CN102249948B - Synthetic method of 5-acetamido-N,N'-bis-(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide - Google Patents
Synthetic method of 5-acetamido-N,N'-bis-(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide Download PDFInfo
- Publication number
- CN102249948B CN102249948B CN201110133234.XA CN201110133234A CN102249948B CN 102249948 B CN102249948 B CN 102249948B CN 201110133234 A CN201110133234 A CN 201110133234A CN 102249948 B CN102249948 B CN 102249948B
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- reaction
- acid
- formula compound
- 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
- 0 CC*(C*C(CO)O)C(C(CC(C(NCC(CO)O)=O)=C)C=C(C)C)=C=O Chemical compound CC*(C*C(CO)O)C(C(CC(C(NCC(CO)O)=O)=C)C=C(C)C)=C=O 0.000 description 1
Abstract
The invention provides a method for synthesizing an iodixanol key intermediate-5-acetamido-N,N'-bis-(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (a compound of a formula I described in the specification), comprising the following steps of: (a) enabling a compound of a formula II described in the specification to undergo acetylation reaction under the catalysis of protonic acid to generate a compound of a formula III described in the specification; (b) enabling the compound of the formula III to undergo catalytic hydrogenation reaction to obtain a compound of a formula IV described in the specification; (c) enabling the compound of the formula IV to undergo iodination reaction with an iodinating regent to obtain a compound of a formula V described in the specification; (d) enabling the compound of the formula V to undergo the acetylation reaction under the catalytic action of the protonic acid to obtain a compound of a formula VI described in the specification; and (e) enabling the compound of the formula VI to undergo hydrolysis reaction under the catalytic action of organic base to obtain the compound of the formula I, i.e. the 5-acetamido-N,N'-bis-(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide. The synthetic method provided by the invention has the advantages of easiness and convenience for operation, low cost, high yield, easiness in industrialized production, and the like.
Description
Technical field
the present invention relates to a kind of synthetic method of compound, relate more specifically to the intermediate of Visipaque 320---5-acetylaminohydroxyphenylarsonic acid N, N '-bis--(2,3-dihydroxypropyl)-2,4, the synthetic method of 6-triiodo isophthaloyl amine.
Background technology
a kind of third generation non-ionic type dimer hexaiodo x-ray contrast agent of Visipaque 320 Shi You Norway Nycomed company research and development, strengthens inspection etc. for angiocardiography, cerebral angiograpathy, peripheral arterial radiography, abdominal angiography, urography, phlebography and the CT-being grown up.Visipaque 320 took the lead in going on the market with commodity Vispaqune in Germany April nineteen ninety-five, obtained FDA in March, 1996 and passed through, and in succession go on the market in France, Italy in the U.S., and at present domestic only have from Irish imported materials and injection.
compound " 5-acetylaminohydroxyphenylarsonic acid N, N-pair-(2,3-dihydroxypropyl)-2,4,6-triiodo isophthaloyl amine " (
) be the key intermediate of synthetic Visipaque 320, the 5-acetylaminohydroxyphenylarsonic acid N reporting at present, N-pair-(2,3-dihydroxypropyl)-2,4, the synthetic route of 6-triiodo isophthaloyl amine mainly comprises following three kinds.
, as shown in equation (1), this kind of method is with formula for the first synthetic route (can referring to document WO2002044125 and CN1132743, CA2710131 etc.)
compound be raw material, first nitroreduction obtains formula
compound, formula then
compound generation iodide reaction obtain formula
compound, last formula
compound after acetylize, hydrolysis reaction, obtain the intermediate (formula of Visipaque 320
).In this kind of synthetic method, due to formula
compound and formula
compound be all polyol, have extraordinary water-soluble, therefore, in building-up process, react excessive reagent, such as iodine monochloride, diacetyl oxide, sodium hydroxide etc., and a large amount of by products of following reaction to produce, as inorganic salt etc., can not remove via washing, be difficult to purifying, thereby cause the finished product purity low, productive rate is not high;
equation (1).
