阅读说明：本技术 制备碘美醇的方法 (Method for preparing iomesol ) 是由 伊日·毛利纳克 伊万·赫拉瓦切克 彼得·扎赫拉德尼克 于 2018-04-27 设计创作，主要内容包括：本发明涉及制备碘美醇的5步法,该方法从3-氨基-5-(氨基羰基)苯甲酸铵开始,使用二氯化碘钠(NaICl<Sub>2</Sub>)首先将3-氨基-5-(氨基羰基)苯甲酸铵转化为3-氨基-5-(氨基羰基)-2,4,6-三碘苯甲酸。本发明还涉及纯化碘美醇的方法。(The invention relates to a 5-step process for preparing iomesol, starting from 3-amino-5- (aminocarbonyl) ammonium benzoate, using sodium iodochloride (NaICl) 2 ) The ammonium 3-amino-5- (aminocarbonyl) benzoate is first converted to 3-amino-5- (aminocarbonyl) -2,4, 6-triiodobenzoic acid. The invention also relates to a method for purifying iomesol.)

1. A method for preparing iomesol, which is shown as the following scheme:

[ chemical formula 1]

2. The process according to claim 1, wherein the crude product C-III in step 1 is purified by crystallization at 20 to 100 ℃ in a solvent comprising methanol and/or a mixture of methanol and water (methanol: 1-99 wt%).

3. The process according to claim 1 or 2, wherein C-III in step 2 is chlorinated with thionyl chloride under reflux conditions in a solvent comprising ethyl acetate and/or toluene in the presence or absence of a catalytic amount of N, N-dimethylformamide.

4. The process according to any one of claims 1 to 3, wherein the crude C-IV in step 2 is purified using an anion exchange resin to remove organic impurities, wherein the resin is a polystyrene based resin, a polyacrylate based resin, preferably a styrene-divinylbenzene copolymer based resin.

5. the process of any one of claims 1 to 4, wherein C-IV in step 3 is coupled with malonic acid in the presence of phosphorus trichloride.

6. The method of any one of claims 1 to 4, wherein C-IV in step 3 is coupled with activated malonic acid.

7. The process according to claim 6, wherein as the activated malonic acid, an active ester or mixed anhydride thereof can be used, preferably prepared in situ by adding dicyclohexylcarbodiimide/N-hydroxybenzotriazole and/or dicyclohexylcarbodiimide/hydroxysuccinimide and/or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, HCl/N-hydroxybenzotriazole and/or 1-propanephosphonic acid cyclic anhydride.

8. The process according to any one of claims 5 to 7, wherein the reaction is carried out in freshly distilled tetrahydrofuran or methyltetrahydrofuran.

9. The process of any one of claims 5 to 8, wherein the crude product C-V is purified by stirring in a solvent comprising tetrahydrofuran, methyltetrahydrofuran, diethyl ether, dioxane or a mixture thereof.

10. The method according to any one of claims 5 to 8, wherein the C-V is not dried and used directly in the next step (step 4).

11. The process according to any one of claims 1 to 10, wherein C-V in step 4 is reacted with 3-amino-propane-1, 2-diol in an organic solvent in the presence of a base at 2-25 ℃.

12. The process according to claim 11, wherein the organic solvent is N, N-dimethylformamide in the presence of triethylamine.

13. The process according to claim 11 or 12, wherein the C-VI reaction mixture is stirred with an anion exchange resin suspended in aqueous methanol to separate organic impurities.

14. The process according to claim 13, wherein the anion exchange resin is a polystyrene based resin, a polyacrylate based resin, preferably a styrene-divinylbenzene copolymer based resin.

15. The process according to any one of claims 11 to 14, wherein C-VI is isolated and purified directly by precipitation from the reaction mixture by adding an organic solvent selected from methanol, ethanol, n-propanol, 2-propanol or combinations thereof at pH 5-7.

16. The process of any one of claims 11 to 15, wherein the precipitated C-VI is crystallized from a solvent mixture consisting of water, acetone, and acetic acid.

17. The process according to any one of claims 1 to 16, wherein in step 5C-VI is reacted with an alkylating agent incorporating 2, 3-dihydroxypropyl groups in the presence of 2-methoxyethanol (0-99%) in the presence of an inorganic base in an organic solvent selected from N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methyl-2-pyrrolidone, ethylene glycol, propylene glycol, glycerol, methanol or a combination thereof.

