CN100537524C - Preparation method of ioxaglic alcohol - Google Patents
Preparation method of ioxaglic alcohol Download PDFInfo
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- CN100537524C CN100537524C CNB200710038355XA CN200710038355A CN100537524C CN 100537524 C CN100537524 C CN 100537524C CN B200710038355X A CNB200710038355X A CN B200710038355XA CN 200710038355 A CN200710038355 A CN 200710038355A CN 100537524 C CN100537524 C CN 100537524C
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- 238000002360 preparation method Methods 0.000 title claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 title claims description 7
- NBQNWMBBSKPBAY-UHFFFAOYSA-N iodixanol Chemical compound IC=1C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C(I)C=1N(C(=O)C)CC(O)CN(C(C)=O)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NBQNWMBBSKPBAY-UHFFFAOYSA-N 0.000 claims abstract description 44
- 238000000034 method Methods 0.000 claims abstract description 41
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- -1 diamine amide Chemical class 0.000 claims abstract description 24
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 15
- 238000011084 recovery Methods 0.000 claims abstract 2
- 238000006471 dimerization reaction Methods 0.000 claims description 19
- 239000002585 base Substances 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 16
- 239000007787 solid Substances 0.000 claims description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 10
- 239000007858 starting material Substances 0.000 claims description 10
- 150000001335 aliphatic alkanes Chemical group 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 238000000605 extraction Methods 0.000 claims description 7
- 238000006068 polycondensation reaction Methods 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- 239000007810 chemical reaction solvent Substances 0.000 claims description 6
- 239000000463 material Substances 0.000 claims description 6
- PMPBFICDXLLSRM-UHFFFAOYSA-N 1-propan-2-ylnaphthalene Chemical compound C1=CC=C2C(C(C)C)=CC=CC2=C1 PMPBFICDXLLSRM-UHFFFAOYSA-N 0.000 claims description 4
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 3
- 238000004821 distillation Methods 0.000 claims description 3
- 239000012065 filter cake Substances 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 abstract description 9
- 239000002994 raw material Substances 0.000 abstract description 5
- 229960004359 iodixanol Drugs 0.000 abstract description 4
- 238000000746 purification Methods 0.000 abstract description 3
- 239000000376 reactant Substances 0.000 abstract 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 38
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000008367 deionised water Substances 0.000 description 6
- 229910021641 deionized water Inorganic materials 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 5
- 229940126062 Compound A Drugs 0.000 description 4
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- 230000007613 environmental effect Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000007086 side reaction Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- NBDAHKQJXVLAID-UHFFFAOYSA-N 5-nitroisophthalic acid Chemical compound OC(=O)C1=CC(C(O)=O)=CC([N+]([O-])=O)=C1 NBDAHKQJXVLAID-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 238000013507 mapping Methods 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 238000004237 preparative chromatography Methods 0.000 description 2
- 238000004064 recycling Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- JRLTTZUODKEYDH-UHFFFAOYSA-N 8-methylquinoline Chemical group C1=CN=C2C(C)=CC=CC2=C1 JRLTTZUODKEYDH-UHFFFAOYSA-N 0.000 description 1
- LNGZQTXTLGRTPW-UHFFFAOYSA-N CC(C)C1=CC=CC2=CC=CC=C12.C(C)(C)C1=CC=CC2=CC=CC=C12 Chemical compound CC(C)C1=CC=CC2=CC=CC=C12.C(C)(C)C1=CC=CC2=CC=CC=C12 LNGZQTXTLGRTPW-UHFFFAOYSA-N 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 238000007098 aminolysis reaction Methods 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- QQVIHTHCMHWDBS-UHFFFAOYSA-N isophthalic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 1
- 238000004262 preparative liquid chromatography Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
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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
- Y02P20/582—Recycling of unreacted starting or intermediate materials
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
This invention relates a method that use dimeric 5 - azodermine - N, N - double ( 2, 3 - dioxy- propyl) - 2 and 4, 6 - triiodo meta xyylene diamine amide to prepare iodixanol. The characteristic is it takes reagent has following structure general expression (1) or (2) as dimeric reagent. After the dimeric step, generated iodixanol is extracted from hybrid for purification, and the rest not reactant raw material could be recovered. The iodixanol produced by this method not only be able to control and decrease subsidiary reaction effectively, advance reaction positive direction ongoing degree and greatly short reaction time, but also be able to recovery utilize not reactant raw material.
Description
Technical field
The invention belongs to the chemicals field, specifically, relate to a kind of preparation method of Visipaque 320.