the second synthetic route (can referring to document WO2007026140, CN1721393 etc.) as shown in equation (2), this kind of synthetic method be with amino-2,4, the 6-triiodo of compound 5-m-phthalic acid for raw material, its first chlorination obtain formula
chloride compounds, formula then
compound obtain formula through acetylization reaction
chloride compounds
, last formula
compound through amidation, obtain the intermediate of Visipaque 320, i.e. formula
compound.Similarly, in this kind of method, formula
compound have extraordinary water-soluble, therefore react excessive reagent and follow that reaction produces a large amount of by products---inorganic salt etc. can not be removed via washing, thereby cause the finished product purity difference, productive rate is low; Secondly, at synthesis type
compound time need to use the reagent such as sulfur oxychloride that corrodibility is very strong, phosphorus oxychloride, while making the method be applied to industrialized production, difficulty is higher; In addition, due to formula
chloride compounds and and formula
chloride compounds unstable chemcial property, so purification ratio is more difficult, causes the finished product purity lower, is not suitable for suitability for industrialized production;
equation (2).
, as shown in equation (3), the method is with 5-acetylaminohydroxyphenylarsonic acid 2,4 for the third synthetic route (can referring to document CN101195587 etc.), and 6-triiodo isophthaloyl amine is raw material, and it reacts the formula of obtaining with epoxy chloropropane or 1-halo glycerine under alkaline condition
compound.In this in method, due at raw materials 5-acetylaminohydroxyphenylarsonic acid 2,4, in the process of 6-triiodo isophthaloyl amine, need to use equally the chlorination reagents such as sulfur oxychloride that erosion property is very strong, phosphorus oxychloride, increased the difficulty that the method is applied to industrialized production.In addition, similarly due to formula
compound have extraordinary water-solublely, cause a large amount of inorganic salt to be difficult to remove, thereby the aftertreatment of this kind of method is also very difficult;
equation (3).
Summary of the invention
for overcoming the problems referred to above of the prior art, the invention provides a kind of easy and simple to handle and be applicable to the synthetic 5-acetylaminohydroxyphenylarsonic acid N of suitability for industrialized production, N '-bis--(2,3-dihydroxypropyl)-2,4,6-triiodo isophthaloyl amine.
the technical solution used in the present invention is: a kind of 5-acetylaminohydroxyphenylarsonic acid N, and N '-bis--(2,3-dihydroxypropyl)-2,4, the synthetic method of 6-triiodo isophthaloyl amine, comprises the following steps: (a) make formula
compound generation acetylization reaction, obtain formula
compound; (b) make the formula of gained in step (a)
compound generation catalytic hydrogenation, obtain formula
compound; (c) make the formula of gained in step (b)
compound and iodo reagent generation iodide reaction, obtain formula
compound; (d) make the formula of gained in step (c)
compound generation acetylization reaction, obtain formula
compound; (e), under the katalysis of organic bases, make the formula of gained in step (d)
compound generation hydrolysis reaction, obtain formula
compound, i.e. 5-acetylaminohydroxyphenylarsonic acid N, N '-bis--(2,3-dihydroxypropyl)-2,4,6-triiodo isophthaloyl amine,
further, in step (a), formula
compound take diacetyl oxide and under the katalysis of protonic acid, acetylization reaction occur as solvent, acetylization reaction carries out 3 ~ 8 h at the temperature of 10 ℃ ~ 100 ℃, protonic acid is sulfuric acid or tosic acid, the consumption of protonic acid is formula
compound molar weight 5% ~ 10%.
further, in step (a), after acetylization reaction completes, also comprise following treatment step: in solution, add methylene dichloride to extract; With saturated sodium bicarbonate solution, wash; With solution after anhydrous sodium sulfate drying washing, and solvent evaporated; Recrystallization.
preferably, in step (b), formula
compound be dissolved in catalytic hydrogenation occur in alcoholic solvent, 3 ~ 8 h are carried out in reaction at the temperature of 0 ~ 50 ℃, the pressure of the hydrogen using in reaction is 1 ~ 5 normal atmosphere, catalyzer is 5% ~ 10% palladium carbon.
