CN1197842C - Method for purifying ioversol - Google Patents
Method for purifying ioversol Download PDFInfo
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- CN1197842C CN1197842C CN 03131753 CN03131753A CN1197842C CN 1197842 C CN1197842 C CN 1197842C CN 03131753 CN03131753 CN 03131753 CN 03131753 A CN03131753 A CN 03131753A CN 1197842 C CN1197842 C CN 1197842C
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- ioversol
- recrystallization
- crude product
- methyl cellosolve
- mixed solvent
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Abstract
The present invention discloses a method for purifying ioversol, which relates to a method for purifying ioversol for an x-ray non-ionic contrast agent. The method comprises the following steps: an ioversol crude product is recrystallized twice by a solvent recrystallization method, recrystallization solvent comprises normal butyl alcohol, a mixed solvent of 2-methyl cellosolve and isopropanol, and a mixed solvent of 2-methyl cellosolve and normal butyl alcohol, and the content ioversol reaches more than 99.0 % after recrystallization. The method has the advantages of economy, practicability and simple operation, and is suitable for commercial production.
Description
Technical field
The invention belongs to the purification process of Western medicine compounds, be specifically related to a kind of purification process of X line non-ionic contrast agent ioversol.
Background technology
Nineteen eighty-two U.S. Wan Lingke company has succeeded in developing non-ionic contrast agent ioversol (Ioversol, commodity are called MP-328, Optiray), chemistry N by name, N '-two (2, the 3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)-hydroxyl acetamido]-2,4,6-three iodo-1, the 3-benzenedicarboxamide, chemical structure is seen structural formula one.
Structural formula one:
Ioversol is water-soluble fine, osmotic pressure is also very low, chemical property is also more stable, can tolerate high-temperature sterilization, can be made into the injection liquid supply the market, can in blood vessel, use widely and (be applicable to angiography, urography, phlebography and radiography strengthen cat scanner), arachnoid membrane is used down and (is applicable to adult and children's waist, chest and cervical spinal radiography, and be applied to injection pond cat scanner of the laggard capable end under the arachnoid membrane) and the interior (arthrography of using of body cavity, endoscopic retrograde pancreatography (ERP), endoscope retrogradation cholangiography and the ductus pancreaticus radiography (ERLP) that coincide, the hernia radiography, hysterosalpingography, sialography) and gastrointestinal examination etc.
Because the ioversol injection liquid is injected directly in the human vas, so the purifying of its bulk drug ioversol must be thoroughly.For commercial medicine, its purge process efficient and cost-effective also is very important simultaneously.
We have carried out preliminary purification to ioversol earlier according to United States Patent (USP) (US4396598), get the ioversol crude product.This purge process: the final step reaction of ioversol preparation is at aqueous phase, and reaction finishes the back evaporated under reduced pressure, removes ion with negatively charged ion and Zeo-karb, again with behind the activated carbon decolorizing, be evaporated to drying, get the ioversol crude product, HPLC detects the ioversol content in crude product and is about 92.0%.Containing some non-ionic type impurity in this ioversol crude product, mainly is 5-amido-N, N '-two (2; the 3-dihydroxypropyl)-2,4,6-three iodo-1; 3-benzenedicarboxamide (seeing structural formula two), 5-hydroxyl acetamido-N, N '-two (2, the 3-dihydroxypropyl)-2; 4,6-three iodo-1,3-benzenedicarboxamide (seeing structural formula three), N; N '-two (2, the 3-dihydroxypropyl)-5-[[N-(2-hydroxyethyl) formamyl] methoxyl group]-2,4; 6-three iodo-1,3-benzenedicarboxamide (seeing structural formula four).Because the chemical structure of these non-ionic type impurity also is to be parent nucleus with the phenyl triiodide, has a plurality of hydroxyls, and is similar with the molecular structure of ioversol, so bring certain difficulty for the purifying of ioversol.
Structural formula two structural formulas three
More abroad to the purification process report of ioversol, mainly contain following three kinds:
1.US4396598 report adopts the high performance liquid phase preparative column to isolate ioversol, though this method can be thorough with regard to purifying by a post separation, its column packing costs an arm and a leg, and uses a large amount of solvents, is not suitable for industrial big production.
