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Iopamidol is a radiographic contrast agent.
Synonyms: B-15000; SQ-13396; Niopam
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CAS No. : | 60166-93-0 |
Formula : | C17H22I3N3O8 |
M.W : | 777.09 |
SMILES Code : | O=C(C1=C(I)C(NC([C@@H](O)C)=O)=C(I)C(C(NC(CO)CO)=O)=C1I)NC(CO)CO |
Synonyms : |
B-15000; SQ-13396; Niopam
|
MDL No. : | MFCD00867931 |
InChI Key : | XQZXYNRDCRIARQ-LURJTMIESA-N |
Pubchem ID : | 65492 |
GHS Pictogram: | ![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P280-P301+P312-P302+P352-P305+P351+P338 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With Amberlite IRA400; In water; for 32h;pH 6 - 7;Product distribution / selectivity; | Exam ple 1 : Preparation of ( 5) via Smiles rearrangement in the presence of an anion exchanger solid phase, in an aqueous medium (general procedure).A solution havi ng a pH of 6-7 of the compound (4) in an appropriate aqueous solvent was loaded into a column packed with an anion exchanger solid phase, and eluted through the column at a constant flow. At intervals of 6 and 24 hours, the elution was stopped and the thus eluted solution, which showed a pH from about 9 to about 11, was partially evaporated and diluted with the aqueous reaction solvent, setting the pH to its initial value, by addition of a base. The reaction was continuously monitored, and the HPLC analysis showed a progressive decrease of the compound (4) in favour of (5).Example 3: preparation of iopamidol, from (4a) prepared in accordance with the procedure of Example 2.The compound of formula (4a), obtained with the procedure of Example 2, was su bjected to a Smiles rearrangement, according to the general procedure of the Example 1.The final product was crystallized from ethanol to give the title compound with a yield of 95%.Overall yield from (2) (Example 2 + Example 3) = 82%, HPLC 99.9%, [D]20 436 = + 144.3 (c 2.5 Cu (II) L2, H20) = 99.5% over the theoretical value of 145. |
95% | With Amberlite IRA400; In water; for 32h; | The general procedure of the Example 1 was repeated, using the compound of formula (4a) (7.5 g, 9.6 mmol) in H2O (150 mL) in the presence of Amberlite IRA-400, being this latter packed into a column. The elution time was 32 hours at a constant flow rate of 600 mL/hour. The HPLC analysis of the reaction showed that the concentration of (4a) decreases over the time in favour of iopamidol (93% yield, ee>99%) substantially without the concomitant formation of undesired by-products. The compound of formula (4a), obtained with the procedure of Example 2, was subjected to a Smiles rearrangement, according to the general procedure of the Example 1. [0071] The final product was crystallized from ethanol to give the title compound with a yield of 95%. [0072] Overall yield from (2) (Example 2+Example 3)=82%, HPLC 99.9%, [?]20436=+144.3 (c 2.5 Cu (II) L2, H2O)=99.5% over the theoretical value of 145. |
With potassium hydroxide; In methanol; water; | EXAMPLE 3 Preparation of IOPAMIDOL starting from (S)-5-(2-amino-1-methyl-2-oxoethoxy)-N,N'-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-2,4,6-triiodo-1,3-benzenedicarboxamide STR16 To 10.1 g of (S)-5-(2-amino-1-methyl-2-oxoethoxy)-N,N'-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-2,4,6-triiodo-1,3-benzenedicarboxamide (prepared according to the procedure described in EXAMPLE 2) (0.013 mol) dissolved in 50 mL of MeOH, and maintained under reflux, are swiftly added 56 mL of KOH 1N in MeOH (0.056 mol) then the mixture is refluxed for 2 h. After cooling to room temperature, MeOH is removed by vacuum distillation. The solid residue is diluted in water (100 mL) and percolated on cation exchange resin Amberlite IR 120 and anion exchange resin Duolite A 30B eluted with water. After evaporation of the aqueous solution the residue is crystallized from EtOH (35 mL) to give 8.9 g of the desired product (0.0114 mol). Yield: 88%. Sample purity: 99.8%. [alpha]43620 =+137.00 (c=1.25% w/v as Cu(II) complex), optical purity 96% ?literature [alpha]43620 =+142.28+-0.13! 