further, in step (c), iodide reaction is with KICl
2
or iodine monochloride is iodo reagent, at 30 ℃ ~ 80 ℃ temperature, carry out 5 ~ 12 h, the solvent of reaction is methylene dichloride, or acetic acid, or toluene, or trichloromethane, formula
compound be 1:3 ~ 1:5 with the ratio of the molar weight of iodo reagent.
further, in step (c), after iodide reaction completes, also comprise following treatment step: with the washing of sodium bisulfite saturated solution; With saturated sodium bicarbonate, wash; By anhydrous sodium sulphate, solution is dried, and solvent evaporated; Recrystallization.
preferably, in step (d), formula
compound take diacetyl oxide and under the katalysis of protonic acid, acetylization reaction occur as acetylation reagent; acetylization reaction carries out 8 ~ 15 h at the temperature of 10 ℃ ~ 50 ℃; reaction solvent is methylene dichloride or toluene or chloroform, and protonic acid is sulfuric acid or tosic acid, and the consumption of protonic acid is formula
compound molar weight 1% ~ 5%, formula
compound and the mol ratio of diacetyl oxide be 1:1 ~ 1:3.
further, in step (d), after acetylization reaction finishes, also comprise following treatment step: with saturated sodium bicarbonate solution, wash; With anhydrous sodium sulfate drying gained solution, and solvent evaporated; Recrystallization.
preferably, in step (e), hydrolysis reaction be take methyl alcohol and at 40 ℃ ~ 80 ℃ temperature, is carried out 3 ~ 10 h as reaction solvent, and organic bases is sodium methylate, and the consumption of sodium methylate is formula
compound molar weight 5% ~ 20%.
further, in step (e), after hydrolysis reaction finishes, also comprise the treatment step that steams methyl alcohol and recrystallization, recrystallization solvent is ethyl acetate, or acetone, or acetonitrile.
compared with prior art, the present invention has following advantages: 5-acetylaminohydroxyphenylarsonic acid N provided by the present invention, and N '-bis--(2,3-dihydroxypropyl)-2,4, the synthetic method of 6-triiodo isophthaloyl amine, in building-up process, starting compound (formula
) on four oh groups be acetylation, make intermediate product (formula
,
,
,
) water-solublely greatly reduce, fat-soluble increase, thus can water or alkaline aqueous solution wash to remove excessive reagent, by product etc., make reacted processing simpler; In addition, in formula
compound hydrolysis generate 5-acetylaminohydroxyphenylarsonic acid N, N '-bis--(2,3-dihydroxypropyl)-2,4,6-triiodo isophthaloyl amine (formula
) reaction in, use the sodium methylate of catalytic amount to react in methanol solution, wherein, the methyl acetate generating can be removed by the method for simple distillation, and sodium methylate can be removed by simple recrystallization method, thereby avoid the generation of stoichiometric inorganic salt, made product (formula
) purifying easier; Thereby that synthetic method provided by the present invention has is easy and simple to handle, condition is easily controlled, aftertreatment is easy, productive rate is higher, be easy to the multiple advantages such as suitability for industrialized production.
Embodiment
in order more clearly to understand technology contents of the present invention, existing further description in conjunction with the embodiments.
embodiment 1
step 1.1: formula
compound, i.e. N, the preparation of N '-bis--(2,3-diacetoxy propyl group)-5-nitro isophthaloyl amine
at room temperature, in three mouthfuls of reaction flasks, add respectively 3.13 g formulas
compound (N, N '-bis--(2,3-dihydroxypropyl)-5-nitro isophthaloyl amine), 5 ml diacetyl oxides and 0.10 g tosic acid, reactant is slowly heated to 50 ℃, and reacts 3 h; After question response finishes, in bottle, add 30 ml methylene dichloride, then with saturated sodium bicarbonate solution washing gained solution, and by dried over sodium sulfate, after solvent evaporated, obtain formula
the crude product of compound, add re-crystallizing in ethyl acetate, obtain 4.28g formula
compound, yield is 80%.