Background technology
(chemistry is by name: 1 for Visipaque 320, two (the acetamido)-N of 3-, N '-two [3,5-two (2,3-dihydroxypropyl aminocarbonyl)-2,4, the 6-triiodophenyl]-the 2-hydroxy propane) be a kind of phenyl triiodide lopps non-ionic type X-ray contrast medium, by the exploitation of Norway Nycomed company and in listing in 1993, commodity prestige by name is looked Parker (Visipaque), and it is just produced at present in a large number, some preparation methods are well-known, but these preparation methods' technological process all is that multistep is rapid, and therefore, it is very important coming these processes are optimized from the factor of aspects such as economy and environmental protection.
The preparation method of Visipaque 320 mainly contains three kinds (EP108638, WO0047549 and CN1340042), and they are all from the 5-nitroisophthalic acid:
The operational path that first kind of technological process (NO161358) for preparing Visipaque 320 adopts as shown in Figure 1, be by two polycondensation 5-acetamido-N at last, N '-two (2, the 3-dihydroxypropyl)-2,4,6-triiodo isophthaloyl amine (calling " compd A " in the following text) obtains Visipaque 320.
Adopt this technological process to prepare Visipaque 320, in the report of document example, have only 18% yield, and need to make with extra care with preparative chromatography.In existing document (EP108638, WO0047549 and CN1340042), employing to be exactly with the compd A be raw material, and dimerization reagent is Epicholorohydrin.When repeating this test examples, we find because starting compound A fails complete dimerization is the product Visipaque 320, make yield low.Input raw material about 40% by reaction consumes after, the excessive alkylated reaction of target product begins more to preponderate than needed reaction, causes the Visipaque 320 content that needs in reaction mixture to descend.This is consistent with description in the document.Though document provides the method that reclaims compd A from reaction system, because transformation efficiency is low, generate the material complexity, be suitable for medicinal purity with still very difficult Visipaque 320 is purified to of traditional chemical purification method.Unique like this method that can obtain necessary purity Visipaque 320 is exactly a preparative liquid chromatography.Low yield adds expensive preparative chromatography purification process, just becomes the major defect of this method in industrial preparation Visipaque 320 flow process.
The operational path that second kind of technological process for preparing Visipaque 320 adopts as shown in Figure 2, this technological process comprises synthetic 5-amino-2,4, make its dichloride (WO9637459) behind the 6-triiodo m-phthalic acid (WO9637458), then the dichloride aminolysis is converted into compd A (US5705692, CN1228079 and WO9854124), last the same with first kind of preparation process, need carry out dimerization.So this method not only has the shortcoming same with first method, but also to adopt the chlorinating step that has corrosive thionyl chloride.
Priebe, Dugstad etc. (Acta Radiologica 36:21-31suppl.399,1995) have described the operational path of another kind of preparation Visipaque 320.Though it can avoid final step two polycondensation reaction of difficulty in above-mentioned 2 kinds of processes, but because this operational path is since 5-nitroisophthalic acid, need through the reaction of eight steps, reactions steps is long, and before and after synthetic, introduce the iodine atom in the order too early, and iodine is the most expensive reagent in this technical process.In addition, in this technological process, also need to adopt the chlorinating step that has corrosive thionyl chloride.
Summary of the invention
The present inventor finds under study for action, at existing two polycondensation 5-acetamido-N, N '-two (2, the 3-dihydroxypropyl)-2,4,6-triiodo isophthaloyl amine prepares in the method for Visipaque 320, adopts to contain the halogenating agents such as dimerization reagent table chloropharin that following general structure (I) or reagent (II) substitute document, can control and reduce generation, the degree that the raising reaction forward is carried out of side reaction effectively and shorten the reaction times greatly.
Therefore, the objective of the invention is to overcome existing shortcoming and defect in the existing method for preparing Visipaque 320, thereby a kind of new method for preparing Visipaque 320 is provided.
Similar with the preparation method of existing Visipaque 320, the present invention is also by two polycondensation 5-acetamido-N, N '-two (2, the 3-dihydroxypropyl)-2,4,6-triiodo isophthaloyl amine prepares Visipaque 320, and its main difference is that usefulness contains following general structure (I) or reagent (II) is used as dimerization reagent:
Wherein:
The R of general formula (I) is selected from: (1) is contained straight chain or substituted straight chain alkane group, the branched paraffin of C1 to C12 or is replaced the branched paraffin group; (2) contain the substituted aroma group that contains substituted radical on the aromatic group of C6 to C14 or the aromatic nucleus;
R1, the R2 of general formula (II) are selected from: (1) contains the straight or branched alkane group of C1 to C12; (2) contain the substituted aroma group that contains substituted radical on the aromatic group of C6 to C14 or the aromatic nucleus;
R3 be the H atom or
Group, wherein R4 is fat alkane or the aromatic group that contains C1 to C6.
