RU2173315C2 - Method of preparing ionexol - Google Patents

Method of preparing ionexol

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RU2173315C2
RU2173315C2 RU99106419A RU99106419A RU2173315C2 RU 2173315 C2 RU2173315 C2 RU 2173315C2 RU 99106419 A RU99106419 A RU 99106419A RU 99106419 A RU99106419 A RU 99106419A RU 2173315 C2 RU2173315 C2 RU 2173315C2
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Russia
Prior art keywords
iohexol
solvent
isopropanol
methoxyethanol
reaction
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RU99106419A
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Russian (ru)
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RU99106419A (en
Inventor
Дик МАЛЬТЕ-СЕРЕНССЕН
Одд Эйнар ИНГВОЛЛСТАД
Эспен МЮРБРОТЕН
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Нюкомед Имагинг АС
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Application filed by Нюкомед Имагинг АС filed Critical Нюкомед Имагинг АС
Publication of RU99106419A publication Critical patent/RU99106419A/en
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Abstract

FIELD: chemical industry. SUBSTANCE: described is method of purifying raw iohexol by isolation of iohexol in the form of solid substance from first solvent and washing of solid iohexol with additional solvent to prepare iohexol of higher purity. Said first solvent comprises isopropanol and 2-methoxyethanol in volume ratio from 93:7 to 85:15 and said additional solvent comprises isopropanol. EFFECT: simplified process. 9 cl, 1 tbl _

