CN106366015A - Preparation method and intermediates of iopromide - Google Patents
Preparation method and intermediates of iopromide Download PDFInfo
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Abstract
The present invention relates to a preparation method and intermediates of iopromide. The method specifically comprises: adopting a compound represented by a formula VIII as a starting raw material, and sequentially carrying out an acylation reaction, a further acylation reation, a bislactonization reaction, a reduction reaction, an iodination reaction, a re-acylation reaction and a final hydrolysis reaction to obtain the iopromide represented by a formula I, wherein a compound represented by a formula III and a compound represented by a formula V are introduced as the intermediates so as to avoid the generation of the bismer by-product, the bislactonization of the compound represented by the formula V is complete, the di-lactone ring is not easily subjected to ring opening removing during the iodination reaction process, and the introduced intermediates are easy to separate and purify, such that the high-purity iopromide can be prepared in the high-yield manner.
Description
Technical field
The present invention relates to organic synthesiss and medicinal chemistry art, specifically, the present invention relates to n, double (2,3- bis- hydroxypropyls of n'-
Base) the iodo- 5- of -2,4,6- three [(Methoxyacetyl) amino]-n- methyl isophthalic acid, the Preparation Method And Their Intermediate of 3- benzenedicarboxamide.
Background technology
Iopromide (iopromide) is the nonionic Iodine contrast medium of German Schering Plough company research and development, and chemical name is n, n'-
Double (2,3- dihydroxypropyls) -2,4,6- tri- iodo- 5- [(Methoxyacetyl) amino]-n- methyl isophthalic acids, 3- benzenedicarboxamide, its structure such as formula
Shown, Iopromide is widely used in x- ray-contrast media field.
United States Patent (USP) us4364921 discloses the preparation method of three kinds of Iopromide, and reaction scheme is as follows:
Route one:
Route two:
In above-mentioned route one, during formula 2 preparation of compounds of formula 3 compound, shown in easy production 18 two is acylated secondary
Product (bismer)；
Above-mentioned route two it can be avoided that the generation of two acylated by-product shown in formula 18, but by formula 7 preparation of compounds of formula 8 chemical combination
During thing, the easily not exclusively acetylizad product of four hydroxyls of generation, and be difficult to isolate and purify, thus reducing in the middle of subsequently
Body and the purity of finished product；And during the iodide reaction by formula 9 preparation of compounds of formula 10 compound, Acetyl Protecting Groups are easily
Taken off, thus reducing yield, improving cost, being unfavorable for industrialized production.
Above-mentioned route three equally can avoid the generation of two acylated by-product shown in formula 18, but during iodide reaction, formula
The acetyl group of 13 compounds is equally easily taken off.
The present invention is intended to provide a kind of new preparation method being suitable to industrialized production of Iopromide.
Content of the invention
On the one hand, the invention provides a kind of preparation method of Iopromide is it is characterised in that include:
There is acylation reaction in formula compound and methoxyacetyl chloride, obtain formula compound；There are hydrolysis in formula compound,
Obtain Iopromide；
Wherein, x is carbon or sulfur.
In some embodiments, above-mentioned acylation reaction can be carried out in a solvent, described solvent include but is not limited to oxolane,
Acetonitrile, n, n- dimethyl acetylamide or n, n- dimethylformamide, preferably n, n- dimethyl acetylamide or n, n- dimethyl formyl
Amine, most preferably n, n- dimethyl acetylamide；In some embodiments, above-mentioned acylation reaction can be carried out at 0-50 DEG C, excellent
Select 20-30 DEG C, most preferably 25-30 DEG C；In some embodiments, above-mentioned acylation reaction formula compound and methoxyacetyl chloride
Molar ratio be 1:1.5-3, preferably 1:1.5-2, most preferably 1:2.
In some embodiments, above-mentioned hydrolysis can be carried out in the presence of alkali and solvent, and described solvent includes but do not limit
One or more of Yu Shui, isopropanol, Isosorbide-5-Nitrae-dioxane, acetonitrile, oxolane, methanol or ethanol mixed solvent, preferably
Water or the mixed solvent of water and methanol, most preferably water；Described alkali includes but is not limited to sodium carbonate, potassium carbonate, sodium bicarbonate, hydrogen
Sodium oxide or potassium hydroxide, preferably sodium hydroxide or potassium hydroxide, most preferably sodium hydroxide.In some embodiments, above-mentioned
Hydrolysis can be carried out at 0-50 DEG C, preferably 20-30 DEG C, most preferably 25-30 DEG C.
Another further aspect, the invention provides a kind of formula and formula compound:
Wherein, x is carbon or sulfur.
On the other hand, the invention provides a kind of formula and formula compound purposes in preparation Iopromide.
On the other hand, the invention provides a kind of preparation method of formula compound is it is characterised in that include:
There is reduction reaction in formula compound in the presence of reducing agent, obtain formula compound；Formula compound and iodination reagent
There is iodination reaction, obtain formula compound；
Wherein, x is carbon or sulfur.
