CN105001114B - Prepare the new method of Iopromide - Google Patents
Prepare the new method of Iopromide Download PDFInfo
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- CN105001114B CN105001114B CN201410158535.1A CN201410158535A CN105001114B CN 105001114 B CN105001114 B CN 105001114B CN 201410158535 A CN201410158535 A CN 201410158535A CN 105001114 B CN105001114 B CN 105001114B
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Abstract
The present invention relates to the preparation methods of Iopromide, provide three new methods for preparing Iopromide：Method one：It is starting material with formula II, reacts to obtain formula III with allylamine, formula III reacts to obtain formula IV with N- methyl allyl amine, and formula IV reacts to obtain formula V with methoxyacetyl chloride, and formula V obtains Iopromide formula I through peroxidating；Method two：It is starting material with formula II, reacts to obtain formula III with allylamine, formula III reacts to obtain formula IV -1 with methoxyacetyl chloride, and formula IV -1 reacts to obtain formula V with N- methyl allyl amine, and formula V obtains Iopromide formula I through peroxidating；Method three：It is starting material with formula II, reacts to obtain formula III with allylamine, formula III reacts to obtain formula IV -1 with methoxyacetyl chloride, and formula IV -1 reacts to obtain formula V -1 with 3- methylamino -1,2-PD, and formula V -1 obtains Iopromide formula I through peroxidating；Method four：It is starting material with formula II, reacts to obtain formula III -1 with methoxyacetyl chloride, formula III -1 reacts to obtain formula IV -1 with allyl amine, and formula IV -1 reacts to obtain formula V with N- methacrylic amine, and formula V obtains Iopromide formula I through peroxidating.
Description
Technical field：
The present invention relates to the preparation methods of Iopromide, provide three new methods for preparing Iopromide：Method one：With
Formula II is starting material, reacts to obtain formula III with allylamine, formula III reacts to obtain formula IV, formula IV and methoxy with N- methyl allyl amine
Base excess acetyl chloride obtains formula V, and formula V obtains Iopromide formula I through peroxidating；Method two：It is starting material with formula II, with alkene
Propylamine reacts to obtain formula III, and formula III reacts to obtain formula IV -1 with methoxyacetyl chloride, and formula IV -1 is reacted with N- methyl allyl amine
To formula V, formula V obtains Iopromide formula I through peroxidating；Method three：It is starting material with formula II, reacts to obtain formula with allylamine
III, formula III reacts to obtain formula IV -1 with methoxyacetyl chloride, and formula IV -1 reacts to obtain formula V-with 3- methylamino -1,2-PD
1, formula V -1 obtains Iopromide formula I through peroxidating；Method four：It is starting material with formula II, is reacted with methoxyacetyl chloride
To formula III -1, formula III -1 reacts to obtain formula IV -1 with allyl amine, and formula IV -1 reacts to obtain formula V, formula with N- methacrylic amine
V obtains Iopromide formula I through peroxidating.
According to the present invention, by simply crystallizing III intermediate of formula, the preparation in Iopromide can easily be removed
The bismer by-product for causing Iopromide purity to reduce generated in the process, without described in other purification step removing
Bismer by-product, can finally obtain the Iopromide of high-purity in high yield.
Background technique
Iopromide (formula I) is clinically widely used as x-ray contrast agent.It is reported in the literature about its preparation side at present
Method is published in patent US4364921, CN200980115336.X, CN201110205473.1, in CN201210497200.3.
Patent US4364921 discloses the preparation method of three kinds of Iopromides.Method one is as follows：
Method one：
According to the preparation method of method one, during by 2 preparation 3, inevitably generate a large amount of disubstituted
By-product, i.e. compound 3 ', and since compound 3 ' and 3 polarity are too big, it is difficult to purify, therefore there are low yields, purity for this step
Low disadvantage.
Method two：
Method three：
Method two and method three are although can have that reaction step is more, rear place to avoid the generation of disubstituted by-product
The shortcomings that reason trouble, production cycle length, low yield.
Subsequent Korean Patent CN200980115336.X improves technique, and synthetic method is as shown in method four：
Method four：
Method four reduces the polarity of compound by introducing intermediate 17, removes disubstituted by-product using crystallization mode,
Although can remove disubstituted by-product, due to introducing, removing protecting group, reaction step is increased, production efficiency is reduced.
Chinese patent CN201110205473.1, also improves technique, and synthetic method is as shown in method five：
Method five：
Method five can also to avoid the generation of disubstituted by-product, but since raw material 18 is expensive, is difficult to obtain, so
Method production cost is higher.