According to the present invention, R1 in the general formula (II) and R2 can be identical, also can be different.
According to the present invention, the R base in the described general structure (I) is: p-methylphenyl, dodecyl, m-nitro base or methyl.
According to the present invention, the R2 in the described general structure (II) is: methyl, p-methylphenyl, dodecyl, m-nitro base, propenyl, heptane base, 4-isopropyl naphthalene or 4-tert.-butylbenzene.
In a preferred embodiment of the invention, described two polycondensation reaction may further comprise the steps: with starting compound 5-acetamido-N, and N '-two (2, the 3-dihydroxypropyl)-2,4,6-triiodo isophthaloyl amine, alkali are dissolved in the reaction solvent, add dimerization reagent then, reacted 18-20 hours.
According to the present invention, described reaction solvent is a polar protic type solvent, (C1-C6) and their mixture also can be aprotic, polar type solvents, as dimethyl formamide (DMF), N,N-DIMETHYLACETAMIDE (DMA) and methyl-sulphoxide (DMSO) as water, low carbon chain fatty alcohol.
According to the present invention, after dimerization step finishes, use traditional chemical extraction method that the product Visipaque 320 is extracted from mixture, can obtain being suitable for the Visipaque 320 of pharmaceutical grade after being further purified.
In a preferred embodiment of the invention, after described dimerization reaction is finished, the pH value of reaction solution is transferred to nearly neutrality.
According to the present invention, the unreacted starting compound 5-acetamido-N of remainder behind the dimerization reaction, N '-two (2, the 3-dihydroxypropyl)-2,4,6-triiodo isophthaloyl amine after further recycling, can be used for the dimerization step of a new round.
Adopt method provided by the invention to produce Visipaque 320, not only can control effectively and reduce side reaction generation, improve the degree that reaction forward carries out and shorten the reaction times greatly (foreshortening to about 20 hours) by original 46 hours, but also can further recycle unreacted starting compound 5-acetamido-N, N '-two (2, the 3-dihydroxypropyl)-2,4,6-triiodo isophthaloyl amine, thus further reduce production costs.In the ability of on industrial production, strengthen producing in batches, make process compliance with environmental protection requirements more, operate easier.
Description of drawings
Fig. 1 is first kind of technological process for preparing the method for Visipaque 320 mentioning in the background technology.
Fig. 2 is second kind of technological process for preparing the method for Visipaque 320 mentioning in the background technology.
Fig. 3 is the HPLC figure that method of the present invention prepares the product concentration and the reaction times relation of Visipaque 320, and curve 1,2,3 is respectively the result who maps and obtained with the data of embodiment 6,12 and 17 among the figure.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described.Should be understood that following examples only are used to the present invention is described but not are used to limit scope of the present invention.
Embodiment 1-8, Visipaque 320 preparation
Press shown in the table 1, get the 0.6mol solid sodium hydroxide, be dissolved in the 400ml solvent, be warming up to 45 ℃, add 0.501mol compound 5-acetamido-N, N '-two (2, the 3-dihydroxypropyl)-2,4,6-triiodo isophthaloyl amine (to call " compd A " in the following text).
Behind all solids material dissolution, cool the temperature to below 15 ℃, add the dimerization reagent that 0.167mol contains general structure (I), be warming up to room temperature reaction in stirring reaction below 10 ℃ after 2 hours; Got one time sample in the reaction process every 2 hours, sample detects wherein Visipaque 320 content with the HPLC method, with the reaction times to Visipaque 320 content mapping (embodiment 6), the result is as shown in Figure 3.
As seen from Figure 3, react about 18-20 hours after, the content of Visipaque 320 no longer obviously increases in the reaction mixture, can determine that thus the reaction times is 18-20 hours.
Hydrochloric acid with 9% is neutralized to pH for nearly neutral (6-8) with reaction solution, and with termination reaction, then according to different reaction solvents, under 30-100 ℃ of outer baths, underpressure distillation removes and desolvates, and obtains white solid.In the gained white solid, add extraction agent (deionized water or low carbon chain fatty alcohol or their mixture), fully extract after-filtration; Filter cake is with an amount of dehydrated alcohol or washing with acetone, in 50 ℃ of reduced vacuum dry white solids, this white solid is the intact starting compound A of unreacted, can directly reclaim the dimerization reaction step that is used for next step; Filtrate then is further used for purifying and obtains highly purified Visipaque 320.