In some embodiments, above-mentioned reduction reaction can be carried out in the presence of reducing agent and solvent, described reducing agent include but
Be not limited to raney-ni, pd/c, zinc powder, iron powder, stannum dichloride, sodium sulfide, feooh/ hydrazine hydrate, feooh/ activated carbon/
Hydrazine hydrate, fecl3/ hydrazine hydrate or fecl3/ activated carbon/hydrazine hydrate, preferably pd/c or zinc powder；Described solvent includes but is not limited to n, n-
One or more of dimethylformamide, Isosorbide-5-Nitrae-dioxane, acetonitrile, oxolane, water, methanol or ethanol mixed solvent,
Preferably methanol or oxolane, most preferably methanol；In some embodiments, above-mentioned reduction reaction can be entered under 3-5mpa
OK, preferably 4mpa；In some embodiments, above-mentioned reduction reaction can be carried out at 25-40 DEG C, preferably 25-35 DEG C,
Most preferably 25-30 DEG C；In some embodiments, the inventory of above-mentioned 10% pd/c is the mass fraction of formula compound
4%-10%, preferably 4%-6%, most preferably 5%；In some embodiments, the feeding intake mole of above-mentioned zinc powder and formula compound
Than for 4-10:1, preferably 4-6:1, most preferably 5:1.
In some embodiments, above-mentioned iodination reaction can be carried out in the presence of iodination reagent and solvent, described iodination reagent
Including but not limited to elemental iodine, iodic acid, N-iodosuccinimide or naicl2, preferably naicl2Or iodic acid, most preferably naicl2；
Described solvent includes but is not limited to water, c1-c4Lower alcohol, acetonitrile, oxolane, one of 1,4- dioxane or acetic acid
Or multiple mixed solvent, the preferably mixed solvent of water or water and methanol, most preferably water；In some embodiments, above-mentioned iodate
Reaction can be carried out under catalyst, and described catalyst includes but is not limited to sulphuric acid, phosphoric acid or concentrated hydrochloric acid, preferably concentrated hydrochloric acid；
In some embodiments, above-mentioned iodination reaction can be carried out at 50-85 DEG C, preferably 70-85 DEG C, most preferably 75-80 DEG C；
In some embodiments, above-mentioned iodination reaction formula compound and naicl2Molar ratio be 1:3.1-3.5, preferably
1-1:3.1-3.3, most preferably 1:3.2.
On the other hand, the invention provides a kind of formula and formula compound:
Wherein, x is carbon or sulfur.
On the other hand, the invention provides a kind of formula and formula compound are in formula compound and preparation Iopromide
Purposes.
In some embodiments, formula compound can occur dilactoneization reaction to prepare by formula compound；
Wherein, x is carbon or sulfur.
In some embodiments, above-mentioned dilactoneization reaction can be carried out in the presence of condensing agent and solvent, described condensing agent bag
Include but be not limited to cdi, triphosgene, thionyl chloride, ethyl chloroformate, preferably cdi, triphosgene or thionyl chloride；Described molten
Agent includes but is not limited to acetonitrile, oxolane, dichloromethane, chloroform or dmf, preferably dmf or chloroform, most preferably dmf；
In some embodiments, above-mentioned dilactoneization reaction can be carried out at 10-50 DEG C, preferably 10-30 DEG C, most preferably 10-20 DEG C；
In some embodiments, above-mentioned dilactone reaction equation compound and the molar ratio of condensing agent are 1:2.5-4, preferably
1:2.5-3.5, most preferably 1:3.
In some embodiments, formula compound is referred to the method disclosed in us4364921 and prepares；Real at some
Apply in scheme, formula compound can also be by for example: formula compound and chlorination reagent generate acyl chlorides through chlorination reaction, then
Acyl chlorides, through acylation reaction, is prepared into formula compound；There is acylation reaction in formula compound, prepare formula chemical combination further
Thing；
r1For methyl or hydrogen.
In some embodiments, r1For methyl, formula compound generates acyl chlorides through formula compound and chlorination reagent reaction,
Then there is acylation reaction in acyl chlorides and 3- methylamino -1,2-PD, is prepared into formula compound；Formula compound again with 3- amino
There is acylation reaction in -1,2-PD, prepare formula compound.In some embodiments, r1For hydrogen, formula compound
Generate acyl chlorides through formula compound and chlorination reagent reaction, then acyl chlorides and 3- amino -1,2-PD occur acylation reaction, system
Standby formula compound；There is acylation reaction with 3- methylamino -1,2-PD in formula compound, prepare formula compound again.
In some embodiments, above-mentioned chlorination reaction can carried out in the presence of chlorination reagent and solvent, described chlorination reagent
Including but not limited to thionyl chloride, oxalyl chloride, Phosphorous chloride., phosphorus pentachloride, phosphorus oxychloride or triphosgene, preferably oxalyl chloride or
Thionyl chloride, most preferably oxalyl chloride；Described solvent includes but is not limited to dichloromethane, oxolane, 1,4- dioxane, acetic acid
Ethyl ester or chloroform, preferably dichloromethane or chloroform, most preferably dichloromethane；In some embodiments, above-mentioned chlorination reaction can
To carry out at 0-40 DEG C, preferably 20-30 DEG C, most preferably 25-30 DEG C.
In some embodiments, the above-mentioned acylation reaction by acyl chlorides formula compound can be carried out in the presence of solvent, institute
State solvent and include but is not limited to dichloromethane, dmf or ethyl acetate, preferably dichloromethane or dmf, most preferably dichloromethane；
In some embodiments, above-mentioned acylation reaction can be carried out at -10-10 DEG C, preferably -5-5 DEG C, most preferably -5-0 DEG C.
In some embodiments, the above-mentioned acylation reaction by formula preparation of compounds of formula compound can be entered in the presence of solvent
OK, described solvent includes but is not limited to oxolane, Isosorbide-5-Nitrae-dioxane, n, n- dimethyl acetylamide or dmf, preferably dmf
Or n, n- dimethyl acetylamide, most preferably dmf；In some embodiments, above-mentioned acylation reaction can be at 60-100 DEG C
Carry out, preferably 65-85 DEG C, most preferably 70-80 DEG C.