Chinese patent CN201210497200.3 improves its synthesis technology, is closed by introducing new protecting group
At method as shown in method six：
Method six：
Method six reduces the polarity of compound, and then remove by way of crystallization by the protection of Methoxyacetyl
Disubstituted by-product, this method is although reduce reaction step, and that there are starting materials is more expensive, protecting group is larger, is not easy to be deprotected
The disadvantages of base.
In conclusion current synthesis technology is not easy to remove there are disubstituted by-product, reaction step is more, introduces protection
The disadvantages of base, expensive starting materials are not easy to obtain, therefore develop one kind can effectively to remove disubstituted by-product, reaction step few, no
Introducing protecting group, raw material are cheap and easy to get, and the technique that high yield, high-purity prepare Iopromide is of great significance.
Summary of the invention
Technical purpose：The present invention prepares Iopromide using new synthetic method and new intermediate.
Technological means：The present invention relates to the preparation methods of Iopromide, provide three new methods for preparing Iopromide：
Method one：It is starting material with formula II, reacts to obtain formula III with allylamine, formula III reacts to obtain formula IV with N- methyl allyl amine,
Formula IV reacts to obtain formula V with methoxyacetyl chloride, and formula V obtains Iopromide formula I through peroxidating；Method two：It is with formula II
Beginning raw material reacts to obtain formula III with allylamine, and formula III reacts to obtain formula IV -1, formula IV -1 and N- methyl alkene with methoxyacetyl chloride
Propylamine reacts to obtain formula V, and formula V obtains Iopromide formula I through peroxidating；Method three：It is starting material with formula II, with allylamine
Reaction obtains formula III, and formula III reacts to obtain formula IV -1 with methoxyacetyl chloride, and formula IV -1 is reacted with 3- methylamino -1,2-PD
Formula V -1 is obtained, formula V -1 obtains Iopromide formula I through peroxidating.Method four：It is starting material with formula II, with methoxyl group acetyl
Chlorine reacts to obtain formula III -1, and formula III -1 reacts to obtain formula IV -1 with allyl amine, and formula IV -1 is reacted with N- methacrylic amine
To formula V, formula V obtains Iopromide formula I through peroxidating.
Four methods use 5- amino -3- allyl amino formoxyl -2,4,6- triiodo chlorobenzoyl chloride（Formula III）, 5- ammonia
Base-N- methyl-N, N '-diallyl -2,4,6- triiodo isophtalamide (formula IV), 5- methoxyacetyl Amino-N-methyl-N,
N '-diallyl -2,4,6- triiodo isophtalamide (formula V), 5- methoxyacetyl amino -3- allyl amino formoxyl -2,
4,6- triiodo chlorobenzoyl chloride (formula IV -1) and 5- methoxyacetyl amino -2,4,6- triiodo M-phthalic acid [(allyl amino) -
(2,3- dihydroxy-N- methyl-propyl)] diamides（Formula V -1）As intermediate.
Synthetic method is as follows：
Method one:
Method two:
Method three:
Method four：
Technical effect：By simply crystallizing III intermediate of formula, the preparation in Iopromide can be easily removed
The bismer by-product for causing Iopromide purity to reduce generated in journey, described without other purification step removing
Bismer by-product can finally obtain the Iopromide of high-purity in high yield.
The embodiment of the present invention is merely to illustrate the present invention, without causing to limit to other invention scopes.
Specific embodiment
Embodiment 1：5- amino -3- allyl amino formoxyl -2,4,6- triiodo chlorobenzoyl chloride（Formula III）Synthesis：
Method one：By 5- amino -2,4,6- triiodo M-phthalic acid dichloride (formula II) (100.0g, 0.17mol) is molten
In 500mlTHF, ice salt bath be cooled to 0 DEG C hereinafter, be added dropwise 500mlTHF dissolution allylamine (30.5g, 0.53mol) solution,
Drop finishes, 0 DEG C or less reaction 10h.Reaction is finished, and is filtered, and filtrate is evaporated, and obtains faint yellow white powder, and crude product is beaten with methylene chloride,
It filters, filtrate is evaporated to obtain beige white powder 62.1g, molar yield 60%.
Method two：Using n,N-Dimethylformamide as reaction dissolvent, allylamine（10.96g 0.19mol）, operation is together
On, in room temperature reaction 8h, product yield 61%.
Method two：Using n,N-Dimethylformamide as reaction dissolvent, allylamine（10.96g 0.19mol）, operation is together
On, in room temperature reaction 12h, product yield 63%.