18. The method of claim 17, wherein the alkylating agent that introduces a 2, 3-dihydroxypropyl group is selected from the group consisting of 3-halopropane-1, 2-diol and glycidol.

19. The method of claim 17 or 18, wherein the alkylating agent that introduces a 2, 3-dihydroxypropyl group is a 3-halopropane-1, 2-diol.

20. The process of any one of claims 2, 17 to 19, wherein the alkylating agent incorporating 2, 3-dihydroxypropyl groups is added to the stirred reaction mixture in one or more portions during the reaction.

21. The process of any one of claims 17 to 20, wherein the reaction temperature is from 10 ℃ to 60 ℃.

22. The process according to any one of claims 17 to 21, wherein the inorganic base is selected from alkali metal hydroxides and alkaline earth metal hydroxides.

23. The process of any one of claims 17 to 22, wherein the inorganic base is lithium hydroxide, calcium hydroxide, sodium hydroxide, potassium hydroxide, or a mixture thereof.

24. The process of any one of claims 17 to 23, wherein the reaction to produce iomenol is carried out in the presence of a metal halide in addition to an inorganic base.

25. The method of claim 24, wherein the metal halide is selected from CaCl₂、ZnCl₂、MgCl₂、CaBr₂、ZnBr₂And MgBr₂。

26. A method of making C-III, as shown in the following scheme:

[ chemical formula 2]

wherein the crude product C-III is purified by crystallization in a solvent comprising methanol or a mixture of methanol and water (methanol: 1-99% by weight) at 20 ℃ to 100 ℃.

27. A crystalline C-III methanol solvate having the formula:

[ chemical formula 3]

Characterized by a powder X-ray diffraction pattern having four or more 2 θ ± 0.2 peaks and selected from about 12.2 °, 12.8 °, 15.0 °, 21.1 °, 21.4 °, 22.7 °, 24.6 °, 25.3 °, 27.2 °, 31.0 °, 31.2 °, 33.4 °, and 33.9 °, wherein the measurement of said crystal is made at a temperature of about 293K.

28. A crystalline C-III methanol solvate having the formula:

[ chemical formula 4]

Characterized in that the unit cell parameters at T293K are substantially equal to: 17.000(1) for a, 13.896(1) for b, 12.597(1) for c, 2975.9 for unit cell volume V³And an orthogonal space group Pbca.

29. A method of making C-IV, as shown in the following scheme:

[ chemical formula 5]

Wherein C-III is chlorinated with thionyl chloride in the presence or absence of a catalytic amount of N, N-dimethylformamide in a solvent comprising ethyl acetate and/or toluene under reflux conditions.

30. The process of claim 29, wherein the crude C-IV is purified using an anion exchange resin to remove organic impurities, wherein the resin is a polystyrene based resin, a polyacrylate based resin, preferably a styrene-divinylbenzene copolymer based resin.

31. A method of making C-V, as shown in the following scheme:

[ chemical formula 6]

Wherein C-IV is coupled to malonic acid in the presence of phosphorus trichloride or to activated malonic acid.

32. The method of claim 31, wherein the C-IV in step 3 is coupled with activated malonic acid.

33. the process according to claim 32, wherein as the activated malonic acid, an active ester or mixed anhydride thereof can be used, preferably prepared in situ by adding dicyclohexylcarbodiimide/N-hydroxybenzotriazole and/or dicyclohexylcarbodiimide/hydroxysuccinimide and/or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide HCl/N-hydroxybenzotriazole and/or 1-propanephosphonic acid cyclic anhydride.

34. The process of any one of claims 31 to 33, wherein the reaction is carried out in freshly distilled tetrahydrofuran or methyltetrahydrofuran.

35. The process of any one of claims 31 to 34, wherein crude product C-V is purified by stirring in a solvent comprising tetrahydrofuran, methyltetrahydrofuran, diethyl ether, dioxane, or a mixture thereof.

36. The process of any one of claims 31 to 35, wherein the C-V is not dried and is used directly in the next reaction step.

37. A process for preparing C-VI as shown in the following scheme:

[ chemical formula 7]

Wherein C-V is reacted with 3-amino-propane-1, 2-diol in an organic solvent in the presence of a base at 2 ℃ to 25 ℃.

38. The method of claim 37, wherein the organic solvent is N, N-dimethylformamide in the presence of trimethylamine.

39. The process according to claim 37 or 38, wherein the C-VI reaction mixture is stirred with the anion exchange resin suspended in aqueous methanol to separate organic impurities.