On the other hand, the invention provides a kind of preparation method of Iopromide, comprise the steps:
There is dilactoneization reaction in formula compound, prepare formula compound；Formula compound is sent out in the presence of reducing agent
Raw reduction reaction, obtains formula compound；There is iodination reaction with iodination reagent in formula compound, obtain formula compound；Formula
There is acylation reaction in compound and methoxyacetyl chloride, obtain formula compound；There are hydrolysis in formula compound, obtain
Iopromide；
Wherein, x is carbon or sulfur.
In some embodiments, x is carbon；In some embodiments, x is sulfur.
In some embodiments, above-mentioned dilactoneization reaction can be carried out in the presence of condensing agent and solvent, described condensing agent bag
Include but be not limited to cdi, triphosgene, thionyl chloride, ethyl chloroformate, preferably cdi, triphosgene or thionyl chloride；Described molten
Agent includes but is not limited to acetonitrile, oxolane, dichloromethane, chloroform or dmf, preferably dmf or chloroform, most preferably dmf；
In some embodiments, above-mentioned dilactoneization reaction can be carried out at 10-50 DEG C, preferably 10-30 DEG C, most preferably 10-20 DEG C；
In some embodiments, above-mentioned dilactone reaction equation compound and the molar ratio of condensing agent are 1:2.5-4, preferably
1:2.5-3.5, most preferably 1:3.
In some embodiments, above-mentioned reduction reaction can be carried out in the presence of reducing agent and solvent, described reducing agent include but
Be not limited to raney-ni, pd/c, zinc powder, iron powder, stannum dichloride, sodium sulfide, feooh/ hydrazine hydrate, feooh/ activated carbon/
Hydrazine hydrate, fecl3/ hydrazine hydrate or fecl3/ activated carbon/hydrazine hydrate, preferably pd/c or zinc powder；Described solvent includes but is not limited to n, n-
One or more of dimethylformamide, Isosorbide-5-Nitrae-dioxane, acetonitrile, oxolane, water, methanol or ethanol mixed solvent,
Preferably methanol or oxolane, most preferably methanol；In some embodiments, above-mentioned reduction reaction can be entered under 3-5mpa
OK, preferably 4mpa；In some embodiments, above-mentioned reduction reaction can be carried out at 25-40 DEG C, preferably 25-35 DEG C,
Most preferably 25-30 DEG C；In some embodiments, the inventory of above-mentioned 10% pd/c is the mass fraction of formula compound
4%-10%, preferably 4%-6%, most preferably 5%；In some embodiments, the feeding intake mole of above-mentioned zinc powder and formula compound
Than for 4-10:1, preferably 4-6:1, most preferably 5:1.
In some embodiments, above-mentioned iodination reaction can be carried out in the presence of iodination reagent and solvent, described iodination reagent
Including but not limited to elemental iodine, iodic acid, N-iodosuccinimide or naicl2, preferably naicl2Or iodic acid, most preferably naicl2；
Described solvent includes but is not limited to water, c1-c4Lower alcohol, acetonitrile, oxolane, one of 1,4- dioxane or acetic acid
Or multiple mixed solvent, the preferably mixed solvent of water or water and methanol, most preferably water；In some embodiments, above-mentioned iodate
Reaction can be carried out under catalyst, and described catalyst includes but is not limited to sulphuric acid, phosphoric acid or concentrated hydrochloric acid, preferably concentrated hydrochloric acid；
In some embodiments, above-mentioned iodination reaction can be carried out at 50-85 DEG C, preferably 70-85 DEG C, most preferably 75-80 DEG C；
In some embodiments, above-mentioned iodination reaction formula compound and naicl2Molar ratio be 1:3.1-3.5, preferably
1-1:3.1-3.3, most preferably 1:3.2.
In some embodiments, above-mentioned acylation reaction can be carried out in a solvent, described solvent include but is not limited to oxolane,
Acetonitrile, n, n- dimethyl acetylamide or n, n- dimethylformamide, preferably n, n- dimethyl acetylamide or n, n- dimethyl formyl
Amine, most preferably n, n- dimethyl acetylamide；In some embodiments, above-mentioned acylation reaction can be carried out at 0-50 DEG C, excellent
Select 20-30 DEG C, most preferably 25-30 DEG C；In some embodiments, above-mentioned acylation reaction formula compound and methoxyacetyl chloride
Molar ratio be 1:1.5-3, preferably 1:1.5-2, most preferably 1:2.
In some embodiments, above-mentioned hydrolysis can be carried out in the presence of alkali and solvent, and described solvent includes but do not limit
One or more of Yu Shui, isopropanol, Isosorbide-5-Nitrae-dioxane, acetonitrile, oxolane, methanol or ethanol mixed solvent, preferably
Water or the mixed solvent of water and methanol, most preferably water；Described alkali includes but is not limited to sodium carbonate, potassium carbonate, sodium bicarbonate, hydrogen
Sodium oxide or potassium hydroxide, preferably sodium hydroxide or potassium hydroxide, most preferably sodium hydroxide.In some embodiments, above-mentioned
Hydrolysis can be carried out at 0-50 DEG C, preferably 20-30 DEG C, most preferably 25-30 DEG C.
In some embodiments, the preparation of formula compound can also include further refining, and described purification condition includes
But it is not limited to ethanol or recrystallisation from isopropanol, preferably isopropanol.