Embodiment 2：5- methoxyl acetamide base -2,4,6- triiodo m-phthaloyl chloride（Formula III -1）Synthesis：
By methoxyacetyl chloride（54.6g 0.50mol）It is dissolved in the dry DMA of 100mL, 10 DEG C of dropwise addition 5- amino of temperature control-
The DMA solution 300mL of 2,4,6- triiodo M-phthalic acid dichloride (formula II) (100.0g, 0.17mol), drop finish, and room temperature is anti-
It answers 24 hours.Reaction is finished, and reaction solution is poured into ice water, there is white solid precipitation immediately, stirs 15min, is filtered, and filter cake is molten
In methylene chloride, successively with saturation NaHCO3Solution, saturation NaCl solution are respectively washed twice, and organic layer is as in refrigerator plus a small amount of
Anhydrous Na2SO4It is dried overnight, desolventizing obtains white solid 101.1g, molar yield 90.2%.
Embodiment:3：The conjunction of 5- Amino-N-methyl-N, N '-diallyl -2,4,6- triiodo isophtalamide (formula IV)
At：
Method one：N- methyl allyl amine (20.76g, 0.29mol) is dissolved in 180mlTHF, is added dropwise to 5- by room temperature
Amino -3- allyl amino formoxyl -2,4,6- triiodo chlorobenzoyl chloride（Formula III）In the 420mlTHF of (60.0g, 0.10mol),
Drop finishes, room temperature reaction.Reaction is finished, and is filtered, and filtrate is evaporated to obtain white powder 62.7g, molar yield 99%.
Method two：Using n,N-Dimethylformamide as reaction dissolvent, operation is same as above, and in room temperature reaction 10h, product is received
Rate 95%.
Method two：Using n,N-Dimethylformamide as reaction dissolvent, operation is same as above, and in room temperature reaction 14h, product is received
Rate 97%.
Embodiment 4：5- methoxyacetyl amino -3- allyl amino formoxyl -2,4,6- triiodo chlorobenzoyl chloride (formula IV -1)
Preparation：
Method one：Methoxyacetyl chloride (31.7g, 0.29mol) is dissolved in 300mlTHF, is added dropwise to 5- by room temperature
Amino -3- allyl amino formoxyl -2,4, in the 300mlTHF of 6- triiodo chlorobenzoyl chloride (formula III) (60.0g, 0.10mol),
Drop finishes, room temperature reaction.Reaction is finished, and evaporated under reduced pressure obtains white powder 65.0g, molar yield 97%.
Method two：Using n,N-Dimethylformamide as reaction dissolvent, operation is same as above, product yield 95%.
Method two：Using n,N-Dimethylformamide as reaction dissolvent, operation is same as above, product yield 97%.
Method four：Using acetonitrile as reaction dissolvent, triethylamine is added（29.0g 0.29mol）, reaction is complete, filters, instead
Liquid evaporated under reduced pressure is answered to obtain product, product yield 96%.
Method five：Using toluene as reaction dissolvent, operate with method four, product yield 93%.
Embodiment 5：5- methoxyacetyl Amino-N-methyl-N, N '-diallyl -2,4,6- triiodo isophtalamide (formula
V) synthesis：
Method one：Methoxyacetyl chloride (30.0g, 0.28mol) is dissolved in 300mlTHF, is added dropwise to 5- by room temperature
Amino-N-methyl-N, N '-diallyl -2,4,6- triiodo isophtalamide (formula IV) (60.0g, 0.09mol)
In 300mlTHF, drop finishes, room temperature reaction 40h or so.Reaction is finished, evaporated under reduced pressure, and methylene chloride 300ml dissolution is added, successively uses
Saturated sodium bicarbonate, water (washing 1 time), saturated salt solution are respectively washed twice, and evaporated under reduced pressure obtains white powder 64.6g, molar yield
97%。
Method two：By 5- methoxyl acetamide base -3- allyl amino formoxyl -2,4,6- triiodo chlorobenzoyl chloride（Formula IV-
1）（30.0g 0.04mol）It is dissolved in 300mLTHF, N- methacrylic amine is added dropwise at room temperature（3.4g, 0.05mol）, it finishes,
It is warming up to 45 DEG C of reactions.End of reaction pours into reaction solution in a large amount of water.It filters, filtrate is extracted with DCM, anhydrous Na2SO4It is dry
It is dry overnight, DCM is boiled off, a light yellow oil is obtained, is beaten with a small amount of anhydrous ether, white solid powder 21.7g can be obtained, mole
Yield is 68.9%.