1 H-NMR, 13 C-NMR, IR and MS spectra are consistent with the structure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In ISOPROPYLAMIDE; at 8 - 20℃; for 10h; | 680 g of S-(-)-5-((2-acetyloxy)-1-oxopropyl)amino)-2,4,6-triiodo-1,3-benzendicarboxylic acid dichloride (prepared as described in WO 96/37460) are dissolved in 1360 g of dimethylacetamide at room temperature and after cooling at 15C [Solution A ]. 181 g of 2-ammino-1,3-propanediol purified with the method described in the previous Example 1 are dissolved in 1360 g of dimethylacetamide and added to the solution A in one hour at 8-15C whilst stirring. The reaction is completed after ten hours at room temperature. The reaction mixture is concentrated at 100C at 10 mbar until 98% of the solvent is distilled. 1700 g of water are added to the residue and the solution is purified using the method described in WO 97/30735.Yield on dry Iopamidol: 94% Contents of by-products determined with HPLC method (according to the method described in USP XXIII-NF, 1996, Vsuppl.) = 0.11% The by-product N-[2-hydroxy-1-(hydroxymethyl)ethyl]-- N'-(2,3-dihydroxypropyl)-5-(2-hydroxy-1-oxopropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide, coming from isoserinol, is under the detection limit. No presence of other by-products derived from 3-amino-1,2-propanediol are detected (see as ref. Pharmeuropa, 6, 343-345, 19949. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | EXAMPLE 6 Preparation of (S)-N,N'-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[(2-hydroxy-1-oxopropyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide (I) (S)-N,N'-Bis[2-acetyloxy-1-[(acetyloxy)methyl]ethyl]-5-[(2-acetyloxy-1-oxopropyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide (4.9 g, 5 mmol) prepared in Example 4 is admixed with deionized water (30 mL) and methanol (30 mL). The suspension is warmed to 50 C., then 2M NaOH (12.8 mL) is dripped therein over a period of 4 hours, keeping the pH of the mixture in the range of from 0 to 11. The solution is purified on ion exchange resins columns and the neutral elude thus obtained is concentrated under vacuum and the residue is crystallized from ethanol to give the compound of the title (2.8 g, 3.6 mmol) Yield: 72%. The 1H-NMR, 13C-NMR, IR and MS are consistent with the indicated structure. | |
EXAMPLE 3 Preparation of Iopamidol A solution of 58 kg of pentaacetyliopamidol in 400 L of methanol containing a catalytic amount, 400 g, of aqueous hydrochloric acid was heated at reflux for about 30 hours. The methanol was removed by distillation and the residue dissolved in water. The acid was neutralized by stirring the solution with an acid-scavenging resin (IRA-68). The resin was removed by filtration and the resulting aqueous solution was passed through a 50 kg column of amberlite XAD-16 resin. The eluant was concentrated to provide an oil and the residue crystallized by heating the oil in a mixture comprising 40 kg of acetonitrile and 150 L of ethanol, followed by cooling. The iopamidol was collected by filtration, washed with ethanol and dried (yield: 34 kg, 74%). Specific Rotation [alpha]D20=-5.0 in methanol. 1H NMR (300 MHz, D2O) 6 1.6(d, 3H), 3.8 (d,8H), 4.2(m, 2H), 4.5(q, 1H). 13C NMR (75 MHz, D2O) delta 21.5, 55.1, 61.8, 70.2, 91.0, 99.8, 144.2, 151.2, 173.8, 178.6. | ||
Example 9 Charcoal (8 Kg) was added to an aqueous solution (2500 1) containing Iopamidol (about 290 Kg). After stirring for 30 minutes and filtration of the charcoal, the resultant solution was concentrated under vacuum up to a final concentration of 70-75% (w/w). The concentrated solution was heated to 85 C. and, while keeping the temperature between 80 C. and 85 C., sec.butanol (1300 Kg) was added. At the end of the addition, the resultant suspension was kept at 80-85 C. for 30 minutes and then cooled to 25 C. After stirring at 25 C. for 2 hours and filtration, the solid residue was washed with sec-butanol (190 Kg) and dried at 50-55 C. under vacuum. Pure Iopamidol (275 Kg) was obtained. |
EXAMPLE 1 Crude, crystalline and desalinated Iopamidol (30 g), resulting from the normal production process, was dissolved in water (30 ml) and concentrated to a volume of 17.5 ml. After heating to 75-80C, 1-propanol (212 ml), previously heated to 75-80C, was added and the mixture refluxed for 30 minutes, during which crystallisation occurred. A mixture of propanol/water (12 ml) was removed by azeotropic distillation at atmospheric pressure, with the concentration of water in the final mixture being 3.3%. After reflux for 30 minutes, cooling to room temperature and stirring for 3 hours, the product was filtered and dried at 60C. The yield of Iopamidol was 29.4 g. | ||
