CN100418945C - Iodine Ioxilan purification method - Google Patents
Iodine Ioxilan purification method Download PDFInfo
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- CN100418945C CN100418945C CNB2006100378133A CN200610037813A CN100418945C CN 100418945 C CN100418945 C CN 100418945C CN B2006100378133 A CNB2006100378133 A CN B2006100378133A CN 200610037813 A CN200610037813 A CN 200610037813A CN 100418945 C CN100418945 C CN 100418945C
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- ioxitol
- ioxilan
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- deionized water
- recrystallization
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Abstract
The present invention relates to a purification method of ioxilan, which belongs to a purification method for western medical compounds. The ioxilan has a chemical name of 5-[acetyl (2, 3-dihydroxy propyl)amido]-N-(2, 3-dihydroxy propyl)-N-(2-hydroxyl ethyl)-2, 4, 6-triiodide-1, 3-benzene diformamide. The ioxilan is a nonionic X-ray contrast agent. The method of the present invention adopts deionized water as solvents to carry out recrystallization on the crude products of the ioxilan, and after recrystallization, the content of the ioxilan is more than 99.0% so as to achieve requirements of pharmacopoeias. The method of the present invention has the advantages of economy, practicality, environmental protection, no pollution and simple and convenient operation, and is suitable for industrial production.
Description
Technical field
A kind of purification process of ioxitol belongs to the purification process of Western medicine compounds, is specifically related to a kind of purification process of non-ionic x-ray contrast medium ioxitol.
Background technology
Ioxitol (Ioxilan; commodity are called Oxilan) be non-ionic x-ray contrast medium by U.S. Cooking contrast medium company and the exploitation of Japanese Chugai; chemistry 5-[ethanoyl (2 by name; the 3-dihydroxypropyl) amido]-N-(2; the 3-dihydroxypropyl)-and N '-(2-hydroxyethyl)-2,4,6-three iodo-1; the 3-benzenedicarboxamide, chemical structural formula (I):
Have lower osmotic pressure and viscosity between the hydrophobic region of ioxitol, thereby whole body tolerance and good radiography performance are preferably arranged owing to unsymmetrical structure in its molecule and intermolecular formation.The ioxitol chemical property is more stable, can tolerate high-temperature sterilization, make the injection liquid supply the market, can in blood vessel, use widely and (be applicable to angiography, urography, phlebography and radiography strengthen), arachnoid membrane is used down and (is applicable to adult and children's waist, chest and cervical spinal radiography, and be applied to the laggard capable brain of injection pond scanning 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 ioxilan inj is injected directly in the human vas, so the purifying of its bulk drug ioxitol must be thoroughly, quality product must reach the pharmacopeia requirement.Because recrystallization solvent might have residual in product and for the protection to environment, the solvent of recrystallization should be selected the solvent of low toxic and environment-friendly safety as far as possible; Simultaneously, for commercial medicine, its purge process efficient and cost-effective also is very important.
United States Patent (USP) (US4954348) is used earlier 95% ethyl alcohol recrystallization to the ioxitol crude product behind activated carbon decolorizing.We have carried out activated carbon decolorizing processing, evaporate to dryness then with reference to it to the ioxitol crude product.HPLC detects the ioxitol content in crude product and is about 96%.Contain some non-ionic type impurity in this ioxitol crude product; mainly be 5-acetamido-N-(2; the 3-dihydroxypropyl)-and N '-(2-hydroxyethyl)-2,4,6-three iodo-1; 3-benzenedicarboxamide (structural formula II) and 5-[ethanoyl (2; the 3-dihydroxypropyl) amido]-N-[3-(2,3-dihydroxyl propoxy-)-2-hydroxyl-propyl group]-N '-(2-hydroxyethyl)-2,4; 6-three iodo-1,3-benzenedicarboxamide (structural formula II I).Because the chemical structure of these non-ionic type impurity also is to be parent nucleus with the triiodo phenyl ring, has a plurality of hydroxyls, and is similar with the molecular structure of ioxitol, so bring certain difficulty for the purifying of ioxitol.
Summary of the invention
The object of the invention provides a kind of purification process of ioxitol, designs a kind of purification process that is suitable for the new ioxitol of big industrial production, more economical, safety, environmental protection, makes the quality of ioxitol reach the pharmacopeia requirement.
Technical scheme of the present invention: adopt deionized water the ioxitol crude product to be carried out recrystallization as solvent, the process of recrystallization is that per 100 gram ioxitol crude products add deionized water 500mL dissolving, pressure reducing and steaming portion water to ioxitol solution gross weight is the 130-200 gram, add ioxitol highly finished product 1-5 gram as crystal seed, stirred 24 hours at 60 ℃, filtering suspension liquid, on filter with 60 ℃ of hot deionized water 20mL washing crystals, repeated washing totally 3 times, vacuum-drying gets the ioxitol highly finished product, and the content of ioxitol is brought up to more than 99.0% from 96.0%.The ioxitol solution gross weights that the consumption of recrystallization solvent is preferably the preceding per 100 gram ioxitol crude products configurations of recrystallization are the 130-200 gram, most preferably are 150 grams.The consumption that adds crystal seed is preferably the 1-5 gram, most preferably is 2 grams.
Beneficial effect of the present invention: used recrystallization solvent is a deionized water, and the content that makes ioxitol behind the recrystallization reaches the pharmacopeia requirement more than 99.0%.This method is economical and practical, and is environment friendly and pollution-free, easy and simple to handle, is suitable for suitability for industrialized production.