Table 1, Visipaque 320 preparation technology's reactive material and usage quantity thereof or reaction conditions
| Embodiment | Solvent | The R base of general formula (I) (dimerization reagent) | |
| 1 | Methyl alcohol | Methyl | Deionized water |
| 2 | Methyl cellosolve | Propenyl | Deionized water+ |
| 3 | Methyl alcohol | The heptane base | Methyl alcohol |
| 4 | Water | Dodecyl | Deionized |
| 5 | Methyl alcohol | The m-nitro base | Ethylene glycol |
| 6 | Water | P-methylphenyl | Methoxyethanol |
| 7 | DMF | 4-isopropyl naphthalene | Diethylene glycol monomethyl ether |
| 8 | Methyl alcohol | 4-tert.-butylbenzene | Deionized water |
Embodiment 9-20, Visipaque 320 preparation
Press shown in the table 1, get the 0.6mol solid sodium hydroxide, be dissolved in the 400ml solvent, be warming up to 45 ℃, add 0.501mol compd A (reclaiming raw material+fresh feed).
Behind all solids material dissolution, cool the temperature to below 10 ℃, add the dimerization reagent that 0.167mol contains general structure (II), be warming up to room temperature reaction in stirring reaction below 15 ℃ after 2 hours; Got one time sample in the reaction process every 2 hours, sample detects wherein Visipaque 320 content with the HPLC method, with the reaction times to Visipaque 320 content mapping (embodiment 12,17), the result is as shown in Figure 3.
As seen from Figure 3, react about 18-20 hours after, the content of Visipaque 320 no longer obviously increases in the reaction mixture, can determine that thus the reaction times is 18-20 hours, and is consistent with the result of embodiment 1-8.
Hydrochloric acid with 9% is neutralized to pH for nearly neutral (6-8) with reaction solution, and with termination reaction, then according to different reaction solvents, under 30-100 ℃ of outer baths, underpressure distillation removes and desolvates, and obtains white solid.In the gained white solid, add extraction agent (deionized water or low carbon chain fatty alcohol or their mixture), fully extract after-filtration; Filter cake is with an amount of dehydrated alcohol or washing with acetone, in 50 ℃ of reduced vacuum dry white solids, this white solid is the intact starting compound A of unreacted, can directly reclaim the dimerization reaction step that is used for next step; Filtrate then is further used for purifying and obtains highly purified Visipaque 320.
Table 2, Visipaque 320 preparation technology's reactive material and usage quantity thereof or reaction conditions
| Embodiment | Solvent | R1 | R2 | R3(H/R4) * | |
|
| 9 | Methyl alcohol | Methyl | Methyl | H | Water | |
| 10 | Methyl alcohol | Propenyl | P-methylphenyl | | Methyl alcohol | |
| 11 | Methyl alcohol | The heptane base | 4-tert.-butylbenzene | H | Methyl alcohol | |
| 12 | Methyl alcohol | Dodecyl | The m-nitro base | CH 3OCH 2— | |
|
| 13 | Methyl cellosolve | The m-nitro base | Propenyl | ClCH 2— | Methyl cellosolve | |
| 14 | Methyl cellosolve | P-methylphenyl | The heptane base | Phenyl | |
|
| 15 | Methyl cellosolve | 4-isopropyl naphthalene | 4-isopropyl naphthalene | Methyl | Methyl cellosolve | |
| 16 | Methyl cellosolve | Dodecyl | Dodecyl | Phenyl | Diethylene |
|
| 17 | Water | 4-tert.-butylbenzene | Methyl | ClCH 2— | Methyl alcohol | |
| 18 | Water | Propenyl | M-nitro | CH 3OCH 2— | |
|
| 19 | DMA | The heptane base | Methyl | Methyl | Methyl alcohol, alcohol mixture | |
| 20 | DMSO | 4-isopropyl naphthalene | P-methylphenyl | H | Ethanol, water mixture |
*: in the 5th row, except that independent H atom is the R3, other group is R4.
Result according to the foregoing description 1-20, adopt the technological process of production provided by the invention to produce Visipaque 320, not only can effectively control and reduce side reaction generation, improve degree that reaction forward carries out and shortened (foreshortened to about 20 hours by original 46 hours and finish) the long reaction times greatly, and further recycling of unreacted starting compound A, thereby further reduce production costs.In the ability of on industrial production, strengthen producing in batches, make process compliance with environmental protection requirements more, operate easier.