EXAMPLE 2 Crude, crystalline and desalinated Iopamidol (30 g) was dissolved in water (30 ml) and concentrated to a volume of 17.5 ml. After heating to 75-80C, 2-propanol (230 ml), previously heated to 75-80C, was added and the mixture refluxed for 30 minutes, during which crystallisation occurred. A mixture of propanol/water (30 ml) was removed by azeotropic distillation at atmospheric pressure, with the concentration of water in the final mixture being 3.8%. After reflux for 30 minutes, cooling to room temperature and stirring for 3 hours, the product was filtered and dried at 60C. The yield of Iopamidol was 29.5 g. | ||
EXAMPLE 5 Crude, crystalline and desalinated Iopamidol (5 g) was dissolved in water (5 ml). After heating to 68-72C, 2-propanol (40 ml), previously heated to 68-72C, was added and the mixture refluxed for 60 minutes, with crystallisation occurring after a 30 minute period. After cooling to 0-5C and stirring for 30 minutes, the product was filtered, washed with 5 ml of 2-propanol and dried at 60C. The yield of Iopamidol was 4.1 g. | ||
EXAMPLE 8 Crude, crystalline and desalinated Iopamidol (30 g) was dissolved in water (30 ml) and concentrated to a volume of 20 ml. After heating to 75-80C, 2-propanol (270 ml), previously heated to 75-80C, was added and the mixture refluxed for 30 minutes, during which crystallisation occurred. A mixture of propanol/water (90 ml) was removed by azeotropic distillation at atmospheric pressure, the concentration of water in the final mixture being 5.0%. After reflux for 30 minutes, cooling to room temperature and stirring for 3 hours, the product was filtered and dried at 60C. The yield of Iopamidol was 29.6 g. | ||
b iopamidol The 5-amino-N,N'-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-2,4,6-triiodo-1,3-benzenedicarboxamide intermediate product obtained by following the procedure of step a) above (21 g, 29.8 mmol) is added to N,N-dimethylacetamide (0.2 L) and anhydrous HCl (0.33 g; 9 mmol) is bubbled therein. The solution is then cooled to 15 C. and (S)-2-(acetyloxy)propanoyl chloride (31.4 g, 208 mmol) is then dripped therein in two hours. The mixture is stirred for 48 hours at 23 C., the solvent is partially evaporated and the residue is taken up with deionized water (0.2 L). The solution is warmed to the temperature of 55 C. and kept at this temperature for 2 hours, to hydrolyse the obtained oxazolidine compounds having the structure indicated below. After cooling to 40 C., 2M NaOH is added until the pH of the mixture reaches 10.5 and this pH value is maintained up to the complete hydrolysis of the acetic group. The reaction mixture cooled to 25 C., is then loaded into a system of ion exchange resin columns, cationic and anionic respectively. The elude is collected, and concentrated to a residue which is then crystallized from ethanol. The solid is filtered, washed on filter with ethanol and dried at a temperature of 45 C. for 5 hours in an oven yielding the desired iopamidol (17.8 g, 22.9 nmol, yield: 77%). The 1H-NMR, 13C-NMR, IR and MS are consistent with the indicated structure. | ||
EXAMPLE 10 Alternative Preparation of (S)-N,N'-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[(2-hydroxy-1-oxopropyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide (I) (S)-2-(Acetyloxy)propanoyl chloride (16.5 g, 110 mmol) is added, over 20 min, to a stirred solution of N,N'-bis[2-acetyloxy-1-[(acetyloxy)methyl]ethyl]-5-amino-2,4,6-triiodo-1,3-benzenedicarboxamide (53.3 g, 61.1 mmol) in N,N-dimethylacetamide (75 mL) while keeping the temperature of the reaction mixture below 30 C. A further amount of (S)-2-(acetyloxy)propanoyl chloride (0.9 g, 6.0 mmol) is added after 24 and 30 hours and the reaction mixture is stirred at the same temperature for additional 15 hours. 