In some embodiments, formula compound is referred to the method disclosed in us4364921 and prepares；Real at some
Apply in scheme, formula compound can be by for example: formula compound and chlorination reagent reaction generate acyl chlorides, and then acyl chlorides is through acyl
Change reaction, be prepared into formula compound；There is acylation reaction in formula compound, prepare formula compound further；
r1For methyl or hydrogen.
In some embodiments, r1For methyl, formula compound generates acyl chlorides through formula compound and chlorination reagent reaction,
Then there is acylation reaction in acyl chlorides and 3- methylamino -1,2-PD, is prepared into formula compound；Formula compound again with 3- amino
There is acylation reaction in -1,2-PD, prepare formula compound.In some embodiments, r1For hydrogen, formula compound
Generate acyl chlorides through formula compound and chlorination reagent reaction, then acyl chlorides and 3- amino -1,2-PD occur acylation reaction, system
Standby formula compound；There is acylation reaction with 3- methylamino -1,2-PD in formula compound, prepare formula compound again.
In some embodiments, above-mentioned chlorination reaction can carried out in the presence of chlorination reagent and solvent, described chlorination reagent
Including but not limited to thionyl chloride, oxalyl chloride, Phosphorous chloride., phosphorus pentachloride, phosphorus oxychloride or triphosgene, preferably oxalyl chloride or
Thionyl chloride, most preferably oxalyl chloride；Described solvent includes but is not limited to dichloromethane, oxolane, 1,4- dioxane, acetic acid
Ethyl ester or chloroform, preferably dichloromethane or chloroform, most preferably dichloromethane；In some embodiments, above-mentioned chlorination reaction can
To carry out at 0-40 DEG C, preferably 20-30 DEG C, most preferably 25-30 DEG C.
In some embodiments, the above-mentioned acylation reaction by acyl chlorides formula compound can be carried out in the presence of solvent, institute
State solvent and include but is not limited to dichloromethane, dmf or ethyl acetate, preferably dichloromethane or dmf, most preferably dichloromethane；
In some embodiments, above-mentioned acylation reaction can be carried out at -10-10 DEG C, preferably -5-5 DEG C, most preferably -5-0 DEG C.
In some embodiments, the above-mentioned acylation reaction by formula preparation of compounds of formula compound can be entered in the presence of solvent
OK, described solvent includes but is not limited to oxolane, Isosorbide-5-Nitrae-dioxane, n, n- dimethyl acetylamide or dmf, preferably dmf
Or n, n- dimethyl acetylamide, most preferably dmf；In some embodiments, above-mentioned acylation reaction can be at 60-100 DEG C
Carry out, preferably 65-85 DEG C, most preferably 70-80 DEG C.
Present invention also offers formula -1 compound and -2 compounds；
Present invention also offers formula -1 compound and -2 compounds；
Present invention also offers formula -1 compound and -2 compounds；
Present invention also offers formula -1 compound and formula -2 compound；
Present invention also offers -1 compound；
Present invention also offers formula -1 compound, -2 compounds, -1 compound, -2 compounds, -1 compound,
- 2 compounds, formula -1 compound, formula -2 compound and -1 compound purposes in preparation Iopromide.
In the present invention, unless otherwise stated,
Term " dmf " refers to n, n- dimethylformamide；
Term " cdi " refers to n, n- carbonyl dimidazoles；
Term " room temperature " refers to 25-30 DEG C.
When there is dilactoneization reaction formula compound by formula compound of present invention offer, the response time is shorter, double interior
Esterification completely, without silica gel chromatography column separating purification highly purified formula compound, advantageously reduce cost, carry
High subsequent intermediates purity；When formula compound is through reduction reaction, iodide reaction formula compound, during due to iodide reaction,
Dilactone ring is difficult open loop removing, and formula compound is easily isolated purification, therefore effectively increases reaction yield, and obtains
Highly purified compound, thus improve yield and the purity of subsequent intermediates and end-product；The Iopromide that the present invention provides
Preparation method is extremely applicable to industrialized production.
Specific embodiment
Following examples are further non-limitingly described in detail to technical solution of the present invention.They should not be considered as to this
The restriction of invention scope, and the simply exemplary illustration of the present invention and Typical Representative.Solvent used in the present invention, reagent and former
Material etc. be commercially available chemistry pure or analyze net product.
Embodiment one: 3- ((2,3- dihydroxypropyl) carbamoyl) -5- nitrobenzene methyl (formula -1)
3- methoxycarbonyl group -5- nitrobenzoic acid (formula) (50g, 0.222mol) is added in reaction bulb, plus 400ml dichloromethane
Alkane is dissolved, Deca oxalyl chloride (28.5ml, 0.335mol) under room temperature, continues stirring 1-2 hour, so after completion of dropping
Afterwards reactant liquor is concentrated, with dichloromethane (125ml), concentrated solution is redissolved, reactant liquor is cooled to less than 0 DEG C, Deca 3- ammonia
Base -1,2-PD (48.5g, 0.53mol), whole Deca process maintains 4 hours, stirs 0.5 hour after completion of dropping,
Reactant liquor washes with water, organic layer anhydrous sodium sulfate drying, filters, is concentrated to give 3- ((2,3- dihydroxypropyl) carbamoyl) -5-
Nitrobenzene methyl (formula -1).
ms m/z[esi]:298.1[m+1]+.