step 1.2: formula
compound, i.e. N, the preparation of N '-bis--(2,3-diacetoxy propyl group)-5-amido isophthaloyl amine
at room temperature, in reaction flask, add respectively the formula that 4.29 g are obtained by step 1.1
the 10% palladium carbon of compound, 20 ml methyl alcohol and 0.44 g, under 1 normal atmosphere, carry out hydrogenation, reach 6 h; Question response finishes in backward solution logical nitrogen to remove unnecessary hydrogen, and filtering solution removes palladium carbon, obtains 3.7 g formulas after concentrated
compound, yield is 91%.
step 1.3: formula
compound, i.e. 5-amido-N, N '-bis--(2,3-diacetoxy propyl group)-2,4, the preparation of 6-triiodo isophthaloyl amine
the formula that 1.0 g are prepared by step 1.2
compound be dissolved in 4 ml acetic acid, and add 0.66 g sodium acetate, then add the KICl of 10 ml 1 mol/L
2
solution, is warmed up to 60 ℃ and react 9 h by solution; After question response finishes, add 25 ml methylene dichloride, and use successively saturated sodium sulfite solution and saturated common salt water washing, then, with dried over sodium sulfate filtration, after concentrating, obtain formula
the crude product of compound, with obtaining 1.3 g formulas after this crude product of re-crystallizing in ethyl acetate
compound, yield is 73%.
step 1.4: formula
compound, i.e. 5-acetamido-N, N '-bis--(2,3-diacetoxy propyl group)-2,4, the preparation of 6-triiodo isophthaloyl amine
the formula that 0.9 g is prepared by step 1.3
compound be dissolved in 10ml methylene dichloride, and add 10 mg tosic acid and 0.3ml diacetyl oxide, temperature rising reflux reaction reaches 10 h; After finishing, question response adds the molten acid elution of saturated sodium bicarbonate, and then with anhydrous sodium sulfate drying filtration, concentrated rear by re-crystallizing in ethyl acetate, obtain 0.87 g formula
compound, yield is 92%.
step 1.5: formula
compound, i.e. 5-acetylaminohydroxyphenylarsonic acid N, N '-bis--(2,3-dihydroxypropyl)-2,4, the preparation of 6-triiodo isophthaloyl amine
the formula that 0.80 g is prepared by step 1.4
compound dissolution in 4 ml anhydrous methanols, and add 5 mg sodium methylates, be heated to 77 ℃ of back flow reaction to 5 ~ 6h.Reaction finishes rear solvent evaporated, after use acetone recrystallization, obtains 0.45 g formula
compound, yield is 70%.
embodiment 2
step 2.1: formula
compound, i.e. N, the preparation of N '-bis--(2,3-diacetoxy propyl group)-5-nitro isophthaloyl amine
at room temperature, in three mouthfuls of reaction flasks, add respectively 3.13 g formulas
compound (N, N '-bis--(2,3-dihydroxypropyl)-5-nitro isophthaloyl amine), 5 ml diacetyl oxides and 0.10 g sulfuric acid, reactant is slowly heated to 50 ℃, and reacts 3 h; After question response finishes, in bottle, add 30 ml methylene dichloride, then with saturated sodium bicarbonate solution washing gained solution, and by dried over sodium sulfate, after solvent evaporated, obtain formula
the crude product of compound, add re-crystallizing in ethyl acetate, obtain 4.0 g formulas
compound, yield is 75%.
step 2.2: formula
compound, i.e. N, the preparation of N '-bis--(2,3-diacetoxy propyl group)-5-amido isophthaloyl amine
at room temperature, in reaction flask, add respectively the formula that 4.29g is obtained by step 2.1
the 5% palladium carbon of compound, 20 ml methyl alcohol and 0.90 g, at 1 normal atmosphere, carry out hydrogenation, reach 6 h; Question response finishes in backward solution logical nitrogen to remove unnecessary hydrogen, and filtering solution removes palladium carbon, obtains 3.83 g formulas after concentrated
compound, yield is 94%.