Description

 The present invention relates to a method for producing iohexol, 5- [N- (2,3-dihydroxypropyl) -acetamido] -N, N'-bis (2,3-dihydroxypropyl) -2,4,6-triiodisophthalamide.
Iohexol is a non-ionic iodinated radiopaque substance that is marketed with great success under the brand name OMNIPAQUE ® .
 The preparation of such non-ionic contrast agents involves the preparation of a chemical drug substance (called primary preparation), followed by the preparation of a finished dosage form (called secondary preparation). Initial preparation usually involves a multi-stage chemical synthesis and a thorough purification step. For a commercial medicinal product, it is important that the initial preparation step is effective and economical.
 The final step for preparing iohexol is an N-alkylation step in which 5-acetamido-N, N'-bis (2,3-dihydroxypropyl) -2,4,6-triiodisophthalamide (hereinafter “5-acetamide") is reacted in a liquid phase with an alkylating agent in order to attach the 2,3-dihydroxypropyl group to the nitrogen of the 5-acetamido group. After this reaction, iohexol is isolated from the reaction mixture. This reaction is described, for example, in Swedish patent 7706792-4, where crude iohexol was obtained by the reaction between 5-acetamide and 1-chloro-2,3-propanediol at ambient temperature in propylene glycol and in the presence of sodium methylate. After repeated additions and evaporations of the propylene glycol solvent and treatment with anion-exchange and cation-exchange resins, the crude product was evaporated to a dry residue and crystallized from a second butanol solvent. Then the product was recrystallized twice from butanol.
 In the N-alkylation step, problems arise due to the possibility of by-products from O-alkylation, and for N-alkylated iodinated radiopaque substances, two (or more) crystallizations are often required in order to remove the O-alkylated by-products. If, as in the case of the synthesis of iohexol, referred to above, the product must be crystallized from the second solvent system, then the reaction solvent must first be removed, for example, by evaporation to a dry residue or extensive azeotropic distillation. However, since it is known from crystallization theory and experience that even small amounts of residual solvents from previous stages can cause the crystallization process to get out of control due to changes in supersaturation conditions, careful removal of the reaction solvent is an important stage. Solvent removal, however, is an energy-intensive operation, which is also associated with the risk of decomposition of the product under prolonged exposure to elevated temperatures.
 Now it was unexpectedly found that 2-methoxyethanol can be used as a solvent both in the 5-acetamide conversion reaction stage and in the subsequent crystallization of the obtained iohexol, thereby eliminating the need for exhaustive removal of the reaction solvent before purification by crystallization of the crude iohexol product, and also reducing the need in multiple recrystallizations.
 Thus, it is an object of the present invention to provide a process for preparing iohexol, which comprises reacting 5-acetamido-N, N-bis (2,3-dihydroxypropyl) -2,4,6-triiodophthalamide with a 2,3-dihydroxypropylating agent in the presence of a solvent ( reaction solvent), wherein said solvent comprises 2-methoxyethanol and optionally isopropanol.
 Another objective of the invention is to develop a method for purifying iohexol, including obtaining a solution of crude iohexol in a first solvent (crystallization solvent), creating conditions for the isolation of iohexol from the specified solvent in solid form, and washing solid iohexol with an additional solvent (washing solvent) to obtain high purity iohexol, wherein said first solvent contains isopropanol and 2-methoxyethanol in a volume ratio of from 93: 7 to 85:15 (preferably from 91: 9 to 87:13 or more dpochtitelno from 90:10 to 88:12), and said further solvent comprises isopropanol.
 In the most preferred embodiment of the method according to the invention, iohexol obtained in the method according to the invention is substantially purified by the method of the invention.
 As described above, the method of preparation and purification according to the invention involves the use of a reaction solvent, a crystallization solvent, and a washing solvent. In all these cases, the solvents may additionally contain cosolvents other than the indicated alcohols. The presence of such additional cosolvents is not preferred, and if present, they preferably comprise a small fraction of the total solvent, for example less than 10% vol., Preferably less than 5% vol., More preferably less than 2% vol. and particularly preferably less than 1% vol. in total. For a crystallization solvent, in particular if methanol and / or water are present as cosolvents, their content is preferably less than 2% vol., More preferably less than 1% vol. and particularly preferably less than 0.5% vol.
 The reaction solvent is preferably 2-methoxyethanol, however, a mixture of 2-methoxyethanol and isopropanol can be used, for example, up to 95% vol. isopropanol, usually up to 90% vol. isopropanol, preferably up to 80% vol., more preferably up to 50% vol. and most preferably less than 10% vol. The isopropanol content should preferably be not so high that iohexol precipitates from the reaction mixture at the reaction temperature.
 In a crystallization solvent or suspension, a lower limit of 2-methoxyethanol is important in order to ensure easy dissolution of the crude iohexol. The upper limit is important in order to cause iohexol to crystallize, rather than form an amorphous solid.
 The method according to the invention is preferably carried out in the presence of a base, usually an organic or inorganic base, which is soluble in the reaction solvent. Inorganic bases such as alkali metal hydroxides, for example sodium hydroxide, are preferred. The base can usually be used in concentrations from 1.0 to 2.0, preferably from 1.0 to 1.5 moles, per mole of 5-acetamide. In the case of using a base, the reaction can be stopped by quenching with acid. Inorganic or organic acids may be used, however, inorganic acids such as HCl are preferred.
 The reaction can be monitored, for example, by means of HPLC, in order to determine the appropriate stage at which the reaction should be quenched. Typically, the reaction takes place before quenching within a few hours, for example from 12 to 48, preferably from 18 to 30.
 The alkylating agent used in the method may be any agent capable of attaching a 2,3-dihydroxypropyl group to the nitrogen of the acetamide group. The most preferred alkylating agents are 1-halide-2,3-propanediols, for example 1-chloro-2,3-propanediol and glycidol.
The method according to the invention is usually carried out at an elevated temperature, for example from 25 to 45 o , preferably from 30 to 40 o and most preferably about 35 o C.
 After completion of the reaction, the iohexol reaction product can be separated from the solvent, for example, by cooling, evaporating the solvent and / or adding a solvent, such as isopropanol, in which iohexol is less soluble. The crude iohexol obtained, optionally after washing with, for example, isopropanol, can then be purified, preferably by recrystallization.
 According to the method of the invention, the original crude iohexol, usually with a purity of less than 97.5% (percent by area HPLC), is first dissolved in a crystallization solvent. In one most preferred embodiment, the solution used may simply be the reaction mixture in which the process of the invention is carried out, optionally after controlling the salt content, where the content of isopropanol / 2-methoxyethanol in the solvent, if necessary, is also controlled, for example, by adding isopropanol to in order to get into the above ratios. If this is done, then only one crystallization of iohexol may be required, which leads to savings in equipment, energy and materials.
The crystallization solvent can then be partially removed, for example, at elevated temperature and / or reduced pressure, the resulting suspension of iohexol is filtered off, and iohexol is washed with a washing solvent, preferably hot isopropanol, before it is dried, preferably at elevated temperature (for example, 50 ° C) and reduced pressure.
 If necessary, one or more additional recrystallizations can be carried out. However, in practice this was not considered necessary, since the first crystallization gives iohexol with a purity of more than 98.5% and, in particular, higher than 99%, which is sufficient for use in secondary cooking. (Iohexol for secondary preparation should preferably contain less than 1%, particularly preferably less than 0.6% (percent by area HPLC) of O-alkylation by-products).
The invention is further illustrated by the following non-limiting examples.
EXAMPLE 1
2-Methoxyethanol (278 ml) and sodium hydroxide (18 g) were charged into a jacketed glass reactor and stirred for 2 hours at 20 ° C. 5-acetamido-N, N'-bis (2,3-dihydroxypropyl) was added to the reactor. ) -2,4,6-triiodisophthalamide (283 g), and the mixture was stirred overnight at 45 o before being allowed to cool to 30 o C. To the solution was added 1-chloro-2,3-propanediol (45 g ), after 90 minutes the temperature rose to 35 ° C, after 2 hours 1-chloro-2,3-propanediol (3 g) was added, and the reaction was allowed to proceed for 24 hours before quenching with concentrated hydrochloric acid (1 ml). The reaction mixture was then analyzed by HPLC (water / acetonitrile, 10 cm column), obtaining the following results:
Iohexol - 97.9%
5-acetamido-N, N'-bis (2,3-dihydroxypropyl) 2,4,6-triiodisophthalamide - 1.03%
O-alkylated substances - 0.56%
Other impurities - 0.56%
EXAMPLE 2
Crude iohexol (75 g) containing 0.16% wt. water, was added to a mixture of 2-methoxyethanol (43 ml) and isopropanol (325 ml) in a 1 liter jacketed reactor equipped with a mechanical stirrer and a refrigerator. The suspension was heated with stirring (400 rpm) with the following temperature gradient:
20 o C for 30 min
20-70 o C for 60 minutes
70 o C for 90 min
70-93 o C for 60 min
After boiling under reflux at 93 ° C, the temperature was kept constant for 20 hours before cooling the mixture in 60 minutes to 75 ° C. The white suspension was then filtered through a hot vacuum suction filter and the crystals were washed on the filter hot isopropanol (5x15 ml) before drying them overnight under reduced pressure at 50 o C.
 HPLC analyzes (water / acetonitrile, 25 cm column) were performed before and after crystallization. The results are shown in table 1 at the end of the description.

