（Hydroxyl second
Acyl group）Methylamino] -2,4,6- tri- iodo- 1,3- benzenedicarboxamides synthesis
By formula（4）Compound N-（1,3- diacetoxy propyl group）-N’-（2,3- diacetoxy propyl group）-5-[（Acetyl
Epoxide acetyl group）Methylamino] -2,4,6- tri- iodo- 1,3- benzenedicarboxamides（5.7g）It is dissolved in methanol（45ml）In, it is added dropwise 30%
Methanol solution of sodium methylate makes pH be 8-9, is finished in 25 DEG C of reaction 1h to reaction.Adding resin cation makes pH be 7, filters, subtracts
Pressure is evaporated methanol, obtains formula（1）Crude compound（4.3g, HPLC purity 96%）.Use water（20ml）Dissolution type（1）Crude compound,
Resin anion (R.A.) is added, stirs 0.5h, filters, evaporated under reduced pressure, obtains formula（1）Compound highly finished product（3.7g, HPLC purity are more than
99%）.1H-NMR (800MHz, DMSO-d 6) δ(ppm):8.45-8.59 (m, 2H), 4.89-4.90 (t, 1H), 4.70-
4.85 (m, 2H), 4.50-4.55 (m, 2H), 4.49-4.50 (m, 2H), 4.33-4.23 (m, 1H), 3.76-3.83 (m,
1H), 3.74-3.76 (m, 4H), 3.63-3.72 (m, 4H), 2.96 (s, 3H).HRMS-ESI (m/z): 799.8429
[M+Na]+。
It is right although applying specific embodiment in this specification to elaborate technical scheme
In those of ordinary skill in the art, some modifications made in specific embodiments and applications according to inventive concept
Or improve, belong to the scope of protection of present invention.Therefore, the content that this specification is recorded should not be construed as to the present invention's
Limitation.
Claims (2)
- A kind of 1. formula（1）The preparation method of shown compound, it is characterised in that by following steps：The first step：Using formula（2）Compound 5- [（Acetoxyacetyl）Methylamino] -2,4,6- tri- iodo- 1,3- benzene diformazans Acyl chlorides and 3- amino -1,2-PD react, then with acetic acid anhydride reactant, by isolating and purifying, obtain formula（3）Compound 3-N- （2,3- diacetoxy propyl group carbamyls）-5-[（Acetoxyacetyl）Methylamino] -2,4,6- triiodo chlorobenzoyl chlorides；Second step：Formula（3）Compound and 2- amino-1,3-propanediols react, then with acetic acid anhydride reactant, obtain formula（4）Compound N-（1,3- diacetoxy propyl group base）-N’-（2,3- diacetoxy propyl group）-5-[（Acetoxyacetyl）Methyl ammonia Base] -2,4,6- tri- iodo- 1,3- benzenedicarboxamides；3rd step：Formula（4）Compound alcoholysis in methanol solution of sodium methylate obtains formula（1）Compound N-（1,3- dihydroxy third Base）-N’-（2,3- dihydroxypropyls）-5-[（Hydroxyacetyl）Methylamino] -2,4,6- tri- iodo- 1,3- benzenedicarboxamides are thick Product；4th step：Formula（1）Crude compound obtains formula by purifying（1）Compound iomeprol impurity sterling.