5M NaOH (90 mL, 450 mmol) is dripped over a period of 2 hours into the reaction mixture vigorously stirred at 45 C. After two hours the mixture is concentrated under vacuum and reintegrated with additional N,N-dimethylacetamide (200 mL). After two hours at room temperature the resulting suspension is filtered and the solid washed with N,N-dimethylacetamide (2*20 mL). The mother liquors, combined with the washings, are concentrated to an oily residue, which is diluted with water (200 mL) and nanofiltered. The retentate is loaded onto an Amberlite XAD-16.00 resin column (160 mL) that is eluted with water. The elude is concentrated and loaded onto two ion exchange resin columns (Dowex C350 15 mL, Relite MG1 10 mL). The elude is concentrated and the solid residue is crystallized from ethanol to afford Iopamidol (41.2 g, 53 mmol). Yield: 87% | ||
EXAMPLE 9 Alternative Preparation of (S)-N,N'-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[(2-hydroxy-1-oxopropyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide (I) (S)-2-(Acetyloxy)propanoyl chloride (16.5 g, 110 mmol) is added, over a period of 20 min, to a stirred solution of N,N'-bis[2-acetyloxy-1-[(acetyloxy)methyl]ethyl]-5-amino-2,4,6-triiodo-1,3-benzenedicarboxamide (53.3 g, 61.1 mmol) in N,N-dimethylacetamide (75 mL) while keeping the temperature of the reaction mixture below 30 C. An additional amount of (S)-2-(acetyloxy)propanoyl chloride (0.9 g, 6.0 mmol) is added after 24 and 30 hours and the reaction mixture is stirred at the same temperature for further 15 hours. The reaction mixture is then concentrated to half volume and diluted with a 1:1 mixture of water/methanol (360 mL). The resulting suspension is heated to 45 C. and 2M NaOH (225 mL, 450 mmol) is added over 30 min. After 2 h the hydrolysis is complete, the solution is concentrated to half volume, extracted with CH2Cl2 (6*100 mL) and loaded onto two ion exchange resin columns (Dowex C350, H+ form, 200 mL; Relite MG1, OH- form, 160 mL) that are eluted with water. The elude is evaporated and the solid residue (49 g) thus obtained is crystallized from ethanol (450 mL). The recovered solid (40.5 g) is dissolved in H2O (400 mL) and the solution loaded onto an Amberlite XAD-16.00 resin column (160 mL) that is eluted with water. The elude is evaporated and the residue dried to afford Iopamidol (40.0 g, 51.5 mmol) as a white solid. Yield: 84% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With sodium hydroxide; for 0.166667h; | Hydrolysis procedures:a) After cooling of the crude reaction (obtained by mechanical milling of compound (II) and serinol) to room temperature, 30% NaOH (about 1 mL) is added directly in the jar, that is then subjected to 400 rpm for 10 mm. The crude reaction is collected by washing the jar and balls with water. The obtained solution was neutralized with 2 N HCI and the yield and purity of the obtained lopamidolwere determined by HPLC of the crude solution, by use of an external standard.b) After cooling of the crude reaction to room temperature, the jar and balls are washed with water and the solution quantitatively recovered. The collected solution may be then directly added with 30% NaOH up to pH 10, and maintained under stirring overnight. Preferably, the obtained aqueous solution of Acetyllopamidol is first eluted over ion-exchange resins, typically a cationic resin such as Dowex C350, fixing optional serinol and bases in excess, for instance by using a ratio between resin and worked Compound (II) of about 3:1 (w/w), and then added with 30% NaOH up to pH 10 and maintained under stirring for 7 hours. The basic solution is then neutralized with 2N HCI. Yield and purity of the derivedlopamidol are determined by HPLC analysis of the crude solution, by use of an external standard. |
76.4% | With water; sodium hydroxide; at 40℃;pH ~ 11; | Example 6:Preparation of lopamidol; The preparation of lopamidol from the (S)-1-((3,5-bis((1,3-dihydroxypropan-2- yl)carbamoyl)-2,4,6-triiodophenyl)amino)-1-oxopropan-2~yl acetate obtained from the previous examples was carried out following the procedures described in the literature. 18 g (22 mmol) of the compound obtained in example 4, was added to water (36 ml) and allowed to react with sodium hydroxide in aqueous solution (1.4 g in 5 ml of water, 35 mmol) at a temperature of below 40 C maintaining the pH at about 11 until complete reaction. The solution was desalinated and purified using cationic and anionic exchange resins, and the water evaporated under vacuum at a temperature of below 85 C until a thick oil was obtained and from which the product was isolated and further purified by crystallization from ethanol (102 ml) to give, after filtration and drying under vacuum at a temperature of below 80 C, high purity lopamidol ( 3.0 g, 16.8 mmol). Yield: 76.4 %HPLC: Impurity B=0.002% area; Impurity C=0.004% area and lopamidol 99.76% area. USP lopamidol Monograph: Impurity B= 0.0011% w/w; Sum of impurities l+H= 0. 1 % w/w; Any unspecified impurity= 0.029% w/w. JP lopamidol Monograph: Related Substances by HPLC, total impurities 0.0389% w/w. |
76.4% | With water; sodium hydroxide; at 40℃;pH Ca. 11; | The preparation of lopamidol from the (S)-1-((3,5-bis((1,3-dihydroxypropan-2-yl)carbamoyl)-2,4,6-triiodophenyl)amino)-1-oxopropan-2-yl acetate obtained from the previous examples was carried out following the procedures described in the literature. 18 g (22 mmol) of the compound obtained in example 4, was added to water (36 ml) and allowed to react with sodium hydroxide in aqueous solution (1.4 g in 5 ml of water, mmol) at a temperature of below 40 C. maintaining the pH at about 11 until complete reaction. The solution was desalinated and purified using cationic and anionic exchange resins, and the water evaporated under vacuum at a temperature of below 85 C. until a thick oil was obtained and from which the product was isolated and further purified by crystallization from ethanol (102 ml) to give, after filtration and drying under vacuum at a temperature of below 80 C., high purity lopamidol (13.0 g, 16.8 mmol). [0032] Yield: 76.4% [0033] [alpha]43620=-5.11 [0034] HPLC: Impurity B=0.002% area; Impurity C=0.004% area and lopamidol 99.76% area. [0035] USP lopamidol Monograph: Impurity B=0.0011% w/w; Sum of impurities I+H=0.11% w/w; Any unspecified impurity=0.029% w/w. JP lopamidol Monograph: Related Substances by HPLC, total impurities 0.0389% w/w. |
Preparation of iopamidol (IV) starting from isolated compound (II), in the presence of calcium hydroxide. A solution of 2-amino-l,3-propandiol in DMA (610 g, 28% w/w, 1.87 mol) was added to a solution of compound (II) (600 g, 0.845 mol) in DMAC (1510 g) under stirring and over about 45 minutes.Calcium hydroxide (70.0 g, 0.945 mol) was then slowly added to the reaction mixture keeping the temperature below 300C. The mixture was further maintained at about 300C for 10 hours, until the completion of the reaction.The crude reaction mixture was then distilled under vacuum (95C, 10 mbar, 7.5 mmHg) to remove the most of the solvent, up to the obtainment of a viscous residue. The hot residue was then treated with deionised water (1455 g) and the pH was adjusted to 1.7 by addition of hydrochloric acid (33 g, 34% w/w).The resulting solution was eluted through 1500 mL of a strong cationic exchange resin (Dowex C350 by DOW) in the Na+ form, to remove the Ca2+ ions, along with the excess of 2-amino-l,3-propandiol. The eluted solution was afterward treated with a solution of sodium hydroxide (250 g, 30%) and kept at about 35C for 7 hours, in order to hydro lyse the acetic ester. The pH was then adjusted at a value of about 7 by addition of hydrochloric acid and the resulting solution was treated with sodium sulphite (0.25 g), purified on a PS-DVB resin (1300 mL, Amberlite XAD 100 by Rohm and Haas) and then desalted by nano- filtration. The final desalting step was performed by a series of two resin plates comprising 425 mL of a strong cationic exchange resin in the H+ form (Dowex C350) and 500 mL of weak anionic exchange resin (Re lite MG1 by Mitsubishi).The resulting solution was then concentrated under vacuum, obtaining by that a water content of 30% w/w, and the residue was crystallized from 2-butanol (1250 g). The crystallization was completed by adding a suitable aliquot of 2-butanol and by simultaneously distilling off the azeotrope at atmospheric pressure, up to a water content in the suspension close to 3% w/w. After cooling the system at about 25C, the product was filtered and dried under vacuum at about 500C, to obtain iopamidol (591 g, 90.0% of yield, starting from compound (II). The thus obtained iopamidol satisfied the purity specifications as required. | ||