2.US5210300, adopt continuous electrodialytic method that the ioversol crude product is carried out purifying with the US5160437 report.Though this method can be removed the ionized impurity of energy such as inorganic salt, organic acid, to non-ionic type impurity DeGrain.
3.US5221485 report adopts the reverse osmosis method that the ioversol crude product is carried out purifying.It is impurity below 400 that this method can only be removed molecular weight, but not the molecular weight of type impurity ion is all near the molecular weight 807 of ioversol, so the thorough purifying ioversol of this method can only be removed the impurity of some small molecular weights.
Summary of the invention
The object of the invention provides a kind of purification process of ioversol.Invention is to design a kind of purification process that is suitable for big industrial production, more economical new ioversol.
1. the present invention at first adopts propyl carbinol as recrystallisation solvent the ioversol crude product to be carried out purifying.This method comprises uses propyl carbinol that the ioversol crude product is carried out recrystallization twice, its content is brought up to more than 99.0% from 92.0%, the consumption of recrystallisation solvent is preferably every gram ioversol crude product and needs 40～60mL recrystallisation solvent at every turn, most preferably be every gram ioversol crude product and need 50mL at every turn, recrystallization temperature is a reflux temperature.The shortcoming of this method is that solvent load is too big.The concrete operations step is seen embodiment 1.
Owing to adopt the single solvent propyl carbinol to have above shortcoming, we adopt the mixed crystallization solvent that the ioversol crude product is carried out recrystallization with regard to considering.This method comprises uses 2-methyl cellosolve and propyl carbinol or 2-methyl cellosolve and Virahol as the recrystallization mixed solvent, the ioversol crude product is carried out recrystallization twice, make its content bring up to more than 99.0% (the ioversol assay adopts area normalization method) from 92.0%, and the recrystallisation solvent consumption to be reduced to be 1/3rd of recrystallisation solvent with propyl carbinol only.Because use the mixed solvent recrystallization, ioversol recrystallization yield has also improved.
2. preferred 2-methyl cellosolve and the Virahol crystallized mixed solvent of attaching most importance to carries out recrystallization
The volume ratio of 2-methyl cellosolve and Virahol is preferably 1: 3～and 6.Most preferably be 1: 4.In recrystallisation solvent, the control of residual moisture content is very important, need be controlled at below 0.7%.The consumption of recrystallization mixed solvent is preferably every gram ioversol crude product and needs 10～25mL recrystallisation solvent at every turn, most preferably is every gram ioversol crude product and needs 15mL at every turn.The ioversol recrystallization temperature is preferably 70～120 ℃, most preferably is 100 ℃.The concrete operations step is seen embodiment 2.
3. preferred 2-methyl cellosolve and the propyl carbinol crystallized mixed solvent of attaching most importance to carries out recrystallization
The volume ratio of 2-methyl cellosolve and propyl carbinol is preferably 1: 4～and 8.Most preferably be 1: 6.7.In recrystallisation solvent, the lower limit of 2-methyl cellosolve content is for guaranteeing that the ioversol crude product is easy to dissolve extremely important, and it is extremely important that its upper limit does not form amorphous solid for guaranteeing the ioversol crystallization.The consumption of recrystallization mixed solvent is preferably every gram ioversol crude product and needs 10～25mL recrystallisation solvent at every turn, most preferably is every gram ioversol crude product and needs 15mL at every turn.The ioversol recrystallization temperature is preferably 90～120 ℃, most preferably is 100 ℃.The concrete operations step is seen embodiment 3.
Embodiment
Embodiment 1
In the 3L there-necked flask of electric mixer and reflux condensing tube is installed, ioversol crude product (45g) is joined in the propyl carbinol (2250mL), stir and progressively be warming up to backflow down, refluxed 5 hours, follow the filtered while hot white suspension, (3 * 15mL) washing crystals after the vacuum-drying, get ioversol 27.5g with hot propyl carbinol on filter.Before crystallization and carry out HPLC afterwards and analyze (water/acetonitrile, C
8Post).The results are shown in the table 1.