- 2. the method for claim 1, it is characterised in that by following steps：The first step：Acylated and esterification：Formula（2）Compound 5- [（Acetoxyacetyl）Methylamino] -2,4,6- tri- is iodo- 1,3- phthalyl chloride and 3- amino -1,2-PD are subsequently added into aceticanhydride, 10 ~ 40 in -10 ~ 10 DEG C of 1 ~ 3h of insulation reaction DEG C insulation reaction 1 ~ 3h, TLC are monitored to raw material reaction and finished；Water and dichloromethane are added, layering, washes dichloromethane layer, then Evaporated under reduced pressure dichloromethane obtains formula（3）Compound 3-N-（2,3- diacetoxy propyl group carbamyls）-5-[（Acetoxyl group Acetyl group）Methylamino] -2,4,6- triiodo chlorobenzoyl chloride crude products；Formula（3）Crude compound purifies by silica gel column chromatography, washes De- agent is dichloromethane：Ethyl acetate=4:1 ~ 2:1, obtain formula（3）Compound highly finished product；Second step：Acylated and esterification：Formula（3）Compound 3-N-（2,3- diacetoxy propyl group carbamyls）-5-[（Second Acyloxy acetyl group）Methylamino] -2,4,6- triiodo chlorobenzoyl chlorides and 2- amino-1,3-propanediols be in 10 ~ 40 DEG C of insulation reactions 1 ~ 3h, aceticanhydride is subsequently added into, in 10 ~ 40 DEG C of insulation reaction 1 ~ 3h, TLC is monitored to raw material reaction and finished；Add water and dichloromethane Alkane, layering, dichloromethane layer is washed, then evaporated under reduced pressure dichloromethane obtains formula（4）Compound N-（1,3- diacetoxy third Base）-N’-（2,3- diacetoxy propyl group）-5-[（Acetoxyacetyl）Methylamino] -2,4,6- tri- iodo- 1,3- benzene two Formamide；3rd step：Alcoholysis reaction：Formula（4）Compound N-（1,3- diacetoxy propyl group）-N’-（2,3- diacetoxy propyl group）- 5-[（Acetoxyacetyl）Methylamino] -2,4,6- tri- iodo- 1,3- benzenedicarboxamides are dissolved in methanol, add methanolic sodium methoxide Solution, pH 8 ~ 10 is adjusted, in 10 ~ 40 DEG C of 1 ~ 3h of stirring reaction；Reaction is finished, and pH is adjusted to neutrality, filtering with resin cation Resin is removed, filtrate decompression is evaporated, and obtains formula（1）Compound N-（1,3- dihydroxypropyl）-N’-（2,3- dihydroxypropyls）- 5-[（Hydroxyacetyl）Methylamino] -2,4,6- tri- iodo- 1,3- benzenedicarboxamides crude products；4th step：Purification：By above-mentioned formula（1）Crude compound is dissolved with water, is added resin anion (R.A.) and is stirred 0.5 ~ 1h, filters, Filtrate decompression is evaporated to obtain formula（1）Compound N-（1,3- dihydroxypropyl）-N’-（2,3- dihydroxypropyls）-5-[（Hydroxyl second Acyl group）Methylamino] -2,4,6- tri- iodo- 1,3- benzenedicarboxamides highly finished product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510326397.8A CN106316878B (en) | 2015-06-15 | 2015-06-15 | A kind of preparation method of iomeprol impurity |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510326397.8A CN106316878B (en) | 2015-06-15 | 2015-06-15 | A kind of preparation method of iomeprol impurity |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106316878A CN106316878A (en) | 2017-01-11 |
| CN106316878B true CN106316878B (en) | 2018-01-19 |
Family
ID=57733308
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510326397.8A Active CN106316878B (en) | 2015-06-15 | 2015-06-15 | A kind of preparation method of iomeprol impurity |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106316878B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116354842A (en) * | 2021-12-20 | 2023-06-30 | 重庆圣华曦药业股份有限公司 | Improved preparation method of iomeprol and application of iomeprol in preparation |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4352788A (en) * | 1979-08-09 | 1982-10-05 | Bracco Industria Chimica S.P.A. | Derivatives of 2,4,6-triiodo-isophthalic acid, processes for their synthesis and X-ray contrasting materials containing these |
| US4396598A (en) * | 1982-01-11 | 1983-08-02 | Mallinckrodt, Inc. | Triiodoisophthalamide X-ray contrast agent |