Claims (13)
1, a kind of preparation method of Visipaque 320 is by two polycondensation 5-acetamido-N, N '-two (2, the 3-dihydroxypropyl)-2,4,6-triiodo isophthaloyl amine obtains Visipaque 320, it is characterized in that, with containing following general structure (I) or reagent (II) as dimerization reagent:
Wherein:
The R of general formula (I) is selected from: (1) contains the straight or branched alkane group of C1 to C12; (2) contain aromatic group or p-methylphenyl, m-nitro base, 4-isopropyl naphthalene or the 4-tert.-butylbenzene of C6 to C14;
R1, the R2 of general formula (II) are selected from: (1) contains the straight or branched alkane group of C1 to C12; (2) contain aromatic group or p-methylphenyl, m-nitro base, 4-isopropyl naphthalene or the 4-tert.-butylbenzene of C6 to C14;
R3 be the H atom or
Group, wherein R4 is fat alkane or the aromatic group that contains C1 to C6.
2, the method for claim 1 is characterized in that, the R base of the straight or branched alkane group that contains C1 to C12 in the general structure (I) is methyl, dodecyl or heptane base.
3, the method for claim 1 is characterized in that, the R1 of the straight or branched alkane group that contains C1 to C12 in the general structure (II) is methyl, dodecyl or heptane base.
4, the method for claim 1 is characterized in that, the R2 of the straight or branched alkane group that contains C1 to C12 in the general structure (II) is methyl, dodecyl or heptane base.
5, the method for claim 1 is characterized in that, described R4 is phenyl or methyl.
6, the method for claim 1 is characterized in that, R1 in the general structure (II) and R2 are identical or different group.
7, the method for claim 1 is characterized in that, described two polycondensation reaction may further comprise the steps: with former
Material compound 5-acetamido-N, N '-two (2, the 3-dihydroxypropyl)-2,4,6-triiodo isophthaloyl amine, alkali are dissolved in the reaction solvent, add dimerization reagent then, react 18-20 hours.
8, method as claimed in claim 7 is characterized in that, described reaction solvent is polar protic type solvent or aprotic, polar type solvent.
9, method as claimed in claim 8 is characterized in that, low carbon chain fatty alcohol that described polar protic type solvent is water, C1-C6 or their mixture.
10, method as claimed in claim 8 is characterized in that, described aprotic, polar type solvent is dimethyl formamide, N,N-DIMETHYLACETAMIDE or methyl-sulphoxide.
11, method as claimed in claim 7 is characterized in that, the pH value of the reaction solution after described dimerization reaction is finished transfers to nearly neutrality.
12, as each described method in the claim 1-11, it is characterized in that, also be included in after the dimerization reaction, reclaim unreacted starting compound 5-acetamido-N, N '-two (2, the 3-dihydroxypropyl)-2,4, the step of 6-triiodo isophthaloyl amine.
13, method as claimed in claim 12 is characterized in that, the recovery of described unreacted starting compound may further comprise the steps:
The pH value transfers to reaction solution after the nearly neutrality and removes by underpressure distillation and desolvate, the solid that obtains further adds extraction agent, fully extract after-filtration, reduced vacuum is dry after with dehydrated alcohol or washing with acetone obtains unreacted starting compound for filter cake, described extraction agent is water, low carbon chain fatty alcohol or their mixture, and described low carbon chain fatty alcohol is C1-C6 alcohol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200710038355XA CN100537524C (en) | 2007-03-23 | 2007-03-23 | Preparation method of ioxaglic alcohol |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200710038355XA CN100537524C (en) | 2007-03-23 | 2007-03-23 | Preparation method of ioxaglic alcohol |
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| US7696381B1 (en) * | 2009-07-21 | 2010-04-13 | Ge Healthcare As | Alternative dimerisation reagents for synthesis of iodixanol |
| US20110021832A1 (en) * | 2009-07-21 | 2011-01-27 | Ge Healthcare As | Synthesis of iodixanol in water |
| US20110021825A1 (en) * | 2009-07-21 | 2011-01-27 | Ge Healthcare As | Process for isolating iodixanol from an aqueous solution |
| US8969619B2 (en) * | 2009-07-21 | 2015-03-03 | Ge Healthcare As | Synthesis of iodixanol in propyleneglycol |
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