In the above-mentioned recrystallization gained ioversol first time (27.5g) water-soluble (150mL), add propyl carbinol (1375mL) after the evaporated under reduced pressure, carry out the recrystallization second time, operation steps is with the recrystallization first time, get ioversol 19.3g, carry out HPLC and analyze (water/acetonitrile, C
8Post).The results are shown in the table 1.
Table 1 HPLC analytical results (peak area %)
| The peak | For the first time before the recrystallization | For the first time behind the recrystallization | For the second time behind the recrystallization |
| Ioversol | 92.47 | 97.43 | 99.08 |
| 5-hydroxyl acetamido-N, N '-two (2, the 3-dihydroxypropyl)-2,4,6-three iodo-1,3-benzenedicarboxamide | 2.20 | 0.82 | 0.23 |
| 5-amido-N, N '-two (2, the 3-dihydroxypropyl)-2,4,6-three iodo-1,3-benzenedicarboxamide | 0.72 | 0.25 | 0.08 |
| N; N '-two (2, the 3-dihydroxypropyl)-5-[[N-(2-hydroxyethyl) formamyl] methoxyl group]-2,4; 6-three iodo-1, the 3-benzenedicarboxamide | 2.05 | 0.56 | 0.29 |
| Other impurity | 2.56 | 0.94 | 0.32 |
Embodiment 2
In the 1L there-necked flask of electric mixer and reflux condensing tube is installed, ioversol crude product (45g) is added in the mixture of 2-methyl cellosolve (135mL) and Virahol (540mL), stir down and progressively be warming up to 100 ℃, temperature was kept constant 5 hours, follow the filtered while hot white suspension, (3 * 15mL) washing crystals after the vacuum-drying, get ioversol 29.2g with hot Virahol on filter.Before crystallization and carry out HPLC afterwards and analyze (water/acetonitrile, C
8Post).The results are shown in the table 2.
In the above-mentioned recrystallization gained ioversol first time (29.2g) water-soluble (150mL), add 2-methyl cellosolve (88mL) and Virahol (350mL) after the evaporated under reduced pressure, carry out the recrystallization second time, operation steps is with the recrystallization first time, get ioversol 20.8g, carry out HPLC and analyze (water/acetonitrile, C
8Post).The results are shown in the table 2.
Table 2 HPLC analytical results (peak area %)
| The peak | For the first time before the recrystallization | For the first time behind the recrystallization | For the second time behind the recrystallization |
| Ioversol | 92.47 | 97.5 | 99.26 |
| 5-hydroxyl acetamido-N, N '-two (2, the 3-dihydroxypropyl)-2,4,6-three iodo-1,3-benzenedicarboxamide | 2.20 | 0.77 | 0.17 |
| 5-amido-N, N '-two (2, the 3-dihydroxypropyl)-2,4,6-three iodo-1,3-benzenedicarboxamide | 0.72 | 0.29 | 0.05 |
| N; N '-two (2, the 3-dihydroxypropyl)-5-[[N-(2-hydroxyethyl) formamyl] methoxyl group]-2,4; 6-three iodo-1, the 3-benzenedicarboxamide | 2.05 | 0.51 | 0.24 |
| Other impurity | 2.56 | 0.93 | 0.28 |
Embodiment 3
In the 1L there-necked flask of electric mixer and reflux condensing tube is installed, ioversol crude product (45g) is added in the mixture of 2-methyl cellosolve (90mL) and propyl carbinol (600mL), stir down and progressively be warming up to 100 ℃, temperature was kept constant 5 hours, follow the filtered while hot white suspension, (3 * 15mL) washing crystals after the vacuum-drying, get ioversol 31.5g with hot propyl carbinol on filter.Before crystallization and carry out HPLC afterwards and analyze (water/acetonitrile, C
8Post).The results are shown in the table 3.
In the above-mentioned recrystallization gained ioversol first time (31.5g) water-soluble (150mL), add 2-methyl cellosolve (63mL) and propyl carbinol (420mL) after the evaporated under reduced pressure, carry out the recrystallization second time, operation steps is with the recrystallization first time, get ioversol 25g, carry out HPLC and analyze (water/acetonitrile, C
8Post).The results are shown in the table 3.