Embodiment two: n1,n3- bis--(2,3- dihydroxypropyl)-n1- methyl-5-nitro isophthaloyl amine (formula)
Embodiment one is obtained 3- ((2,3- dihydroxypropyl) carbamoyl) -5- nitrobenzene methyl (formula -1) (29.8g,
0.1mol), 3- methylamino -1,2-PD (15g, 0.14mol) is dissolved in dmf (30ml), 70-80 DEG C of reaction 5h,
Reactant liquor records hplc purity >=95%.
Embodiment three: 3- ((2,3- dihydroxypropyl) methyl-carbamoyl) -5- nitrobenzene methyl (formula -2)
3- methoxycarbonyl group -5- nitrobenzoic acid (formula) (50g, 0.222mol) is added in reaction bulb, plus 400ml dichloromethane
Alkane is dissolved, Deca oxalyl chloride (28.5ml, 0.335mol) under room temperature, continues stirring 1-2 hour, so after completion of dropping
Afterwards reactant liquor is concentrated, with dichloromethane (125ml), concentrated solution is redissolved, reactant liquor is cooled to less than 0 DEG C, Deca 3- first
Amino -1,2-PD (55.7g, 0.53mol), whole Deca process maintains 4 hours, stirs 0.5 hour after completion of dropping
Reaction terminates, and reactant liquor washes with water, organic layer anhydrous sodium sulfate drying, filters, is concentrated to give 3- ((2,3- dihydroxypropyl)
Methyl-carbamoyl) -5- nitrobenzene methyl (formula -2).
Example IV: n1,n3- bis--(2,3- dihydroxypropyl)-n1- methyl-5-nitro isophthaloyl amine (formula)
Embodiment three is obtained 3- ((2,3- dihydroxypropyl) methyl-carbamoyl) -5- nitrobenzene methyl (formula -2) (50g,
0.16mol), 3- amino -1,2-PD (29.1g, 0.32mol) is dissolved in dmf (30ml), and 70-80 DEG C of reaction 6 is little
When, reactant liquor records hplc purity >=95%.
Embodiment five: n1- methyl-5-nitro-n1,n3- bis--((2- oxo -1,3- dioxolanes -4- base) methyl) isophthaloyl amine (formula -1)
The reactant liquor (formula) that embodiment two or example IV are obtained stirs at 10-20 DEG C, is slowly added into cdi (48.6
G, 0.3mol).Finish, stir 15 minutes, then reactant liquor is added drop-wise in dilute hydrochloric acid (500ml) at 0-10 DEG C,
Stirring and crystallizing.Filter, filter cake washes with water, obtains white solid n1- methyl-5-nitro-n1,n3- bis--((2- oxo -1,3- dioxy penta
Ring -4- base) methyl) isophthaloyl amine (formula -1) (57.6g), yield is 85%, hplc purity >=92%.
ms m/z[esi]:424.1[m+1]+.
Embodiment six: n1- methyl-5-nitro-n1,n3- bis--((2- oxo -1,3- dioxolanes -4- base) methyl) isophthaloyl amine (formula -1)
The reactant liquor (formula) that embodiment two or example IV are obtained stirs at 10-20 DEG C, addition triethylamine (40.4g,
0.4mol), then it is slowly added dropwise oxolane (150ml) solution of triphosgene (29.7g, 0.1mol), react 1 hour.
Reactant liquor is slowly added in 500ml frozen water, stirring and crystallizing.Filter, filter cake washes with water 2-3 time, obtains white solid
n1- methyl-5-nitro-n1,n3- bis--((2- oxo-1,3-dioxolanes -4- base) methyl) isophthaloyl amine (formula -1) (30.1g), yield
For 90%, hplc purity >=90%.
ms m/z[esi]:424.1[m+1]+.
Embodiment seven: n1- methyl -5- amino-n1,n3- bis--((2- oxo -1,3- dioxolanes -4- base) methyl) isophthaloyl amine (formula -1)
By n1- methyl-5-nitro-n1,n3- bis--((2- oxo-1,3-dioxolanes -4- base) methyl) isophthaloyl amine (formula -1) (42.3g,
0.1mol) it is dissolved in 1l methanol, in reactant liquor, adds 10% pd/c (2g), react 5-6 hour under room temperature 4mpa.
Then pd/c is filtered to remove, filtrate concentrates, and obtains solid n1- methyl -5- amino-n1,n3- bis--((2- oxo -1,3- dioxolanes
- 4- base) methyl) isophthaloyl amine (formula -1) (38.5g), yield is 98%, hplc purity >=95%.
ms m/z[esi]:393.1[m+1]+.
The iodo- n of embodiment eight: 5- amino -2,4,6- three1- methyl-n1,n3- bis--((2- oxo -1,3- dioxolanes -4- base) methyl) isophthaloyl
Amine (formula -1)
By n1- methyl -5- amino-n1,n3- bis--((2- oxo-1,3-dioxolanes -4- base) methyl) isophthaloyl amine (formula -1) (39.3g,
0.1mol), 393ml water, stir molten clear, the then previously prepared naicl of Deca under 9ml concentrated hydrochloric acid room temperature2(51.9g icl,
18.7g nacl, 200ml water), after completion of dropping, reactant liquor is warming up to 80 DEG C, maintains reaction 3-4 hour.Then plus
Enter sodium sulfite (6.3g, 0.05mol) and reaction is quenched, filter, obtain white solid 5- amino -2,4,6- tri- iodo- n1- methyl-n1,n3-
The crude product of double-((2- oxo-1,3-dioxolanes -4- base) methyl) isophthaloyl amine (formula -1), crude yield is that 85%, hplc is pure
Spend for 96%.