40. The process according to claim 39, wherein the anion exchange resin is a polystyrene based resin, a polyacrylate based resin, preferably a styrene-divinylbenzene copolymer based resin.

41. The process of any one of claims 37 to 40, wherein C-VI is directly isolated and purified by precipitation from the reaction mixture at pH5-7 by addition of an organic solvent selected from methanol, ethanol, n-propanol, 2-propanol, or combinations thereof.

42. The process of any one of claims 37 to 41, wherein the precipitated C-VI is crystallized from a solvent mixture consisting of water, acetone, and acetic acid.

43. A method for preparing iomesol, which is shown as the following scheme:

[ chemical formula 8]

Wherein C-VI is reacted with an alkylating agent incorporating 2, 3-dihydroxypropyl groups in the presence of 2-methoxyethanol (0-99%) in the presence of an inorganic base in an organic solvent selected from the group consisting of N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methyl-2-pyrrolidone, ethylene glycol, propylene glycol, glycerol, methanol, or a combination thereof.

44. The method of claim 43 wherein said alkylating agent incorporating a 2, 3-dihydroxypropyl group is selected from the group consisting of 3-halopropane-1, 2-diol and glycidol.

45. The method of claim 43 or 44, wherein the alkylating agent that introduces a 2, 3-dihydroxypropyl group is a 3-halopropane-1, 2-diol.

46. A process according to any one of claims 43 to 45 wherein the alkylating agent incorporating 2, 3-dihydroxypropyl groups is added in one or more portions to the stirred reaction mixture during the reaction.

47. The process of any one of claims 43 to 46, wherein the reaction temperature is from 10 ℃ to 60 ℃.

48. The method of any one of claims 43 to 47, wherein the inorganic base is selected from the group consisting of alkali metal hydroxides and alkaline earth metal hydroxides.

49. The process of any one of claims 43 to 48, wherein the inorganic base is lithium hydroxide, calcium hydroxide, sodium hydroxide, potassium hydroxide, or a mixture thereof.

50. A process as set forth in any one of claims 43 to 49 wherein the reaction to produce iomenol is carried out in the presence of a metal halide in addition to the inorganic base.

51. The method of claim 50, wherein the metal halide is selected from CaCl₂、ZnCl₂、MgCl₂、CaBr₂、ZnBr₂And MgBr₂。

52. a method for preparing iomesol, which is shown as the following scheme:

[ chemical formula 9]

53. The process of claim 52, wherein the C-VI is protected with 2, 2-dimethoxypropane in N, N-dimethylformamide in the presence of an acidic catalyst.

54. The process according to claim 52 or 53, wherein the C-VI diacetone compound is crystallized from the reaction mixture by the addition of water.

55. The process according to any one of claims 52 to 54, wherein the crystals of C-VI diacetone compound are obtained in high purity and yield.

56. the process according to any one of claims 52 to 55, wherein the C-VI diacetone compound is reacted with an alkylating agent incorporating a 2, 3-dihydroxypropyl group in the presence of an inorganic base in an organic solvent selected from N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methyl-2-pyrrolidone, ethylene glycol, propylene glycol, glycerol, methanol, or a combination thereof, and/or in a mixture of an organic solvent and methoxyethanol (0-99%).

57. the method of any one of claims 52 to 56, wherein the alkylating agent that introduces a 2, 3-dihydroxypropyl group is selected from 3-halopropane-1, 2-diol and glycidol.

58. The process of any one of claims 52 to 57, wherein said alkylating agent that introduces a 2, 3-dihydroxypropyl group is a 3-halopropane-1, 2-diol.

59. A process according to any one of claims 52 to 58 wherein the alkylating agent incorporating 2, 3-dihydroxypropyl groups is added in one or more portions to the stirred reaction mixture during the reaction.

60. The process of any one of claims 52 to 59, wherein the reaction temperature is from 10 ℃ to 60 ℃.

61. the method of any one of claims 52 to 60, wherein the inorganic base is selected from the group consisting of alkali metal hydroxides and alkaline earth metal hydroxides.

62. The process of any one of claims 52 to 61, wherein the inorganic base is lithium hydroxide, calcium hydroxide, sodium hydroxide, potassium hydroxide, or a mixture thereof.

63. The process according to any one of claims 52 to 62, wherein the reaction to prepare ioimenol diacetone compound is carried out in the presence of a metal halide in addition to the inorganic base.