Claims (8)

 1. The method of purification of crude iohexol by separating iohexol in the form of a solid from the first solvent and washing solid iohexol with an additional solvent to obtain high purity iohexol, characterized in that said first solvent contains isopropanol and 2-methoxyethanol in a volume ratio of from 93: 7 to 85 : 15 and said additional solvent contains isopropanol.
 2. The method according to claim 1, characterized in that the crude iohexol is obtained by reacting 5-acetamido-N, N'-bis (2,3-dihydroxypropyl) -2,4,6-triiodisophthalamide with a 2,3-dihydroxypropylating agent in 2-methoxyethanol and, optionally, isopropanol as a reaction solvent, and optionally control the salt content and / or the ratio of isopropanol / 2-methoxyethanol.
 3. A method of producing iohexol, comprising reacting 5-acetamido-N, N'-bis (2,3-dihydroxypropyl) -2,4,6-triiodisophthalamide with a 2,3-dihydroxypropylating agent, characterized in that the process is carried out in the presence of a solvent containing 2-methoxyethanol and optionally isopropanol to obtain a crude iohexol solution, followed by purification of the crude iohexol in a solvent containing isopropanol and 2-methoxyethanol in a volume ratio of 93: 7 to 85:15, and the isolation of iohexol as a solid and washing solid ogek ol additional solvent comprising isopropanol to obtain iohexol of improved purity.
 4. The method according to claim 3, characterized in that the reaction solvent is 2-methoxyethanol.
 5. The method according to claim 3, characterized in that said 2,3-dihydroxypropylating agent is 1-halogen-2,3-propanediol or glycidol.
 6. The method according to claim 3, characterized in that said crude iohexol solution is obtained by the initial reaction of formation of iohexol, optionally after controlling the salt content and / or the ratio of isopropanol / 2-methoxyethanol.
 7. A method of producing iohexol, comprising reacting 5-acetamido-N, N'-bis (2,3-dihydroxypropyl) -2,4,6-triiodisophthalamide with a 2,3-dihydroxypropylating agent, characterized in that the process is carried out in 2 -methoxyethanol as a reaction solvent, followed by adjusting the salt content and / or the ratio of isopropanol / 2-methoxyethanol in the reaction product to obtain a solution of crude iohexol and purification of crude iohexol in a solvent containing isopropanol and 2-methoxyethanol in a volume ratio of from 93: 7 to 85 : 15, pu it isolation of iohexol as a solid and washing the solid iohexol with additional solvent consisting of isopropanol, to produce iohexol of improved purity.
 8. The method according to claim 7, characterized in that said 2,3-dihydroxypropylating agent is 1-halogen-2,3-propanediol or glycidol.
RU99106419A 1996-08-29 1997-08-29 Method of preparing ionexol RU2173315C2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
GB9618056.7 1996-08-29

Publications (2)

Publication Number Publication Date
RU99106419A RU99106419A (en) 2001-01-20
RU2173315C2 true RU2173315C2 (en) 2001-09-10

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