By above-mentioned crude product isopropanol (250ml) recrystallization, obtain white solid 5- amino -2,4,6- tri- iodo- n1- methyl-n1,n3-
The highly finished product (69.4g) of double-((2- oxo-1,3-dioxolanes -4- base) methyl) isophthaloyl amine (formula -1), highly finished product yield is
90%, hplc purity >=98%.
ms m/z[esi]:771.8[m+1]+.
The iodo- 5- of embodiment nine: 2,4,6- tri- (2- methoxyacetyl amino)-n1- methyl-n1,n3- bis--((2- oxo -1,3- dioxolanes -4- base)
Methyl) isophthaloyl amine (formula -1)
By the iodo- n of 5- amino -2,4,6- three1- methyl-n1,n3- bis--((2- oxo -1,3- dioxolanes -4- base) methyl) isophthaloyl amine (formula
- 1) (77.1g, 0.1mol) uses the dmac of 150ml to dissolve, 0-10 DEG C of Deca methoxyacetyl chlorine (21.7g, 0.2mol),
After completion of dropping, it is warmed to room temperature reaction 10 hours.Reactant liquor is poured in 500ml frozen water, crystallize precipitates, filter, filter cake
Wash with water, obtain 2,4,6- tri- iodo- 5- (2- methoxyacetyl amino)-n1- methyl-n1,n3- bis--((2- oxo -1,3- dioxolanes -4- base)
Methyl) isophthaloyl amine (formula -1) (73.3g), yield is 87%, hplc purity >=98%.
ms m/z[esi]:843.8[m+1]+.
Embodiment ten: n, double (2,3- dihydroxypropyl) iodo- 5- of -2,4,6- three [(Methoxyacetyl) the amino]-n- methyl isophthalic acid of n'-, 3- benzene diformazan
Amide (formula)
By iodo- for 2,4,6- tri- 5- (2- methoxyacetyl amino)-n1- methyl-n1,n3- bis--((2- oxo -1,3- dioxolanes -4- base) methyl) is different
Phthalamide (formula -1) (84.3g, 0.1mol) is stirred at room temperature 3 hours together with 5% sodium hydroxide (400ml) that to obtain iodine general
Sieve amine crude product, crude product, through resin column desalination, obtains Iopromide (formula) sterling (63.3g) after spray drying, yield is 80%,
Hplc purity >=99%.
ms m/z[esi]:791.9[m+1]+.1h-nmr(500mhz,dmso-d6): δ=10.07,10.03,9.97,9.90 (4s,
1h)；8.66,8.57,8.52(3t,1h)；4.76-4.74(m,1h)；4.72,4.67(2t,1h)；4.59-4.58(m,1h)；4.54-4.44
(m,1h)；4.00(s,2h)；3.89-3.88(m,1h)；3.69-3.68(m,2h)；3.47(s,3h)；3.44-3.38(m,4h)；
3.23-3.17(m,3h)；2.85-2.83(4s,3h).
Embodiment 11: n1- methyl-5-nitro-n1,n3- bis--((2- oxo -1,3,2- dioxy thia penta ring -4- base) methyl) isophthaloyl amine
(formula -2)
The reactant liquor (formula) that embodiment two or example IV are obtained stirs at 10-20 DEG C, is slowly added into thionyl chloride
(35.7g, 0.3mol), adds continuation reaction 2 hours, then reactant liquor is slowly added in 500ml frozen water, stirring analysis
Brilliant.Filter, filter cake washes with water 2-3 time, obtains white solid n1- methyl-5-nitro-n1,n3- bis--((2- oxo -1,3,2- dioxy
Thia penta ring -4- base) methyl) isophthaloyl amine (formula -2) (39.4g), yield is 85%, hplc purity >=95%.
ms m/z[esi]:464.0[m+1]+.
Embodiment 12: n1- methyl -5- amino-n1,n3- bis--((2- oxo -1,3,2- dioxy thia penta ring -4- base) methyl) isophthaloyl amine
(formula -2)
By n1- methyl-5-nitro-n1,n3- bis--((2- oxo -1,3,2- dioxy thia penta ring -4- ylmethyl) isophthaloyl amine (formula -2)
(46.3g, 0.1mol) uses 500ml methanol to dissolve, and is subsequently adding zinc powder (33g, 0.5mol), stirs 10 minutes, low
The lower Deca ammonium chloride (54g, 1mol) of temperature, drips off and continues reaction 5 hours under rear room temperature.Then it is filtered to remove zinc powder, filtrate
Concentrate and remove methanol, obtain n1- methyl -5- amino-n1,n3- bis--((2- oxo -1,3,2- dioxy thia penta ring -4- base) methyl) isophthaloyl
The aqueous solution of amine (formula -2).
ms m/z[esi]:434.1[m+1]+.
The iodo- n of embodiment 13: 5- amino -2,4,6- three1- methyl-n1,n3- bis--((2- oxo -1,3,2- dioxy thia penta ring -4- base) methyl)
Isophthaloyl amine (formula -2)
The n that embodiment 13 is obtained1- methyl -5- amino-n1,n3- bis--((2- oxo -1,3,2- dioxy thia penta ring -4- base) methyl) is different
Stir molten clear under the aqueous solution of phthalamide (formula -2) (43.3g, 0.1mol), 393ml water, 9ml concentrated hydrochloric acid room temperature,
Then the previously prepared naicl of Deca2(51.9g icl, 18.7g nacl, 200ml water), after completion of dropping, by reactant liquor
It is warming up to 80 DEG C, maintain reaction 3-4 hour.It is subsequently adding sodium sulfite (6.3g, 0.05mol) and reaction is quenched, filter, obtain
To the iodo- n of white solid 5- amino -2,4,6- three1- methyl-n1,n3- bis--((2- oxo -1,3,2- dioxy thia penta ring -4- base) methyl) different phthalein
The crude product of amide (formula -2), crude yield is 78%, hplc purity is 95%.