159 g | With water; sodium hydroxide; at 35℃;pH 12; | Example 12: Preparation of lopamidol (II) starting from Compound (IV) and using a boric acid ester Referring to Scheme 3, 5-Amino-A/,A/-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-2,4,6-triiodo-1 ,3- benzenecarboxamide (IV) (200 g; 0.284 mol) in A/,A/-dimethylacetamide (800 g) was heated at 60C obtaining a solution then tri-n-butyl borate (X = OR2, R? = n-Bu) (137.2 g; 0.596 mol) was added. The solution was stirred and heated at 105C for 2 h then A/,A/-dimethylacetamide and n-butanol were distilled under vacuum collecting about 730 g of distillate. More A/,A/-dimethylacetamide (95 g) was added to the reaction mixture and distilled under vacuum. At this point the formation of intermediate (I) was complete (assessed by H-NMR). The residue was cooled to room temperature and, under nitrogen atmosphere, (S)-2-(acetyloxy)propanoyl chloride (85.5 g; 0.568 mol) was slowly added. The mixture was stirred for 18 h at room temperature and under nitrogen atmosphere then water (1.5 kg) was added, deprotecting the hydroxyl groups and obtaining a diluted solution suitable for the chromatographic purification. After 1 h of stirring the solution was loaded onto a column of XAD 1600 (4 L), the resin was washed with water (3 BV) and the eluate containing boric acid, N,N- dimethylacetamide and butanol was loaded onto a column of IRA743 (4.1 L) for DMAC, butanol and boric acid recovery. Acetyl lopamidol was eluted from XAD 1600 with NaOH (0.20 % w/w; 5 BV), concentrated under vacuum to a final volume of 2 L and hydrolyzed in batch with NaOH at pH=12 at 35 C over 20-24 hours. The solution was loaded onto two ion exchange resins (a cationic Amberjet 1200, 0.9 L; an anionic Relite MG1 , 0.8 L). The eluate was concentrated and the solid residue was crystallized from 2-butanol to afford lopamidol (II) (159 g; 0.205 mol) as a white solid. Yield: 72%. The H-NMR, 3C-NMR, IR and MS are consistent with the indicated structure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
992 g | With water; sodium hydroxide; In N,N-dimethyl acetamide;Large scale; | Example 9. Preparation of lopamidol (II) starting from Compound (IV) and using p-tolylboronic acid Referring to Scheme 3, 5-Amino-N,N'-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-2,4,6-triiodo-1 ,3- benzenecarboxamide (V) (1 kg; 1.42 mol) and p-tolylboronic acid (405 g; 2.98 mol) were mixed in N,N- dimethylacetamide (0.75 kg) and methyl isobutyl ketone (MIBK) (3.25 kg). The suspension was stirred and heated at 90-95C, then MIBK/water mixture (2.8 kg) was distilled under vacuum and brought to a water content lower than 0.5%, assessed by Karl Fischer titration, obtaining a clear yellow solution. At this point the formation of intermediate (I) was complete as assessed by 1 H-NMR. The residue was cooled to 30-35C and, under nitrogen atmosphere, (S)-2-(acetyloxy)propanoyl chloride (380 g; 2.52 mol) was slowly added. The mixture was stirred for 18 h at 30-35C and under nitrogen atmosphere, then diluted NaOH solution was added to neutral pH. Another portion of methyl isobutyl ketone (4 kg) was added to the biphasic mixture and p-tolylboronic acid was extracted. The aqueous phase was loaded onto two ion exchange resin columns (a cationic resin, Dowex C350, 2 L; an anionic resin Relite MG1/P, 2.6 L) and the work-up was continued as described in Example 4 to afford lopamidol (II) (992 g; 1.28 mol) as a white solid. Yield 90 % |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
992 g | With water; sodium hydroxide; In N,N-dimethyl acetamide;Large scale; | Example 10: Preparation of lopamidol (II) starting from Compound (IV) and using butylboronic acid Referring to Scheme 3, 5-Amino-N,N'-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-2,4,6-triiodo-1 ,3- benzenecarboxamide (V) (1 kg; 1.42 mol) and butylboronic acid (303.6 g; 2.98 mol) were mixed in N,N-dimethylacetamide (4.0 kg). The suspension was stirred and heated at 90-95C, then DMA/water mixture (2.8 kg) was distilled under vacuum and brought to a water content lower than 0.5%, assessed by Karl Fischer titration, obtaining a clear yellow solution. At this point the formation of intermediate (I) was complete as assessed by 1 