step 2.3: formula
compound, i.e. 5-amido-N, N '-bis--(2,3-diacetoxy propyl group)-2,4, the preparation of 6-triiodo isophthaloyl amine
the formula that 1.0 g are prepared by step 2.2
compound be dissolved in 4ml acetic acid, and add 1.3 g iodine monochlorides, solution is warmed up to 60 ℃ and react 9 h; After question response finishes, add 25ml methylene dichloride, then use successively saturated sodium sulfite solution and saturated common salt water washing, then, with dried over sodium sulfate filtration, after concentrating, obtain formula
the crude product of compound, with obtaining 1.4 g formulas after this crude product of re-crystallizing in ethyl acetate
compound 5, yield is 77%.
step 2.4: formula
compound, 5-acetamido-N, N '-bis--(2,3-diacetoxy propyl group)-2,4, the preparation of 6-triiodo isophthaloyl amine
the formula that 0.9 g is prepared by step 2.3
compound be dissolved in 10 ml methylene dichloride, and add 10 mg sulfuric acid and 0.3 ml diacetyl oxide, temperature rising reflux reaction reaches 10 h; After finishing, question response adds the molten acid elution of saturated sodium bicarbonate, and then with anhydrous sodium sulfate drying filtration, concentrated afterwards with after re-crystallizing in ethyl acetate, obtain 0.80 g formula
compound, yield is 85%.
step 2.5: formula
compound, i.e. 5-acetylaminohydroxyphenylarsonic acid N, N '-bis--(2,3-dihydroxypropyl)-2,4, the preparation of 6-triiodo isophthaloyl amine
the formula that 0.80 g is prepared by step 2.4
compound dissolution in 4 ml anhydrous methanols, and add 5 mg sodium methylates, be heated to 77 ℃ of back flow reaction to 5 ~ 6h.Reaction finishes rear solvent evaporated, after use acetone recrystallization, obtains 0.45 g formula
compound, yield is 70%.
in sum, 5-acetylaminohydroxyphenylarsonic acid N provided by the present invention, N '-bis--(2,3-dihydroxypropyl)-2,4, the synthetic method of 6-triiodo isophthaloyl amine avoids using water-soluble strong intermediate product and the strong reagent of corrodibility, have easy and simple to handle, cost is low, productive rate is high and be easy to the multiple advantages such as suitability for industrialized production.
above specific embodiment of the present invention is illustrated; but protection content of the present invention is not only limited to above embodiment; under of the present invention, in technical field, the common knowledge of a GPRS just can be carried out diversified change within the scope of its technology main idea.
Claims (5)
1. a 5-acetylaminohydroxyphenylarsonic acid N, N '-bis--(2,3-dihydroxypropyl)-2,4, the synthetic method of 6-triiodo isophthaloyl amine, is characterized in that comprising the following steps:
(a) make formula
compound generation acetylization reaction, obtain formula
compound, described formula
compound take diacetyl oxide and under the katalysis of protonic acid, acetylization reaction occur as solvent, described acetylization reaction carries out 3 ~ 8 h at the temperature of 10 ℃ ~ 100 ℃, described protonic acid is sulfuric acid or tosic acid, the consumption of described protonic acid is formula
compound molar weight 5% ~ 10%;
(b) make the formula of gained in step (a)
compound generation catalytic hydrogenation, obtain formula
compound, described formula
compound be dissolved in alcoholic solvent catalytic hydrogenation occur, 3 ~ 8 h are carried out in described reaction at the temperature of 0 ~ 50 ℃, the pressure of the hydrogen using in reaction is 1 ~ 5 normal atmosphere, catalyzer is 5% ~ 10% palladium carbon;
(c) make the formula of gained in step (b)
compound and iodo reagent generation iodide reaction, obtain formula
compound, described iodide reaction is with KICl