| CN1228079A (en) * | 1997-05-30 | 1999-09-08 | 伯拉考公司 | Process for preparation of 5-[acetyl (2,3-dihydroxypropyl) amino]-N,N'-bis (2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide |
| CN102015624A (en) * | 2008-04-30 | 2011-04-13 | 株式会社Lg生命科学 | Novel process for preparation of iopromide |
| CN102363600A (en) * | 2011-10-24 | 2012-02-29 | 江苏省原子医学研究所 | Iomeprol preparation method |
| CN103265449A (en) * | 2013-05-30 | 2013-08-28 | 四川铂瑞生物医药有限公司 | Synthesis of 5-amino-2,4,6-triiodo-N, N'-bis(2,3-dihydroxy propyl)-1,3-benzenedicarboxamide |
-
2015
- 2015-06-15 CN CN201510326397.8A patent/CN106316878B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4352788A (en) * | 1979-08-09 | 1982-10-05 | Bracco Industria Chimica S.P.A. | Derivatives of 2,4,6-triiodo-isophthalic acid, processes for their synthesis and X-ray contrasting materials containing these |
| US4396598A (en) * | 1982-01-11 | 1983-08-02 | Mallinckrodt, Inc. | Triiodoisophthalamide X-ray contrast agent |
| CN1228079A (en) * | 1997-05-30 | 1999-09-08 | 伯拉考公司 | Process for preparation of 5-[acetyl (2,3-dihydroxypropyl) amino]-N,N'-bis (2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide |
| CN102015624A (en) * | 2008-04-30 | 2011-04-13 | 株式会社Lg生命科学 | Novel process for preparation of iopromide |
| CN102363600A (en) * | 2011-10-24 | 2012-02-29 | 江苏省原子医学研究所 | Iomeprol preparation method |
| CN103265449A (en) * | 2013-05-30 | 2013-08-28 | 四川铂瑞生物医药有限公司 | Synthesis of 5-amino-2,4,6-triiodo-N, N'-bis(2,3-dihydroxy propyl)-1,3-benzenedicarboxamide |
Non-Patent Citations (6)
| Title |
|---|
| 一种非离子型造影剂关键中间体——碘化物的合成;卢小逸 等;《浙江化工》;20110715;第42卷(第7期);第14-16页 * |
| 新型非离子型单体碘造影剂的合成;杨天帅 等;《中国现代应用药学》;20130831;第30卷(第8期);第843-847页 * |
| 碘帕醇的合成;张吉泉 等;《中国医药工业杂志》;20090510;第40卷(第5期);第326-328页 * |
| 碘普罗胺的合成;王哲 等;《中国医药工业杂志》;20120710;第43卷(第7期);第527-529页 * |
| 衍生化气相色谱法测定3-氨基-1,2-丙二醇的含量;李启然 等;《分析测试技术与仪器》;20060930;第12卷(第3期);第166-170页 * |
| 非离子型X射线造影剂中间体1-氨基-2,3-丙二醇的合成;张福根 等;《精细化工》;19981230;第15卷(第6期);第35-37页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106316878A (en) | 2017-01-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103570580B (en) | Preparation method of high-purity iopromide | |
| CN102964269B (en) | Novel preparation method of iopromide | |
| CN107001294A (en) | A kind of method for preparing Gadobutrol | |
| CN112608283A (en) | Preparation method of nitrazepam | |
| CN106316878B (en) | A kind of preparation method of iomeprol impurity | |
| CN105884628A (en) | Preparation method of 2,4-ditertbutyl-5-aminophenol | |
| CN102351735A (en) | Preparation method of Iopromide | |
| CN104231033B (en) | A kind of preparation method of dutasteride | |
| CN110028418A (en) | A kind of preparation method of Ioversol | |
| CN102336800A (en) | Synthesis method for 20-bit sugar connected protopanaxatriol analog ginsenoside and analog | |
| CN105017062B (en) | Prepare the new method of Iopromide | |
| CN107417770A (en) | A kind of preparation method of Icatibant | |
| CN102816085A (en) | Preparation method of iohexol impurity | |
| CN108586250A (en) | A kind of sodium stearyl fumarate auxiliary material and preparation method thereof | |
| CN105001113B (en) | A kind of preparation method of Iopromide | |
| CN104402758B (en) | A kind of preparation method of iohexol impurity | |
| CN110054571A (en) | The different peptide chloride derivative of 5- amino -2,4,6- triiodo and its application in synthesis Iopamidol impurity | |
| CN105001114B (en) | Prepare the new method of Iopromide | |
| CN103242267B (en) | Preparation method for cabazitaxel and intermediate thereof, and cabazitaxel intermediate | |
| CN106518939B (en) | Method for preparing Solithromycin compound | |
| ITPD20100222A1 (en) | PROCESS FOR THE PREPARATION OF CONTRAST AGENTS | |
| EP2655320A1 (en) | Process simplification for precursor compound | |
| US20020170860A1 (en) | Process for the purification of water-soluble non-ionic contrast agents | |
| CN107056736A (en) | A kind of preparation method of MMF | |
| CN107868105A (en) | A kind of preparation method of Suo Feibuwei key intermediates |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |