CN104098484A - Iopamidol preparation method - Google Patents
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Abstract
The invention discloses a preparation method of a chemical drug, and particularly relates to a new method for preparing iopamidol. According to the preparation method, firstly, a compound (II) and (S)-2-(alkoxy) propionyl chloride have an acylation reaction to generate an intermediate product (III), and then, the intermediate product (III) reacts with an iodinated reagent under the action of a catalyst to prepare a compound (IV); then, the compound (IV) and H2NR4 have an amidation reaction to obtain a compound (V) under the alkaline condition; and finally, all acyl groups in the compound (V) are removed under the alkaline condition, and iopamidol (I) is obtained. The iopamidol preparation method has the advantages that the reaction line is novel, the reaction condition is mild, the yield can be effectively improved with the method, the production cost is lower, and the preparation method has a higher industrial application value.
Description
Technical field
The present invention relates to a kind of variation route of preparing iopamidol, be that a kind of amino isophthalic acid derivatives replacing from corresponding 5-starts to prepare iopamidol (i.e. (S)-N, two [2-hydroxyl-1-(methylol) ethyl]-5-[(2-hydroxyl-1-oxopropyls of N'-) amino]-2,4,6-tri-is iodo-1,3-benzenedicarboxamide) variation route.
Background technology
Iopamidol, structural formula is as follows, is a kind of non-ionic water-soluble contrast medium, because amount of iodine is high, thereby makes X ray decay reach radiography video picture object, is applicable to the x-ray imaging that intravascular injection is used.Iopamidol is used for various angiographys clinically, as cerebral angiograpathy, and angiocardiography etc.
The synthetic method of iopamidol has multiple, and prior art mainly adopts following several route:
In route one, US4001323, reported 5-nitro-1; 3-phthalic acid carries out amidate action with (S)-2-(acetoxyl group) propionyl chloride after hydro-reduction, iodo, acidylate; with the amidation of 2-amino-1,3-propanediol, last alkaline hydrolysis obtains iopamidol again.Route is as follows:
The synthetic route of iopamidol is proposed first.But this method easily causes a large amount of wastes of expensive reactant.
Route two, WO2000050385A1 and WO2002044132A1 have reported first by 5-amino-2; 4; 6-tri-iodo-1; 3-phthalic acid and 2-amino-1; ammediol generation amidate action; then after acid anhydrides, ortho ester or aldehyde ketone protection hydroxyl with the condensation of (S)-2-(acetoxyl group) propionyl chloride, then Deprotection obtains iopamidol.
Route three, WO9705097A1 and WO2012007547A1 have reported first by 5-hydroxyl-2,4,6-tri-iodo-1,3-phthalic acid and 2-amino-1, ammediol generation amidate action, react with (R)-2-propanamide derivative, resulting ether intermediate is prepared iopamidol by this rearrangement of David Smail again.
Rearrangement need to be used anionite-exchange resin, advantage: yield is high, and optical purity is high; Shortcoming: be difficult for suitability for industrialized production.
Route four, WO2002044125A1 have reported first by 5-amino-1; 3-phthalic acid methyl esters and 2-amino-1,3-propanediol generation amidate action, then through iodate; with the condensation of (S)-2-(acetoxyl group) propionyl chloride, after Deprotection, obtain iopamidol again.
In synthetic route four; by 5-amino-N; two [2-hydroxyl-1-(methylol) ethyls]-2 of N'-; 4; 6-tri-iodo-1; 3-benzenedicarboxamide reacts this chiral radicals of introducing with (S)-2-(acetoxyl group) propionyl chloride can cause having more on carboxamide groups substituting group the preferential acidylate of reactive hydroxyl, thereby causes a large amount of wastes of expensive chiral reactant.
Summary of the invention
The object of the invention is to find one simple to operate, yield is higher, cost is lower, is suitable for the variation route of the synthetic iopamidol of suitability for industrialized production, synthetic route is as follows:
Comprise the steps:
Step a) in compound (II) by with (S)-2-(alkoxyl group) propionyl chloride generation acylation reaction, prepare compound (III);
R wherein
1, R
2independently selected from carboxyl (COOH), acyl chlorides (COCl), carboxylic acid ester groups (COOR
5), R
3, R
5representative (C1-C4) lower alkyl alkyl;
Step b), by compound (III), under catalyzer exists, adopt iodination reagent to prepare compound (IV); R wherein
1, R
2, R
3as step a) defines;
Step c) under alkaline condition with H
2nR
4there is amidate action to obtain compound (V); R wherein
3as defined above, R
4can be selected from formula A, two groups of formula B:
R wherein
6hydrogen atom, (C1-C4) lower alkyl alkyl or (C1-C4) lower alkoxy; R
7hydrogen atom, (C1-C4) lower alkyl alkyl or (C1-C4) lower alkoxy; And R
8, R
9can be same to each other or different to each other, independently selected from formyl radical, ethanoyl, propionyl, butyryl radicals, pentanoyl, trifluoroacetyl group, tribromo-acetyl base, benzoyl;
Steps d) under alkaline condition, remove all acyl groups in formula (V) and obtain iopamidol (I), work as R
4while being A group, the ring protection of first dissociating under acidic conditions, then under alkaline condition, remove other protecting groups.
(S)-2-(alkoxyl group) propionyl chloride of step described in a) is formula VI
Wherein, R
3representative (C1-C4) lower alkyl alkyl.
The acylation process of step in a) is that compound (II) is dissolved in inertia dipolar aprotic solvent, in 0 ℃-20 ℃, (S)-2-(alkoxyl group) propionyl chloride is added in reactive system gradually, under 20 ℃ of-65 ℃ of temperature of reaction, preferably 25 ℃-50 ℃, abundant reaction 3～24h, concentrated solvent then, resistates is poured in frozen water, separate out, filter to obtain compound (III); Wherein compound (II) is 1:1～5 with the mol ratio of reacting of (S)-2-(alkoxyl group) propionyl chloride, preferably 1:1～3.5.
Wherein said inertia dipolar aprotic solvent is N,N-dimethylacetamide, DMF, 1-Methyl-2-Pyrrolidone, tetrahydrofuran (THF), acetonitrile, hexamethylphosphoramide (HMPA) or its mixture; R in described compound (II)
1, R
2independently selected from carboxyl (COOH), acyl chlorides (COCl), carboxylic acid ester groups (COOR
5), R
3, R
5representative (C1-C4) lower alkyl alkyl.
Step b), under the condition that in, compound (III) exists at catalyzer, react under certain condition and obtain compound (IV) with iodination reagent.Iodination reagent of the present invention adopts: iodine monochloride solution, NaICl
2or KICl
2during solution, add acid reagent to regulate PH to be acid, in 40 ℃-110 ℃ fully reactions.Compound (III) reacts mol ratio with iodination reagent be 1:1～5, preferred 1:1～3.5, and preferably 50 ℃-95 ℃ of described temperature of reaction, the described reaction times is 3-12h, preferably 4-8h.Described solvent can be selected from deionized water, (C1-C4) lower alcohol (methyl alcohol, ethanol, propyl alcohol, Virahol, sec-butyl alcohol, the trimethyl carbinol, ethylene glycol, butyleneglycol etc.), (C1-C6) alkyl oxide (1, and the mixture of described organic solvent and water 4-dioxane etc.).
Iodination reagent of the present invention also can adopt the mixture of iodine and oxygenant, adds acid reagent to regulate PH to be acid, in 40 ℃-110 ℃ fully reactions.The reaction mol ratio of compound (III), iodine, oxygenant is 1:1～5:1～5, preferred 1:1～3.5:1～3.5, and preferably 50 ℃-95 ℃ of described temperature of reaction, the described reaction times is 3-24h.Described oxygenant can be selected from Potassium Persulphate, hydrogen peroxide, potassium periodate, Periodic acid etc., preferred Potassium Persulphate, hydrogen peroxide.Described acid reagent can be selected from acetic acid, hydrochloric acid, sulfuric acid, phosphoric acid.Described catalytic reagent can be selected from BF
3oEt, MeSO
3h, CF
3sO
3h.
Step c) described amidate action is that compound (IV) is dissolved in organic solvent, adds alkali, adds formula H in batches
2nR
4amine, in 10 ℃-60 ℃ fully after reaction, the concentrated crude product that to obtain, then recrystallization obtains compound (V).Of the present invention, compound (IV) and H
2nR
4reaction mol ratio is 1:1～6, preferred 1:1～3, and compound (IV) is 1:1～5 with the mass ratio of solvent.The described reaction times is 1～20h, preferably 5～10h.
Step c) solvent in is lower alcohol, glycol monoalkyl ether, ring-type, straight chain or branched-chain alkyl ether, inertia dipolar aprotic solvent; Described lower alcohol is straight or branched C2-C5 alcohol, preferably selects the trimethyl carbinol and sec-butyl alcohol; Described glycol monoalkyl ether is C3-C7 glycol monomethyl ether, preferably 2-methyl cellosolve, cellosolvo; Described ring-type, straight or branched alkyl oxide are C4-C10 alkyl oxide, preferably Isosorbide-5-Nitrae-dioxane, diglyme and methyl tertiary butyl ether; Described inertia dipolar aprotic solvent can be N, N-N,N-DIMETHYLACETAMIDE, N, dinethylformamide, 1-Methyl-2-Pyrrolidone, tetrahydrofuran (THF), acetonitrile, hexamethylphosphoramide (HMPA), preferred N, N-N,N-DIMETHYLACETAMIDE, DMF, 1-Methyl-2-Pyrrolidone.
Described alkaline reagents can be organic bases or mineral alkali; Wherein organic bases can be triethylamine, pyridine, tripropyl amine, tri-n-butylamine, preferably triethylamine, tri-n-butylamine.Mineral alkali can be alkalimetal oxide, alkali metal hydroxide, preferably Li
2o, Na
2o, K
2o, LiOH, NaOH, KOH.
According to steps d), remove other protecting groups, obtain thus iopamidol.
The solvent of alkaline hydrolysis can be the mixed solvent of water or water and organic solvent, described organic solvent is if C1-C4 straight or branched alkanol or dipolar aprotic organic solvent are (as N, dinethylformamide, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone).
Concrete, the PH of reaction solution passes through to add mineral alkali as NaOH or KOH (conventionally with its aqueous solution form) adjusting PH10～11, in 10 ℃ of-60 ℃ of reactions, and preferred room temperature.The described reaction times is 1～10h, preferably 1～5h.
As mentioned above, as the R of compound (V)
4while being formula A group, the ring protection that must dissociate the hydroxyl in carboxamide groups substituting group before the alkaline hydrolysis of ethanoyl under acidic conditions.Removing ring protection can add the solution of strong inorganic acid example hydrochloric acid or sulfuric acid in the reaction solvent of compound (V); this reaction solvent can be selected from water, water and organic solvent that can be miscible with water if C1-C4 straight or branched alkanol or dipolar aprotic organic solvent are (as N; dinethylformamide, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone) and the mixture of similar solvent.
Useful technique effect of the present invention: the reaction scheme that the present invention proposes is novel, and reaction conditions is gentle, and the production of being undertaken by the present invention, can effectively improve yield, and production cost is lower, has larger industrial applications and is worth.
Embodiment
Below in conjunction with embodiment, the present invention is further elaborated.
Embodiment 1
By 5-amino 1,3-phthalic acid (II) (20g, 0.11mol) is dissolved in the anhydrous N of 50mL, in N'-N,N-DIMETHYLACETAMIDE (DMA) solution, slowly drip (S)-2-(acetoxyl group) propionyl chloride (43.1g, 0.29mol), temperature is controlled at 5 ℃ of left and right.Drip and finish, 50 ℃ of stirring reaction 24h.Be evaporated to 1/3 of volume, residuum is poured in frozen water, has precipitation to generate, and filters, and water rinses, and obtains solid, and 40 ℃ of vacuum-dryings, obtain compound (III) 29.3g.Productive rate 90%,
1h-NMR,
13c-NMR, IR and MS with shown in structure consistent.
Embodiment 2
By 5-amino 1,3-phthalic acid (II) (20g, 0.11mol) is dissolved in the anhydrous N of 50mL, in N'-N,N-DIMETHYLACETAMIDE (DMA) solution, slowly drip (S)-2-(acetoxyl group) propionyl chloride (49.7g, 0.33mol), temperature is controlled at 5 ℃ of left and right.Drip and finish, 50 ℃ of stirring reaction 24h.Be evaporated to 1/3 of volume, residuum is poured in frozen water, has precipitation to generate, and filters, and water rinses, and obtains solid, and 40 ℃ of vacuum-dryings, obtain compound (III) 29.7g.Productive rate 91%,
1h-NMR,
13c-NMR, IR and MS with shown in structure consistent.
Embodiment 3
By the compound (III) of embodiment 1 preparation, [be 5-((2S)-(2-acetoxyl group) propionamido-)-1,3-phthalic acid] (26.55g, 0.09mol), water (600mL) and 2MHCl (30mL) add in 1L reaction flask, mechanical stirring, drips NaICl
2solution (iodine content 35%) (175.2g, 0.30mol), heats 60 ℃ of reaction 3h, 90 ℃ of reaction 1.5h.Filter to obtain solid, use respectively sodium sulfite solution and deionized water wash, then vacuum-drying, obtains compound (IV) 49.6g.Productive rate 82%.
Embodiment 4
By the compound (III) of embodiment 1 preparation, [be 5-((2S)-(2-acetoxyl group) propionamido-)-1,3-phthalic acid] (26.55g, 0.09mol), boron trifluoride diethyl etherate (0.26g), deionized water (600mL) and 2MHCl (30mL) add in 1L reaction flask, mechanical stirring, drips NaICl
2solution (iodine content 35%) (186.5g, 0.30mol), heats 60 ℃ of reaction 3h, 90 ℃ of reaction 1.5h.Filter to obtain solid, use respectively sodium sulfite solution and deionized water wash, then vacuum-drying, obtains compound (IV) 53.3g.Productive rate 88%.
Embodiment 5
By the compound (III) of embodiment 1 preparation, [be 5-((2S)-(2-acetoxyl group) propionamido-)-1,3-phthalic acid] (26.55g, 0.09mol), boron trifluoride diethyl etherate (0.26g), deionized water (600mL) and 2MHCl (30mL) add in 1L reaction flask, mechanical stirring, drips NaICl
2solution (iodine content 35%) (186.5g, 0.30mol), heats 60 ℃ of reaction 2h; 90 ℃ of reaction 4h.Filter to obtain solid, use respectively sodium sulfite solution and deionized water wash, then vacuum-drying, obtains compound (IV) 51.1g.Productive rate 84.4%.
Embodiment 6
By the compound (III) of embodiment 1 preparation, [be 5-((2S)-(2-acetoxyl group) propionamido-)-1,3-phthalic acid] (26.55g, 0.09mol), boron trifluoride diethyl etherate (0.26g), deionized water (600mL) and 2MHCl (30mL) add in 1L reaction flask, mechanical stirring, drips NaICl
2solution (iodine content 35%) (186.5g, 0.30mol), heats 60 ℃ of reaction 4h; 90 ℃ of reaction 2h.Filter to obtain solid, use respectively sodium sulfite solution and deionized water wash, then vacuum-drying, obtains compound (IV) 53.6g.Productive rate 88.5%.
Embodiment 7
By the compound (III) of embodiment 1 preparation, [be 5-((2S)-(2-acetoxyl group) propionamido-)-1,3-phthalic acid] (26.55g, 0.09mol), boron trifluoride diethyl etherate (0.26g), deionized water (600mL) and 2MHCl (30mL) add in 1L reaction flask, mechanical stirring, drips NaICl
2solution (iodine content 35%) (186.5g, 0.30mol), heats 60 ℃ of reaction 4h; 90 ℃ of reaction 1.5h.Filter to obtain solid, use respectively sodium sulfite solution and deionized water wash, then vacuum-drying, obtains compound (IV) 53.4g.Productive rate 88.2%.
Embodiment 8
By the compound (III) of embodiment 1 preparation, [be 5-((2S)-(2-acetoxyl group) propionamido-)-1,3-phthalic acid] (26.55g, 0.09mol), boron trifluoride diethyl etherate (0.26g), deionized water (600mL) and 2MHCl (30mL) add in 1L reaction flask, mechanical stirring, drips NaICl
2solution (iodine content 35%) (186.5g, 0.30mol), heats 60 ℃ of reaction 4h; 90 ℃ of reaction 1.5h.Filter to obtain solid, use respectively sodium sulfite solution and deionized water wash, then vacuum-drying, obtains compound (IV) 51.0g.Productive rate 84.3%.
Embodiment 9
Water (600mL) is added in 1L reaction flask, under mechanical stirring, add iodine (33.0g, 0.13mol), Potassium Iodate (12.8g, 0.06mol), anhydrous sodium sulphate (1.42g, 0.01mol), drip 2M sulfuric acid (25mL), room temperature reaction 1h, heats 60 ℃, and add the compound (III) of embodiment 1 preparation [is 5-((2S)-(2-acetoxyl group) propionamido-)-1 in batches, 3-phthalic acid] (26.55g, 0.09mol), reaction 3h, 90 ℃ of reaction 1.5h.Filter to obtain solid, use respectively sodium sulfite solution and deionized water wash, then vacuum-drying, obtains compound (IV) 53.4g, productive rate 82%.
Embodiment 10
By the compound (III) of embodiment 1 preparation, [be 5-((2S)-(2-acetoxyl group) propionamido-)-1,3-phthalic acid] (26.55g, 0.09mol), water (600mL), 2M sulfuric acid (25mL) adds in 1L reaction flask, under mechanical stirring, add iodine (33.0g, 0.13mol), Potassium Iodate (12.8g, 0.06mol), anhydrous sodium sulphate (1.42g, 0.01mol), drip in three batches 30%H
2o
2the aqueous solution room temperature reaction 1h of (30.6g, 0.27mol), heats 60 ℃, reaction 3h, 90 ℃ of reaction 6h.Filter to obtain solid, use respectively sodium sulfite solution and deionized water wash, then vacuum-drying, obtains compound (IV) 53.4g, productive rate 76%.
Embodiment 11
By 5-amino 1,3-phthalic acid methyl esters (II) (25.00g, 0.12mol) be dissolved in the anhydrous N of 100mL, in N'-N,N-DIMETHYLACETAMIDE (DMA) solution, slowly drip (S)-2-(acetoxyl group) propionyl chloride (46.65g, 0.31mol), temperature is controlled at 5 ℃ of left and right.Drip to finish 25 ℃ of stirring reactions 24 hours.Be evaporated to 1/3 of volume, residuum is poured in frozen water, has precipitation to generate, and filters, and water rinses, and obtains solid, and 40 ℃ of vacuum-dryings, obtain compound III 36.7g.Productive rate 95%,
1h-NMR,
13c-NMR, IR and MS with shown in structure consistent.Gained compound (III), [be 5-((2S)-(2-acetoxyl group) propionamido-)-1,3-benzene dimethyl ester] (28.0g, 0.095mol), deionized water (400ml) and the vitriol oil (5g) add in 1L reaction flask, mechanical stirring drips ICl (solution of 44% iodine chloride in 14.5%HCl) (90.0g, 0.314mol) at 50 ℃, keep thermotonus 6h, be then heated to 90 ℃ of reaction 1.5h.Filter, refining, obtain then vacuum-drying of solid, obtain compound (IV) 53.9g.Productive rate 81%.
Embodiment 12
By 5-amino 1,3-phthalyl chloride (II) (26.0g, 0.12mol) is dissolved in the anhydrous N of 100mL, in N'-N,N-DIMETHYLACETAMIDE (DMA) solution, slowly drip (S)-2-(acetoxyl group) propionyl chloride (53.9g, 0.36mol), temperature is controlled at 5 ℃ of left and right.Drip and finish 25 ℃ of stirring reaction 24h.Be evaporated to 1/3 of volume, residuum is poured in frozen water, has precipitation to generate, and filters, and water rinses, and obtains solid, and 40 ℃ of vacuum-dryings, obtain compound (III) 36.5g.Productive rate 95%,
1h-NMR,
13c-NMR, IR and MS with shown in structure consistent.
Gained compound (III), [be 5-((2S)-(2-acetoxyl group) propionamido-)-1,3-phthalyl chloride] (36.5g, 0.11mol), deionized water (400ml) and the vitriol oil (5.0g) add in 1L reaction flask, mechanical stirring drips ICl (solution of 44% iodine chloride in 14.5%HCl) (94.6g, 0.33mol) at 50 ℃, keep thermotonus 6h, be then heated to 90 ℃ of reaction 1.5h.Filter, refining, obtain then vacuum-drying of solid, obtain compound (IV) [being 5-((2S)-(2-acetoxyl group) propionamido-)-2,4,6-triiodo m-phthaloyl chloride] 64.8g.Productive rate 83%, 215～217 ℃ of fusing points, specific rotation [α]
d 20=-12.3 °,
1h-NMR,
13c-NMR, IR and MS with shown in structure consistent.
Embodiment 13
By compound (IV) [being 5-((2S)-(2-acetoxyl group) propionamido-)-2,4,6-triiodo m-phthalic acid] (20.2g, 0.03mol), SOCl
2(106g, 0.9mol), is heated to after back flow reaction 4h, and excessive SOCl is removed in air distillation
2, obtain yellow solid.Solid is dissolved in ethyl acetate, with saturated solution of sodium bicarbonate, wash, collected organic layer, decolorizing with activated carbon, concentrate and obtain product, it [is 5-((2S)-(2-acetoxyl group) propionamido-)-2,4 that ethyl acetate and sherwood oil recrystallization obtain white solid compound (IV), 6-triiodo m-phthaloyl chloride] 20.4g, yield 96%.
Embodiment 14
By compound (IV), [be 5-((2S)-(2-acetoxyl group) propionamido-)-2, 4, 6-triiodo m-phthaloyl chloride] (21.3g, 0.03mol), DMA (120mL), triethylamine (7.6g, 0.075mol) join in 250mL reaction flask, be heated to 50 ℃, drip 2-amino-1, ammediol (6.8g, 0.075mol) and the mixed solution of 50mLDMA, keep thermotonus 6h, after TLC detection reaction is complete, reclaim under reduced pressure DMA, add methyl alcohol, with activated carbon decolorizing, concentrated, add 100mL water, separate out solid, filter, dry, use Virahol recrystallization, obtain white solid compound (V) 19.2g, productive rate 78%.
Embodiment 15
By compound (V), [(be N, N,-bis-(2-hydroxyl-(methylol)-ethyl)-5-(2S)-(2-acetoxyl group)-propionamido-)-2,4,6-triiodo isophthaloyl amine] (16.4g, 0.02mol), 2mol/L sodium hydroxide solution (30mL) adds in 250mL reaction flask, is heated to 40～50 ℃, reaction 2h, in reaction process, control pH value 11 left and right, question response is complete, except desolventizing, ethanol for crude product (80mL) recrystallization obtains compound (I) 13.13g, productive rate 84.5%.
Embodiment 16
By compound (IV), [be 5-((2S)-(2-acetoxyl group) propionamido-)-2, 4, 6-triiodo m-phthaloyl chloride] (57.4g, 0.081mol), DMA (250mL), triethylamine (37.64g, 0.203mol) join in 500mL reaction flask, be heated to 50 ℃, drip 2, 2-dimethyl-5-amino-1, 3-diox (23.44g, 0.179mol) and the mixed solution of 80mLDMA, keep thermotonus 6h, after TLC detection reaction is complete, reclaim under reduced pressure DMA, add methyl alcohol, with activated carbon decolorizing, concentrated, add 200mL water, separate out solid, filter, dry, use Virahol recrystallization, obtain white solid compound (V) 67.0g, productive rate 92%.
Embodiment 17
By compound (IV), [be 5-((2S)-(2-acetoxyl group) propionamido-)-2, 4, 6-triiodo m-phthaloyl chloride] (57.4g, 0.081mol), DMA (250mL), triethylamine (18.05g, 0.203mol) join in 500mL reaction flask, be heated to 50 ℃, drip 2-methyl-2-ethyl-5-amino-1, 3-diox (25.8g, 0.179mol) and the mixed solution of 80mLDMA, keep thermotonus 6h, after TLC detection reaction is complete, reclaim under reduced pressure DMA, add methyl alcohol, with activated carbon decolorizing, concentrated, add 200mL water, separate out solid, filter, dry, with Virahol (300mL) recrystallization, obtain white solid compound (V) 68.0g, productive rate 90.6%.By compound (V) (68.0g, 0.073mol), 0.2mol/LHCl (30mL), add in 250mL reaction flask with 60mL methyl alcohol, be heated to 40～50 ℃, reaction 2h, then add 2mol/L sodium hydroxide solution 30mL, keep thermotonus 2h, in reaction process, control pH value 11 left and right, question response is complete, except desolventizing, crude product obtains compound (I) 48.4g, productive rate 85% with ethyl alcohol recrystallization.
Embodiment 18
By compound (IV), [be 5-((2S)-(2-acetoxyl group) propionamido-)-2, 4, 6-triiodo m-phthaloyl chloride] (54.65g, 0.081mol), DMA (250mL), triethylamine (18g, 0.179mol) join in 500mL reaction flask, be heated to 50 ℃, drip 2-oxyethyl group-5-amino-1, 3-diox (26.2g, 0.179mol) and the mixed solution of 80mLDMA, keep thermotonus 6h, after TLC detection reaction is complete, reclaim under reduced pressure DMA, add methyl alcohol, with activated carbon decolorizing, concentrated, add 200mL water, separate out solid, filter, dry, use Virahol recrystallization, obtain white solid compound (V) 69.2g, productive rate 91.8%.
By compound (V) (68.0g, 0.073mol), 0.2mol/LHCl (30mL), add in 250mL reaction flask with 60mL methyl alcohol, be heated to 40～50 ℃, reaction 2h, then add 2mol/L sodium hydroxide solution 30mL, keep thermotonus 2h, in reaction process, control pH value 11 left and right, question response is complete, except desolventizing, crude product obtains compound (I) 48.4g, productive rate 85% with ethyl alcohol recrystallization.
Embodiment 19
By compound (IV), [be 5-((2S)-(2-acetoxyl group) propionamido-)-2, 4, 6-triiodo m-phthaloyl chloride] (57.4g, 0.081mol), DMA (250mL), triethylamine (18.05g, 0.179mol) join in 500mL reaction flask, be heated to 50 ℃, drip 2-amino-1, ammediol diethyl ester (31.2g, 0.179mol) and the mixed solution of 80mLDMA, keep thermotonus 6h, after TLC detection reaction is complete, reclaim under reduced pressure DMA, add methyl alcohol, with activated carbon decolorizing, concentrated, add 200mL water, separate out solid, filter, dry, with Virahol (300mL) recrystallization, obtain white solid compound (V) 76.4g, productive rate 95.6%.
By compound (V), [(be N, N,-bis-(2-hydroxyl-(methylol)-ethyl)-5-(2S)-(2-acetoxyl group)-propionamido-)-2,4,6-triiodo isophthaloyl amine] (16.4g, 0.02mol), 4mol/L sodium hydroxide solution (30mL) adds in 250mL reaction flask, is heated to 40～50 ℃, reaction 2h, in reaction process, control pH value 11 left and right, question response is complete, except desolventizing, ethanol for crude product (80mL) recrystallization obtains compound (I) 13.13g, productive rate 84.5%.
Claims (10)
1. a preparation method for iopamidol, wherein the structural formula of iopamidol is as shown in (I);
It is characterized in that, comprise the steps:
A) compound (II) by with (S)-2-(alkoxyl group) propionyl chloride generation acylation reaction, prepare compound (III),
Wherein (S)-2-(alkoxyl group) propionyl chloride is formula VI
R wherein
1, R
2independently selected from carboxyl (COOH), acyl chlorides (COCl), carboxylic acid ester groups (COOR
5), R
3, R
5representative (C1-C4) lower alkyl alkyl;
B), by compound (III), under catalyzer exists, adopt iodination reagent to prepare compound (IV)
R wherein
1, R
2, R
3define in a) consistent with step;
C) under alkaline condition with H
2nR
4there is amidate action to obtain compound (V)
R wherein
3with step b) in define consistent, R
4be selected from formula A, two groups of formula B:
R wherein
6hydrogen atom, (C1-C4) lower alkyl alkyl or (C1-C4) lower alkoxy; R
7hydrogen atom, (C1-C4) lower alkyl alkyl or (C1-C4) lower alkoxy; And R
8, R
9independently selected from formyl radical, ethanoyl, propionyl, butyryl radicals, pentanoyl, trifluoroacetyl group, tribromo-acetyl base, benzoyl;
D), under alkaline condition, the acyl group of removing in compound (V) obtains iopamidol (I); If R
4while being A group, the ring protection of first dissociating under acidic conditions, then under alkaline condition, remove other protecting groups.
2. method according to claim 1, it is characterized in that, the acylation process of wherein said step in a) is that compound (II) is dissolved in inertia dipolar aprotic solvent, under 0 ℃ of-20 ℃ of condition, (S)-2-(alkoxyl group) propionyl chloride added in reactive system gradually, under 20 ℃ of-65 ℃ of temperature of reaction, abundant reaction 3～24h, concentrated solvent then, resistates is poured in frozen water, separate out, filter to obtain compound (III); Wherein compound (II) is 1:1～5 with the mol ratio of reacting of (S)-2-(alkoxyl group) propionyl chloride, and compound (II) is 1:1～5 with the mass ratio of solvent.
3. method according to claim 2, it is characterized in that described inertia dipolar aprotic solvent is N, N-N,N-DIMETHYLACETAMIDE, DMF, 1-Methyl-2-Pyrrolidone, tetrahydrofuran (THF), acetonitrile, hexamethylphosphoramide (HMPA) or its mixture; R in described compound (II)
1, R
2independently selected from carboxyl (COOH), acyl chlorides (COCl), carboxylic acid ester groups (COOR
5), R
3, R
5representative (C1-C4) lower alkyl alkyl.
4. method according to claim 1, is characterized in that described step b) in compound (III) react mol ratio with iodination reagent be 1:1～3.5, add acid reagent to regulate pH to be acid simultaneously, in 50 ℃-95 ℃, fully react 4-8h.
5. method according to claim 1, is characterized in that described step b) iodination reagent adopts iodine monochloride solution, NaICl
2or KICl
2solution, and compound (III) react mol ratio with iodination reagent be 1:1～3.5; Method according to claim 1, it is characterized in that described step b) in iodination reagent be the mixture of iodine and oxygenant, described oxygenant is acid iodide, Periodic acid, iodate, periodate, Potassium Persulphate or hydrogen peroxide, and the reaction mol ratio of compound (III), iodine, oxygenant is 1:1～3.5:1～3.5; Add acid reagent to regulate PH to be acid simultaneously, under 50 ℃ of-95 ℃ of temperature of reaction, fully react 4-8h; Its solvent is the lower alcohol of deionized water, C1-C4 or the alkyl oxide of C1-C6, or the mixture of described organic solvent and water.
6. method according to claim 5, is characterized in that described acid reagent is the mixture of acetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, sulphur trioxide or described acid.
7. method according to claim 1, is characterized in that described catalytic reagent is selected from BF
3oEt, MeSO
3h or F
3cSO
3h.
8. method according to claim 1, is characterized in that described step c) described amidate action is that compound (IV) is dissolved in organic solvent, adds alkali, adds H in batches
2nR
4, under 10 ℃ of-60 ℃ of temperature of reaction, fully react 5～10h, concentrate to obtain crude product, then recrystallization obtains compound (V); Wherein compound (IV) and H
2nR
4reaction mol ratio is 1:2～3; Compound (IV) is 1:1～5 with the mass ratio of solvent.
9. method according to claim 8, is characterized in that described solvent is lower alcohol, glycol monoalkyl ether, ring-type, straight chain or branched-chain alkyl ether, or inertia dipolar aprotic solvent; Described lower alcohol is the trimethyl carbinol or sec-butyl alcohol; Described glycol monoalkyl ether is 2-methyl cellosolve or cellosolvo; Described ring-type, straight or branched alkyl oxide are Isosorbide-5-Nitrae-dioxane, diglyme or methyl tertiary butyl ether; Described inertia dipolar aprotic solvent is N,N-dimethylacetamide, DMF or 1-Methyl-2-Pyrrolidone.
10. method according to claim 1, is characterized in that described step c) in method, add organic bases or mineral alkali to regulate pH to alkalescence; Wherein organic bases is triethylamine or tri-n-butylamine; Mineral alkali is Li
2o, Na
2o, K
2o, LiOH, NaOH or KOH.
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| CN107400062A (en) * | 2017-08-22 | 2017-11-28 | 川金药业有限公司 | A kind of new method for synthesizing Ioxilan |
| CN109293526A (en) * | 2018-10-23 | 2019-02-01 | 湖北天舒药业有限公司 | A kind of synthesis of Iopamidol and its preparation of synthetic intermediate |
| CN114904575A (en) * | 2022-06-28 | 2022-08-16 | 万华化学集团股份有限公司 | Catalyst and preparation method thereof, and preparation method of 3, 6-dialkoxy-2, 7-dimethyl-4-octenedialdehyde |
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