Embodiment 6：5- methoxyacetyl amino -2,4,6- triiodo M-phthalic acid [(allyl amino)-(2,3- dihydroxy -
N- methyl-propyl)] diamides（Formula V -1）Preparation：
3- methylamino -1,2-PD (18.3g, 0.17mol) is dissolved in 180ml acetonitrile-dioxane by room temperature（v/v=
1:1）In, it is added dropwise to 5- methoxyacetyl amino -3- allyl amino formoxyl -2,4,6- triiodo chlorobenzoyl chloride (formula IV -1)
420ml acetonitrile-the dioxane of (60.0g, 0.09mol)（v/v=1:1）In, drop finishes, room temperature reaction.Reaction is finished, and is filtered, filtrate
It is evaporated, ethyl alcohol mashing filters to obtain white solid 60.0g, molar yield 91%.
Embodiment 7：The preparation of Iopromide (formula I)：
By 5- methoxyacetyl Amino-N-methyl-N, N '-diallyl -2,4,6- triiodo isophtalamide (formula V)
(60.0g, 0.08mol) is dissolved in 900mlAcetone：H20（3：1）In, sequentially add NMO (23.4g, 0.18mol), OsO4
(110ml, 0.003mol, 1%) reacts at room temperature 13h.Reaction is finished, and decompression boils off acetone, and a small amount of water is added into residue, is added appropriate
Sodium thiosulfate stirs 0.5h, by the separation of reaction solution macroporous absorbent resin, purifies to obtain black solid, is returned with methanol activity charcoal
Flow 1h decoloration.Obtain beige white powder 55.8g, molar yield 85%.
Claims (7)
1. a kind of method for preparing Iopromide (formula I), which is characterized in that reaction equation is as follows:
Include the following steps：
Step (a3)：- 2,4,6 triiodo M-phthalic acid dichloride (formula II) of 5- amino reacts to obtain 5- amino-with allylamine
3- allyl amino formoxyl -2,4,6- triiodo chlorobenzoyl chloride (formula III)；
Step (b3)：5- amino -3- allyl amino formoxyl -2,4,6- triiodo chlorobenzoyl chloride (formula III) and methoxyacetyl chloride
Reaction obtains 5- methoxyacetyl amino -3- allyl amino formoxyl -2,4,6- triiodo chlorobenzoyl chloride (formula IV -1)；
Step (c3)：5- methoxyacetyl amino -3- allyl amino formoxyl -2,4,6- triiodo chlorobenzoyl chloride (formula IV -1) and 3-
Methylamino -1,2- propylene glycol react to obtain 5- methoxyacetyl amino -2,4,6- triiodo M-phthalic acid [(allyl amino)-(2,
3- dihydroxy-N- methyl-propyl)] diamides (formula V -1)；
Step (d3)：5- methoxyacetyl amino -2,4,6- triiodo M-phthalic acid [(allyl amino)-(2,3- dihydroxy-N-
Methyl-propyl)] diamides (formula V -1) through peroxidating obtains Iopromide (formula I)；
Wherein, in step (a3), following VI compound of by-product formula of generation is purified by crystallizing to III compound of formula
It removes
2. the method according to claim 1, it is characterised in that：In step (c3), compound and the 1.0-6.0 equivalent of formula IV -1
The reaction of 3- methylamino -1,2- propylene glycol.
3. the method according to claim 1, it is characterised in that：In step (c3), the solvent used is selected from N, N- dimethyl formyl
Amine, DMAC N,N' dimethyl acetamide, tetrahydrofuran, acetone, toluene, N-Methyl pyrrolidone, dioxane, ethyl acetate, dichloro
One of methane, chloroform, acetonitrile, dimethyl sulfoxide are a variety of.
4. the method according to claim 1, it is characterised in that：In step (d3), the oxidant used is selected from osmium tetroxide, starves acid
Potassium, potassium permanganate, hydrogen peroxide, Peracetic acid, metachloroperbenzoic acid, peroxyformic acid, peroxy trifluoroacetic acid, tert-Butanol peroxide,
One of sodium metaperiodate, OXONE, ruthenium trichloride, oxygen are a variety of.
5. the compound of formula III is preparing the application in Iopromide,
6. the compound of formula IV -1 is preparing the application in Iopromide,
7. the compound of formula V -1 is preparing the application in Iopromide,
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| CN114716340B (en) * | 2022-05-10 | 2023-11-14 | 杭州微流汇科技有限公司 | Preparation method of iopromide intermediate |
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| US20100111875A1 (en) * | 2007-04-04 | 2010-05-06 | Veronique Morrison-Iveson | Trisubstituted triazamacrocyclic compounds and their use as contrast agents |
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| CN103570580B (en) * | 2012-08-08 | 2015-04-01 | 北京京卫信康医药科技发展有限公司 | Preparation method of high-purity iopromide |
| CN102964269B (en) * | 2012-11-29 | 2015-01-28 | 浙江海昌药业有限公司 | Novel preparation method of iopromide |
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