2or iodine monochloride is iodo reagent, at 30 ℃ ~ 80 ℃ temperature, carry out 5 ~ 12 h, the solvent of reaction is methylene dichloride, or acetic acid, or toluene, or trichloromethane, described formula
compound be 1:3 ~ 1:5 with the ratio of the molar weight of iodo reagent;
(d) make the formula of gained in step (c)
compound generation acetylization reaction, obtain formula
compound, described formula
compound take diacetyl oxide and under the katalysis of protonic acid, acetylization reaction occur as acetylation reagent; described acetylization reaction carries out 8 ~ 15 h at the temperature of 10 ℃ ~ 50 ℃; reaction solvent is methylene dichloride or toluene or chloroform; described protonic acid is sulfuric acid or tosic acid, and the consumption of described protonic acid is formula
compound molar weight 1% ~ 5%, described formula
compound and the mol ratio of diacetyl oxide be 1:1 ~ 1:3;
(e), under the katalysis of organic bases, make the formula of gained in step (d)
compound generation hydrolysis reaction, obtain formula
compound 5-acetylaminohydroxyphenylarsonic acid N, N '-bis--(2,3-dihydroxypropyl)-2,4,6-triiodo isophthaloyl amine, described hydrolysis reaction be take methyl alcohol and at 40 ℃ ~ 80 ℃ temperature, is carried out 3 ~ 10 h as reaction solvent, described organic bases is sodium methylate, and the consumption of described sodium methylate is formula
compound molar weight 5% ~ 20%;
2. 5-acetylaminohydroxyphenylarsonic acid N according to claim 1, N '-bis--(2,3-dihydroxypropyl)-2,4, the synthetic method of 6-triiodo isophthaloyl amine, it is characterized in that: in step (a), after described acetylization reaction completes, also comprise following treatment step: in solution, add methylene dichloride to extract; With saturated sodium bicarbonate solution, wash; With solution after anhydrous sodium sulfate drying washing, and solvent evaporated; Recrystallization.
3. 5-acetylaminohydroxyphenylarsonic acid N according to claim 1, N '-bis--(2,3-dihydroxypropyl)-2,4, the synthetic method of 6-triiodo isophthaloyl amine, it is characterized in that: in step (c), after described iodide reaction completes, also comprise following treatment step: with the washing of sodium bisulfite saturated solution; With saturated sodium bicarbonate, wash; By anhydrous sodium sulphate, solution is dried, and solvent evaporated; Recrystallization.
4. 5-acetylaminohydroxyphenylarsonic acid N according to claim 1, N '-bis--(2,3-dihydroxypropyl)-2,4, the synthetic method of 6-triiodo isophthaloyl amine, is characterized in that, in step (d), after described acetylization reaction finishes, also comprise following treatment step: with saturated sodium bicarbonate solution, wash; With anhydrous sodium sulfate drying gained solution, and solvent evaporated; Recrystallization.
5. 5-acetylaminohydroxyphenylarsonic acid N according to claim 1, N '-bis--(2,3-dihydroxypropyl)-2,4, the synthetic method of 6-triiodo isophthaloyl amine, it is characterized in that: in step (e), after described hydrolysis reaction finishes, also comprise the treatment step that steams methyl alcohol and recrystallization, recrystallization solvent is ethyl acetate, or acetone, or acetonitrile.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110133234.XA CN102249948B (en) | 2011-05-23 | 2011-05-23 | Synthetic method of 5-acetamido-N,N'-bis-(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110133234.XA CN102249948B (en) | 2011-05-23 | 2011-05-23 | Synthetic method of 5-acetamido-N,N'-bis-(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102249948A CN102249948A (en) | 2011-11-23 |
| CN102249948B true CN102249948B (en) | 2014-01-29 |
Family
ID=44977561