64. The method of claim 63, wherein the metal halide is selected from CaCl₂、ZnCl₂、MgCl₂、CaBr₂、ZnBr₂And MgBr₂。

65. The process according to any one of claims 52 to 64, wherein ioimenol diacetone compound is obtained by crystallization from an organic solvent selected from methanol, ethanol, n-propanol, 2-propanol or a combination thereof.

66. The process according to any one of claims 52 to 65, wherein iomesol is obtained by deprotecting iomesol diacetone compound in the presence of a strong acid in aqueous or methanol or ethanol solution or in methanol-water or ethanol-water.

67. A process for the purification of iomesol, wherein crude iomesol is purified by crystallization in the presence of water in (i) a binary or ternary solvent mixture of an alcohol selected from the group consisting of 2-methoxyethanol, 1-methoxy-2-propanol and an alcohol selected from the group consisting of methanol, ethanol, 2-propanol, n-butanol and/or 2-butanol, (ii) diethylene glycol and/or triethylene glycol, or (iii) 2-ethoxyethanol and/or 1-methoxy-2-propanol.

68. A method of purifying iomesol from a saturated or supersaturated solution of said compound, said method comprising:

Step 1: suspending the deionized iomesol in a solvent mixture comprising one or more organic solvents and water,

Step 2: heating and/or sonicating the mixture to completely dissolve the mixture,

And step 3: the solution continues to be subjected to the same or different heating and/or sonication to deposit crystals,

And 4, step 4: the solvent or solvent mixture is added continuously during the crystallization, or the solvent or solvent mixture is added in individual portions,

And 5: the resulting crystals were collected on a filter.

69. The method of claim 68, wherein the heating in step 2 and/or step 3 and/or step 4 is performed using microwaves.

70. The method of any one of claims 68 or 69, wherein the organic solvent in step 1 and step 4 comprises one or more C₁-C₆Straight or branched chain or alkoxy alkanol, C₂-C₈Aliphatic ethers, C₄-C₆Cyclic ethers and/or glycols.

71. the process according to any one of claims 68 to 70, wherein the organic solvent in step 1 and 4 is selected from the group consisting of methanol, ethanol, n-propanol, 2-propanol, n-butanol, iso-butanol, sec-butanol, tert-butanol, pentanol including iso-butanol, hexanol, 2-methoxyethanol, 2-ethoxyethanol, 1-methoxy-2-propanol, 2-isopropoxyethanol, ethylene glycol, diethylene glycol and triethylene glycol.

72. The process of any one of claims 68 to 71, wherein the solvent mixture in step 1 and step 4 comprises up to 20% water.

73. A process according to any one of claims 68 to 72, wherein the crystallisation process in step 3 can be initiated by the addition of seeds of crystals of iomesol at the same time as or after the temperature is raised.

74. A process according to any one of claims 68 to 73, wherein tromethamine is used to buffer the pH during crystallization.

75. The process of any one of claims 68 to 74, wherein steps 2,3 and 4 are carried out at a temperature of 70 ℃ -140 ℃ and a pressure of 0 bar-10 bar.

76. The process according to any one of claims 68 to 75, wherein the concentration of iomesol as starting material in step 1 and step 4 is from 10 w/v% to 60 w/v%.

Technical Field

The present invention generally relates to a process for the preparation of iomenol and each step thereof.

background

Iomesol, N '-bis [ 3-carbamoyl-5- (2, 3-dihydroxypropyl-carbamoyl) -2,4, 6-triiodophenyl ] -N, N' -bis (2, 3-dihydroxypropyl) -malonamide, has a structure shown below and has been proposed by Milos Sovak in 1995 as a useful nonionic X-ray contrast agent (patent document 1).

[ chemical formula 1]

In order to make iomesol suitable for commercial use as an X-ray contrast agent, it is necessary to produce iomesol in high yield and then purify the product efficiently. In addition, X-ray contrast agents are generally administered to the human body at high doses, and therefore it is particularly required that iomesol as an X-ray contrast agent has high purity. However, since iomesol has a chiral center and pseudo-asymmetric carbon atoms on the bridge and the chiral axis, it is difficult to purify such a large amount of iomesol efficiently.