By above-mentioned crude product isopropanol (250ml) recrystallization, obtain white solid 5- amino -2,4,6- tri- iodo- n1- methyl-n1,n3-
The highly finished product (52.7g) of double-((2- oxo -1,3,2- dioxy thia penta ring -4- base) methyl) isophthaloyl amine (formula -2), highly finished product are received
Rate is 83.3%, hplc purity >=97%.
ms m/z[esi]:811.7[m+1]+.
The iodo- 5- of embodiment 14: 2,4,6- tri- (2- methoxyacetyl amino)-n1- methyl-n1,n3- bis--((2- oxo -1,3,2- dioxy thia penta
Ring -4- base) methyl) isophthaloyl amine (formula -2)
By the iodo- n of 5- amino -2,4,6- three1- methyl-n1,n3- bis--((2- oxo -1,3,2- dioxy thia penta ring -4- base) methyl) isophthaloyl amine
(formula -2) (81.1g, 0.1mol) uses the dmac dissolving of 150ml, and 0-10 DEG C of Deca methoxyacetyl chlorine (21.7g, 0.2
Mol), after completion of dropping, it is warmed to room temperature reaction 10 hours.Reactant liquor is poured in 500ml frozen water, crystallize precipitates, filters,
Filter cake washes with water, obtains 2,4,6- tri- iodo- 5- (2- methoxyacetyl amino)-n1- methyl-n1,n3- bis--((2- oxo -1,3,2- dioxy thia
Penta ring -4- base) methyl) isophthaloyl amine (formula -2) (75g), yield is 85%, hplc purity >=95%.
ms m/z[esi]:883.8[m+1]+.
Embodiment 15: n, double (2,3- dihydroxypropyl) iodo- 5- of -2,4,6- three [(Methoxyacetyl) the amino]-n- methyl isophthalic acid of n'-, 3- benzene two
Methanamide (formula)
By iodo- for 2,4,6- tri- 5- (2- methoxyacetyl amino)-n1- methyl-n1,n3- bis--((2- oxo -1,3,2- dioxy thia penta ring -4- base) first
Base) isophthaloyl amine (formula -2) (88.3g, 0.1mol) is stirred at room temperature together with 5% sodium hydroxide (400ml) 3 hours must
To Iopromide crude product, crude product, through resin column desalination, obtains Iopromide (formula) sterling (59.3g) after spray drying, receives
Rate is 75%, hplc purity >=99%.
ms m/z[esi]:791.9[m+1]+.1h-nmr(500mhz,dmso-d6): δ=10.07,10.03,9.97,9.90 (4s,
1h)；8.66,8.57,8.52(3t,1h)；4.76-4.74(m,1h)；4.72,4.67(2t,1h)；4.59-4.58(m,1h)；4.54-4.44
(m,1h)；4.00(s,2h)；3.89-3.88(m,1h)；3.69-3.68(m,2h)；3.47(s,3h)；3.44-3.38(m,4h)；
3.23-3.17(m,3h)；2.85-2.83(4s,3h).
Claims (34)
1. a kind of preparation method of Iopromide (formula compound) is it is characterised in that through following steps:
Step one: formula compound occurs acylation reaction with methoxyacetyl chloride in the presence of solvent, obtains formula compound；
Step 2: formula compound occurs hydrolysis in the presence of alkali and solvent, obtains Iopromide.
2. preparation method according to claim 1 is it is characterised in that x is carbon or sulfur.
3. preparation method according to claim 1 it is characterised in that the solvent described in step one be oxolane, acetonitrile,
N, n- dimethyl acetylamide or n, n- dimethylformamide, wherein preferred n, n- dimethyl acetylamide or n, n- dimethylformamide,
Most preferably n, n- dimethyl acetylamide.
4. preparation method according to claim 1 is it is characterised in that the throwing of step one Chinese style compound and methoxyacetyl chloride
Material mol ratio is 1:1.5-3, wherein preferred 1:1.5-2, most preferably 1:2.
5. preparation method according to claim 1 is it is characterised in that the alkali described in step 2 is sodium carbonate, potassium carbonate, carbon
Sour hydrogen sodium, sodium hydroxide or potassium hydroxide, wherein preferred sodium hydroxide or potassium hydroxide, most preferably sodium hydroxide.
6. preparation method according to claim 1 it is characterised in that the solvent described in step 2 be water, isopropanol, Isosorbide-5-Nitrae-
One or more of dioxane, acetonitrile, oxolane, methanol or ethanol mixed solvent, wherein preferred water or water and methanol
Mixed solvent, most preferably water.
7. preparation method according to claim 1, also includes the preparation method of formula compound it is characterised in that through following
Step:
Step 3: formula compound occurs reduction reaction in the presence of reducing agent and solvent, obtains formula compound；
Step 4: formula compound occurs iodination reaction in the presence of iodination reagent, catalysts and solvents, obtains formula compound；
Formula compound obtains refined sterling through the further recrystallization of organic solvent.