H-NMR. The residue was cooled to 25 C and, under nitrogen atmosphere, (S)-2-(acetyloxy)propanoyl chloride (380 g; 2.52 mol) was slowly added. The mixture was stirred for 18 h at RT and under nitrogen atmosphere, then diluted NaOH solution was added to neutral pH. A portion of methyl isobutyl ketone (5 kg) was added to the biphasic mixture and butylboronic acid was extracted. The aqueous phase was loaded onto two ion exchange resin columns (a cationic resin, Dowex C350, 2 L; an anionic resin Relite MG1/P, 2.6 L) and the work-up was continued as described in Example 4 to afford lopamidol (II) (992 g; 1.28 mol) as a white solid. Yield 90 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
992 g | With water; sodium hydroxide; In N,N-dimethyl acetamide;Large scale; | Example 3: Preparation of lopamidol (II) starting from Compound (IV) and using a boronic acid Referring to Scheme 3, 5-Amino-A/,A/-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-2,4,6-triiodo-1 ,3- benzenecarboxamide (V) (1 kg; 1.42 mol) and phenylboronic acid (X = Ph) (360 g; 2.95 mol) were mixed in A/,A/-dimethylacetamide (0.76 kg) and methyl isobutyl ketone (MIBK) (3.24 kg). The suspension was stirred and heated at 90-95C, then MIBK/water mixture (2.8 kg) was distilled under vacuum and brought to a water content lower than 0.5%, assessed by Karl Fischer titration, obtaining a clear yellow solution. At this point the formation of intermediate (I) was complete (assessed by H- NMR). The residue was cooled to 30-35C and, under nitrogen atmosphere, (S)-2- (acetyloxy)propanoyl chloride (380 g; 2.52 mol) was slowly added. The mixture was stirred for 18 h at 30-35C and under nitrogen atmosphere then diluted NaOH solution was added to neutral pH. Another portion of methyl isobutyl ketone (4-5 kg) was added to the biphasic mixture and phenylboronic acid was extracted. The aqueous phase was loaded onto two ion exchange resin columns (a cationic resin, Dowex C350, 2 L; an anionic resin Relite MG1/P, 2.6 L). The columns were eluted with 2 BV of water. The solution obtained was loaded onto Relite 3ASFB column for the hydrolysis: lopamidol (II) was recovered by elution with 2 BV of an aqueous acidic solution (diluted hydrochloric acid), and washed with 3-4 bed volumes of water. The obtained solution was neutralized to pH 7, concentrated by vacuum distillation over 2 hours. The solution was loaded onto a column of Amberlite XAD 1600 (3.6 L) and eluted with 4 BV of highly diluted sodium hydroxide solution. The solution was loaded onto two ion exchange resin columns (cationic Dowex C350, 4.7 L; anionic Relite MG1/P, 2 L). The eluate was concentrated and the solid residue was crystallized from 2-butanol to afford lopamidol (II) (992 g; 1.28 mol) as a white solid. Yield 90 %. PBA was recovered with a yield of 95 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45.6% | With sulfuric acid; In N,N-dimethyl acetamide; at 55℃; for 24h; | Add <strong>[60166-93-0]iopamidol</strong> (Substance II) to 40 mL of anhydrous N,N-dimethylacetamide10.0 g, concentrated sulfuric acid 0.520 g,Then, a hydroxyl protective agent 2,2-dimethoxypropane 6.40 mL was added dropwise with stirring.The reaction temperature was maintained at about 55 C, and the reaction was stopped after stirring for 24 h.Neutralize the reaction solution with a sodium carbonate solution of 3% by mass.Most of the solvent was removed by rotary evaporation to give a pale yellow oil.150 mL of distilled water was added to the oil, stirred at room temperature for 2 h, and then centrifuged to obtain a white solid.It was washed twice with distilled water to remove unreacted raw materials and impurities.The obtained product was dried in a vacuum oven at 50 C to give 8.0 g of crude product.The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1)5 g of white compound III were obtained with a final yield of 45.6%. |
Tags: Iopamidol | B-15000 | Chiral Building Blocks | Iodides | Amines | Aryls | Amides | Alcohols | Fluorinated Building Blocks | Aliphatic Chain Hydrocarbons | Organic Building Blocks | Asymmetric Synthesis | 60166-93-0
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H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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