CN100418945C - Iodine Ioxilan purification method - Google Patents
Iodine Ioxilan purification method Download PDFInfo
- Publication number
- 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
- Authority
- CN
- China
- Prior art keywords
- ioxitol
- ioxilan
- gram
- deionized water
- recrystallization
- 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.)
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- UUMLTINZBQPNGF-UHFFFAOYSA-N ioxilan Chemical compound OCC(O)CN(C(=O)C)C1=C(I)C(C(=O)NCCO)=C(I)C(C(=O)NCC(O)CO)=C1I UUMLTINZBQPNGF-UHFFFAOYSA-N 0.000 title claims abstract description 55
- 229960002611 ioxilan Drugs 0.000 title claims abstract description 54
- 238000000746 purification Methods 0.000 title claims abstract description 12
- 238000000034 method Methods 0.000 title claims abstract description 9
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 title 1
- 229910052740 iodine Inorganic materials 0.000 title 1
- 239000011630 iodine Substances 0.000 title 1
- 238000001953 recrystallisation Methods 0.000 claims abstract description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000012043 crude product Substances 0.000 claims abstract description 14
- 239000008367 deionised water Substances 0.000 claims abstract description 13
- 229910021641 deionized water Inorganic materials 0.000 claims abstract description 13
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 239000013078 crystal Substances 0.000 claims description 8
- 239000000047 product Substances 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 3
- 239000000725 suspension Substances 0.000 claims description 3
- 238000001291 vacuum drying Methods 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 2
- 238000010025 steaming Methods 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 abstract description 5
- 239000002872 contrast media Substances 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 4
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- -1 2, 3-dihydroxy propyl Chemical group 0.000 abstract 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 abstract 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 abstract 1
- AIDQCFHFXWPAFG-UHFFFAOYSA-N n-formylformamide Chemical compound O=CNC=O AIDQCFHFXWPAFG-UHFFFAOYSA-N 0.000 abstract 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- UFNGEZFIBCOLBF-UHFFFAOYSA-N NC(=O)C1=CC=CC(C(N)=O)=C1I Chemical compound NC(=O)C1=CC=CC(C(N)=O)=C1I UFNGEZFIBCOLBF-UHFFFAOYSA-N 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000002601 radiography Methods 0.000 description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 210000000576 arachnoid Anatomy 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 206010019909 Hernia Diseases 0.000 description 1
- 238000002583 angiography Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 238000013189 cholangiography Methods 0.000 description 1
- 238000010411 cooking Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000007487 urography Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
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 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100378133A CN100418945C (en) | 2006-01-13 | 2006-01-13 | Iodine Ioxilan purification method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1800150A CN1800150A (en) | 2006-07-12 |
| CN100418945C true CN100418945C (en) | 2008-09-17 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2006100378133A Expired - Fee Related CN100418945C (en) | 2006-01-13 | 2006-01-13 | Iodine Ioxilan purification method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100418945C (en) |
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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| Publication number | Publication date |
|---|---|
| CN1800150A (en) | 2006-07-12 |
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Owner name: JIANGSU ZHENGDA TIANQING PHARMACEUTICALS INDUSTRY Free format text: FORMER OWNER: JIANGSU ATOMIC MEDICAL SCIENCES INSTITUTE Effective date: 20100108 |
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Effective date of registration: 20100108 Address after: No 8 North dragon road, Sinpo District, Jiangsu, Lianyungang Patentee after: JIANGSU CHIATAI TIANQING PHARMACEUTICAL Co.,Ltd. Address before: Jiangsu city of Wuxi province Qian Rong Lu No. 20 Patentee before: Jiangsu Institute of Nuclear Medicine |
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Owner name: CHIA TAI TIANQING PHARMACEUTICAL GROUP CO., LTD. Free format text: FORMER NAME: JIANGSU ZHENGDA TIANQING PHARMACEUTICAL CO., LTD. |
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Address after: 222006 Sinpo City, Lianyungang Province, North Road, No. 8, No. Patentee after: CHIA TAI TIANQING PHARMACEUTICAL GROUP Co.,Ltd. Address before: 222006 Sinpo City, Lianyungang Province, North Road, No. 8, No. Patentee before: JIANGSU CHIATAI TIANQING PHARMACEUTICAL Co.,Ltd. |
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