8. preparation method according to claim 7 is it is characterised in that x is carbon or sulfur.
9. preparation method according to claim 7 it is characterised in that the reducing agent described in step 3 be raney-ni, pd/c,
Zinc powder, iron powder, stannum dichloride, sodium sulfide, feooh/ hydrazine hydrate, feooh/ activated carbon/hydrazine hydrate, fecl3/ hydrazine hydrate or
fecl3/ activated carbon/hydrazine hydrate, wherein preferred pd/c or zinc powder.
10. preparation method according to claim 7, it is characterised in that the reducing agent described in step 3 is 10%pd/c, accounts for
The 4%-10% of formula compound quality fraction, wherein preferably 4%-6%, most preferably 5%.
11. preparation methoies according to claim 7 are it is characterised in that the reducing agent described in step 3 is zinc powder, with formula
Compound molar ratio is 4-10:1, wherein preferred 4-6:1, most preferably 5:1.
12. preparation methoies according to claim 7 it is characterised in that the solvent described in step 3 be n, n- dimethyl formyl
One or more of amine, Isosorbide-5-Nitrae-dioxane, acetonitrile, oxolane, water, methanol or ethanol mixed solvent, wherein preferred first
Alcohol or oxolane, most preferably methanol.
13. preparation methoies according to claim 7 are it is characterised in that the iodination reagent described in step 4 is elemental iodine, iodine
Acid, N-iodosuccinimide or naicl2, wherein preferably naicl2Or iodic acid, most preferably naicl2.
14. preparation methoies according to claim 7 are it is characterised in that the formula compound described in step 4 and iodination reagent
naicl2Molar ratio be 1:3.1-3.5, wherein preferably 1-1:3.1-3.3, most preferably 1:3.2.
15. preparation methoies according to claim 7 it is characterised in that the catalyst described in step 4 be sulphuric acid, phosphoric acid or
Concentrated hydrochloric acid, wherein preferred concentrated hydrochloric acid.
16. preparation methoies according to claim 7 are it is characterised in that the solvent described in step 4 is water, c1-c4Rudimentary
Alcohol, acetonitrile, oxolane, Isosorbide-5-Nitrae-one or more of dioxane or acetic acid mixed solvent, wherein preferred water or water and methanol
Mixed solvent, most preferably water.
17. preparation methoies according to claim 7 are it is characterised in that the purification condition described in step 4 is ethanol or isopropyl
Alcohol recrystallization, wherein preferred isopropanol.
18. preparation methoies according to claim 7, also include the preparation method of formula compound it is characterised in that through with
Lower step:
Step 5: formula compound occurs dilactoneization to react in the presence of condensing agent and solvent, obtains formula compound.
19. preparation methoies according to claim 18 are it is characterised in that x is carbon or sulfur.
20. preparation methoies according to claim 18 it is characterised in that the condensing agent described in step 5 be cdi, triphosgene,
Thionyl chloride or ethyl chloroformate, wherein preferred cdi, triphosgene or thionyl chloride.
21. preparation methoies according to claim 18 are it is characterised in that the formula compound described in step 5 and condensing agent
Molar ratio is 1:2.5-4, preferably 1:2.5-3.5, most preferably 1:3.
22. preparation methoies according to claim 18 it is characterised in that the solvent described in step 5 be acetonitrile, oxolane,
Dichloromethane, chloroform or dmf, wherein preferred dmf or chloroform, most preferably dmf.
23. preparation methoies according to claim 18, also include the preparation method of formula compound it is characterised in that through with
Lower step:
Step 6: formula compound and chlorination reagent occur chlorination reaction to generate acyl chlorides, then further by acyl in the presence of solvent
There is acylation reaction in chlorine, obtain formula compound in the presence of solvent；
Step 7: formula compound occurs acylation reaction in the presence of solvent further, obtains formula compound.
24. preparation methoies according to claim 23 are it is characterised in that r1For h or methyl.
25. preparation methoies according to claim 23 it is characterised in that the chlorination reagent described in step 6 be thionyl chloride,
Oxalyl chloride, Phosphorous chloride., phosphorus pentachloride, phosphorus oxychloride or triphosgene, wherein preferred oxalyl chloride or thionyl chloride, most preferably grass
Acyl chlorides.
26. preparation methoies according to claim 23 are it is characterised in that the solvent in the chlorination reaction described in step 6 is two
Chloromethanes, oxolane, Isosorbide-5-Nitrae-dioxane, ethyl acetate or chloroform, wherein preferred dichloromethane or chloroform, most preferably dichloro
Methane.
27. preparation methoies according to claim 23 are it is characterised in that the solvent in the acylation reaction described in step 6 is two
Chloromethanes, dmf or ethyl acetate, wherein preferred dichloromethane or dmf, most preferably dichloromethane.
28. preparation methoies according to claim 23 are it is characterised in that the solvent in the acylation reaction described in step 7 is four
Hydrogen furan, Isosorbide-5-Nitrae-dioxane, n, n- dimethyl acetylamide or dmf, wherein preferably dmf or n, n- dimethyl acetylamide,
Most preferably dmf.
29. formula compounds:
Wherein x is carbon or sulfur.
30. formula compounds:
Wherein x is carbon or sulfur.
31. formula compounds:
Wherein x is carbon or sulfur.
32. formula compounds:
Wherein x is carbon or sulfur.
33. formula compounds:
Wherein r1For hydrogen.
34. formula compounds, formula compound, formula compound, formula compound and formula compound are in preparation Iopromide
Purposes.
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