Table 3 HPLC analytical results (peak area %)
| The peak | For the first time before the recrystallization | For the first time behind the recrystallization | For the second time behind the recrystallization |
| Ioversol | 92.47 | 97.7 | 99.38 |
| 5-hydroxyl acetamido-N, N '-two (2, the 3-dihydroxypropyl)-2,4,6-three iodo-1,3-benzenedicarboxamide | 2.20 | 0.71 | 0.19 |
| 5-amido-N, N '-two (2, the 3-dihydroxypropyl)-2,4,6-three iodo-1,3-benzenedicarboxamide | 0.72 | 0.27 | 0.06 |
| N; N '-two (2, the 3-dihydroxypropyl)-5-[[N-(2-hydroxyethyl) formamyl] methoxyl group]-2,4; 6-three iodo-1, the 3-benzenedicarboxamide | 2.05 | 0.45 | 0.13 |
| Other impurity | 2.56 | 0.87 | 0.24 |
Claims (7)
1. the purification process of an ioversol, it is characterized in that adopting the solvent recrystallization method that the ioversol crude product is carried out recrystallization, used recrystallization solvent is selected from any in the mixed solvent of mixed solvent, 2-methyl cellosolve and propyl carbinol of propyl carbinol, 2-methyl cellosolve and Virahol.
2. the purification process of a kind of ioversol according to claim 1, it is characterized in that adopting propyl carbinol that the ioversol crude product is carried out recrystallization twice, the consumption of recrystallization solvent is that every gram ioversol crude product needs the 40-60mL propyl carbinol at every turn, and recrystallization temperature is a reflux temperature.
3. the purification process of a kind of ioversol according to claim 2 is characterized in that every gram ioversol crude product needs to carry out recrystallization with the 50mL propyl carbinol at every turn.
4. the purification process of a kind of ioversol according to claim 1, it is characterized in that adopting 2-methyl cellosolve and isopropyl alcohol mixed solvent that the ioversol crude product is carried out recrystallization twice, the consumption of recrystallization mixed solvent is that every gram ioversol crude product needs 10-25mL 2-methyl cellosolve and isopropyl alcohol mixed solvent at every turn, 2-methyl cellosolve: the Virahol volume ratio is 1: 3-6, recrystallization temperature is 70-120 ℃.
5. the purification process of a kind of ioversol according to claim 4 is characterized in that every gram ioversol crude product need use 15mL 2-methyl cellosolve and isopropyl alcohol mixed solvent at every turn, and 2-methyl cellosolve: the Virahol volume ratio is 1: 4.
6. the purification process of a kind of ioversol according to claim 1, it is characterized in that adopting 2-methyl cellosolve and n-butanol mixed solvent that the ioversol crude product is carried out recrystallization twice, the consumption of recrystallization mixed solvent is that every gram ioversol crude product need be used 10-25mL 2-methyl cellosolve and n-butanol mixed solvent at every turn, 2-methyl cellosolve: the propyl carbinol volume ratio is 1: 4-8, recrystallization temperature is 90-120 ℃.
7. the purification process of a kind of ioversol according to claim 6, it is characterized in that every gram ioversol crude product needs carry out recrystallization, 2-methyl cellosolve with 15mL 2-methyl cellosolve and n-butanol mixed solvent at every turn: the propyl carbinol volume ratio is 1: 6.7.
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|---|---|---|---|
| CN 03131753 CN1197842C (en) | 2003-07-25 | 2003-07-25 | Method for purifying ioversol |
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|---|---|---|---|
| CN 03131753 CN1197842C (en) | 2003-07-25 | 2003-07-25 | Method for purifying ioversol |
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| CN1197842C true CN1197842C (en) | 2005-04-20 |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100344609C (en) * | 2006-06-30 | 2007-10-24 | 江苏省原子医学研究所 | Improved process for synthesizing ioversol |
| CN101337907B (en) * | 2007-07-06 | 2012-04-25 | 江苏恒瑞医药股份有限公司 | Process for purifying ioversol |
| CN112724035A (en) * | 2021-03-01 | 2021-04-30 | 江苏汉邦科技有限公司 | Method for purifying and preparing ioversol hydrolysate |
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