Embodiment
Embodiment 1
In the 1L single port flask of weighing in advance, add ioxitol crude product (100g) and the deionized water (500mL) that activated carbon treatment is crossed, not to be higher than 40 ℃ of dissolvings, underpressure distillation to solution weight is 150g on Rotary Evaporators, add stirrer 60 ℃ of stirrings on magnetic stirring apparatus, add refining ioxitol (2g) as crystal seed, load onto reflux condensing tube, stirred 24 hours, the filtered while hot white suspension, on filter, use hot deionized water (60 ℃) (3 * 20mL) washing crystals, after the vacuum-drying, get ioxitol 71.5g.To before the deionized water recrystallization and sample afterwards carry out HPLC and analyze (water/acetonitrile, NH
2Post).The results are shown in the table 1.
Table 1 HPLC analytical results (peak area %)
| The peak | Before the recrystallization | Behind the recrystallization |
| Ioxitol (structural formula I) | 96.58 | 99.12 |
| 5-acetamido-N-(2, the 3-dihydroxypropyl)-N '-(2-hydroxyethyl)-2,4,6-three iodo-1,3-benzenedicarboxamide (structural formula II) | 1.25 | 0.15 |
| 5-[ethanoyl (2, the 3-dihydroxypropyl) amido]-N-[3-(2,3-dihydroxyl propoxy-)-2-hydroxyl-propyl group]-N '-(2-hydroxyethyl)-2,4,6-three iodo-1,3-benzenedicarboxamide (structural formula II I) | 1.27 | 0.42 |
| Other impurity | 0.90 | 0.31 |
Embodiment 2
Other gets ioxitol crude product 100 grams, carries out recrystallization by embodiment 1 the same terms and handles, and gets ioxitol 73.1g.To before the deionized water recrystallization and sample afterwards carry out HPLC and analyze (water/acetonitrile, NH
2Post).The results are shown in the table 2.
Table 2 HPLC analytical results (peak area %)
| The peak | Before the recrystallization | Behind the recrystallization |
| Ioxitol (structural formula I) | 96.74 | 99.15 |
| 5-acetamido-N-(2, the 3-dihydroxypropyl)-N '-(2-hydroxyethyl)-2,4,6-three iodo-1,3-benzenedicarboxamide (structural formula II) | 1.16 | 0.13 |
| 5-[ethanoyl (2, the 3-dihydroxypropyl) amido]-N-[3-(2,3-dihydroxyl propoxy-)-2-hydroxyl-propyl group]-N '-(2-hydroxyethyl)-2,4,6-three iodo-1,3-benzenedicarboxamide (structural formula II I) | 1.22 | 0.39 |
| Other impurity | 0.88 | 0.33 |
Claims (3)
1. the purification process of an ioxitol, it is characterized in that adopting deionized water the ioxitol crude product to be carried out recrystallization as solvent, the process of recrystallization is that per 100 gram ioxitol crude products add deionized water 500mL dissolving, pressure reducing and steaming portion water to ioxitol solution gross weight is the 130-200 gram, add ioxitol highly finished product 1-5 gram as crystal seed, stirred 24 hours at 60 ℃, filtering suspension liquid, on filter with 60 ℃ of hot deionized water 20mL washing crystals, repeated washing totally 3 times, vacuum-drying gets the ioxitol highly finished product, and its ioxitol content reaches more than 99%.
2. the purification process of a kind of ioxitol according to claim 1 is characterized in that per 100 gram ioxitol crude products add that to steam to ioxitol solution gross weight behind the deionized water dissolving be that 150 grams carry out recrystallization.
3. the purification process of a kind of ioxitol according to claim 1 is characterized in that adding ioxitol highly finished product 2 grams in the ioxitol solution of per 100 gram ioxitol crude products configurations carries out recrystallization as crystal seed.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100378133A CN100418945C (en) | 2006-01-13 | 2006-01-13 | Iodine Ioxilan purification method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100378133A CN100418945C (en) | 2006-01-13 | 2006-01-13 | Iodine Ioxilan purification method |
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| Publication Number | Publication Date |
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| CN1800150A CN1800150A (en) | 2006-07-12 |
| CN100418945C true CN100418945C (en) | 2008-09-17 |
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| CNB2006100378133A Expired - Fee Related CN100418945C (en) | 2006-01-13 | 2006-01-13 | Iodine Ioxilan purification method |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4396598A (en) * | 1982-01-11 | 1983-08-02 | Mallinckrodt, Inc. | Triiodoisophthalamide X-ray contrast agent |
| CN1070843C (en) * | 1995-09-08 | 2001-09-12 | 伯拉考国际股份公司 | Process for crystallization from water of (S)-N,N'-bis[2-hydroxy-1-(hydroxymethyl) ethyl]-5-[(2-hydroxy-1-oxopropyl)amino]-2,4,6-triiodo-1,3-benzendicarboxamide |
-
2006
- 2006-01-13 CN CNB2006100378133A patent/CN100418945C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4396598A (en) * | 1982-01-11 | 1983-08-02 | Mallinckrodt, Inc. | Triiodoisophthalamide X-ray contrast agent |
| CN1070843C (en) * | 1995-09-08 | 2001-09-12 | 伯拉考国际股份公司 | Process for crystallization from water of (S)-N,N'-bis[2-hydroxy-1-(hydroxymethyl) ethyl]-5-[(2-hydroxy-1-oxopropyl)amino]-2,4,6-triiodo-1,3-benzendicarboxamide |
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| CN1800150A (en) | 2006-07-12 |
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