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110133234.XA Active CN102249948B (en) | 2011-05-23 | 2011-05-23 | Synthetic method of 5-acetamido-N,N'-bis-(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102249948B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103382160B (en) * | 2012-05-02 | 2017-10-27 | 上海海神化学生物科技有限公司 | The synthesis of Iopamidol and its preparation of synthetic intermediate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4250113A (en) * | 1976-06-11 | 1981-02-10 | Nyegaard & Co. A/S | Chemical compounds |
| CN101962337A (en) * | 2009-07-21 | 2011-02-02 | 通用电气医疗集团股份有限公司 | Continuous acetylize technology in non-ionic x-ray contrast agents synthetic |
-
2011
- 2011-05-23 CN CN201110133234.XA patent/CN102249948B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4250113A (en) * | 1976-06-11 | 1981-02-10 | Nyegaard & Co. A/S | Chemical compounds |
| CN101962337A (en) * | 2009-07-21 | 2011-02-02 | 通用电气医疗集团股份有限公司 | Continuous acetylize technology in non-ionic x-ray contrast agents synthetic |
Non-Patent Citations (4)
| Title |
|---|
| 5-乙酰胺基-N,N’-双( 2,3-二羟基丙基)-2,4,6-三碘-1,3-苯二甲酰胺的合成;张婷婷等;《中国新药杂志》;20101231;第19卷(第19期);第1812页右栏倒数第1段至第1813页左栏第2段，图1 * |
| 张婷婷等.5-乙酰胺基-N,N’-双( 2,3-二羟基丙基)-2,4,6-三碘-1,3-苯二甲酰胺的合成.《中国新药杂志》.2010,第19卷(第19期),第1812页右栏倒数第1段至第1813页左栏第2段，图1. |
| 罗世能等.非离子型X-CT造影剂碘海醇的合成.《中国医药工业杂志》.1995,第26卷(第10期),第434页左栏倒数第1段至右栏第3段,第433页左栏第2段. |
| 非离子型X-CT造影剂碘海醇的合成;罗世能等;《中国医药工业杂志》;19951021;第26卷(第10期);第434页左栏倒数第1段至右栏第3段,第433页左栏第2段 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102249948A (en) | 2011-11-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103570580B (en) | Preparation method of high-purity iopromide | |
| CN100588646C (en) | Industrial preparation method for 3-amino-2, 2-dimethyl propionamide | |
| CN102351735B (en) | Preparation method of Iopromide | |
| CN102850325B (en) | Preparation method of Dabigatran etexilate key intermediate | |
| CN108069831A (en) | A kind of method for synthesizing 2,3- dimethyl -4- fluorophenols | |
| CN102295638A (en) | Novel method for preparing lapatinib | |
| CN102249948B (en) | Synthetic method of 5-acetamido-N,N'-bis-(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide | |
| CN102659605B (en) | Synthesizing method of spermidine | |
| CN101962342A (en) | Continuous deacetylated and purifying process in non-ionic x-ray contrast agents synthetic | |
| CN110028419B (en) | Preparation method of iopromide | |
| CN104628577A (en) | Method for synthesizing bromhexine hydrochloride | |
| CN105085290A (en) | Method for synthesizing pregabalin | |
| CN102206170A (en) | Preparation method for agomelatine | |
| CN113149823B (en) | 2-R 1 Process for preparing valeric acid | |
| CN101875658B (en) | Preparation method of 3-carbonyl-2,8-diazepine helix[4.5]decane-8-carboxylic acid tert-butyl ester | |
| CN102250005B (en) | Preparation method of Eslicarbazepine | |
| CN108047032A (en) | By α-ketoglutaric acid to glutaric acid synthetic method | |
| CN105001114B (en) | Prepare the new method of Iopromide | |
| CN103508898A (en) | Novel preparation method of alverine citrate | |
| CN103288650A (en) | Hydrochloric acid 1-amino-3, 5-dimethyl adamantane preparation method | |
| CN106565769B (en) | The synthesis technology of entecavir midbodies | |
| CN102532164A (en) | Synthesis method for sulbactam | |
| CN104402721A (en) | Synthetic method of 4-aldehyde butyrate | |
| CN103755748A (en) | Preparation process for chiral (R)-1-ferrocenyl ethyl dimethylamine | |
| CN102731600B (en) | Preparation method of zidovudine and its intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C56 | Change in the name or address of the patentee | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 215011 Jiangsu high tech Zone Suzhou City Binhe Road, No. 1326 Patentee after: Suzhou Hao Fan biological Limited by Share Ltd Address before: 215011 Jiangsu high tech Zone Suzhou City Binhe Road, No. 1326 Patentee before: Suzhou Highfine Biotech Co.,Ltd. |