For example, patent document 2 discloses some synthesis methods of iomesol. In patent document 2 (example 9), iomesol is produced by reacting 5,5' - [ (1, 3-dioxo-1, 3-propanediyl) diimino ] bis [ N- (2, 3-dihydroxypropyl) -2,4, 6-triiodo-1, 3-benzenedicarboxamide ] (hereinafter referred to as "C-VI") with 3-chloro-propane-1, 2-diol in water, but the yield is low and the product purity is low. Further, the crude iomenol was purified by the following steps: deionization, ion exchange resin adsorption, and wood carbonization by purification using LC reverse phase chromatography (example 10 in patent document 2). When starting from 85% deionized crude iomesol, the average HPLC purity achieved was about 95%.

[ chemical formula 2]

further, patent document 1 discloses a method for producing iomenol, as shown below. In this process, the C-VI is protected beforehand with isopropylidene and the protected C-VI (C-VI diacetone) is then reacted with 3-chloro-propane-1, 2-diol in methanol. The inventors actually examined the process, but both the yield and purity were low.

[ chemical formula 3]

As mentioned above, for commercial purposes it is important to produce high purity iomesol, and therefore the crude product of iomesol must be purified in some way. However, there are some practical limitations to the manufacturing process for purifying iomesol using HPLC. Clearly, the HPLC method represents a powerful and efficient method to meet the purity requirements. On the other hand, the HPLC method has many disadvantages such as low yield, extremely high amount of water waste containing organic solvent (1,000 kg per kg of purified material), and extremely high investment cost. The combination of all these drawbacks constitutes a considerable production cost.

List of cited documents

Patent document

[ patent document 1] US 5,698,739B

[ patent document 2] WO 2009/091758

Disclosure of Invention

Technical problem

The main object of the present invention is to provide an efficient preparation and/or purification of iomesol in high yield and purity.

Means for solving the problems

The present inventors have intensively studied to achieve the above object and then have found specific conditions of a process for preparing iomesol from C-II in high yield and high purity and specific conditions of purification. The present invention has been completed based on the new findings.

the present invention provides a method for preparing iomenol and each step thereof, as shown in the following clauses 1 to 10.

Clause 1. a process for preparing iomenol, as shown in the following scheme:

[ chemical formula 4]

Clause 2. the method of clause 1, wherein the crude product C-III in step 1 is purified by crystallization at 20 ℃ to 100 ℃ in a solvent comprising methanol and/or a mixture of methanol and water (methanol: 1-99 wt%).

Clause 3. the method of clause 1 or 2, wherein the C-III in step 2 is chlorinated with thionyl chloride under reflux conditions in a solvent comprising ethyl acetate and/or toluene in the presence or absence of a catalytic amount of N, N-dimethylformamide.

Clause 4. the method of any one of clauses 1 to 3, wherein the crude C-IV in step 2 is purified using an anion exchange resin to remove organic impurities, wherein the resin is a polystyrene-based resin, a polyacrylate-based resin, preferably a styrene-divinylbenzene copolymer-based resin.

Clause 5. the method of any one of clauses 1 to 4, wherein the C-IV in step 3 is coupled with malonic acid in the presence of phosphorus trichloride.

Clause 6. the method of any one of clauses 1 to 4, wherein the C-IV in step 3 is coupled with activated malonic acid.

Clause 7. the method of clause 6, wherein as the activated malonic acid, an active ester or mixed anhydride thereof can be used, which is preferably prepared in situ by adding dicyclohexylcarbodiimide/N-hydroxybenzotriazole and/or dicyclohexylcarbodiimide/hydroxysuccinimide and/or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, HCl/N-hydroxybenzotriazole and/or 1-propanephosphonic acid cyclic anhydride.

Clause 8. the method of any one of clauses 5 to 7, wherein the reaction is carried out in freshly distilled tetrahydrofuran or methyltetrahydrofuran.

Clause 9. the method of any one of clauses 5 to 8, wherein the crude product C-V is purified by stirring in a solvent comprising tetrahydrofuran, methyltetrahydrofuran, diethyl ether, dioxane, or a mixture thereof.

clause 10. the method of any one of clauses 5 to 8, wherein the C-V is not dried and is used directly in the next step (step 4).

Clause 11. the method of any one of clauses 1 to 10, wherein C-V in step 4 is reacted with 3-amino-propane-1, 2-diol in an organic solvent in the presence of a base at 2 ℃ to 25 ℃.

Clause 12. the method of clause 11, wherein the organic solvent is N, N-dimethylformamide in the presence of triethylamine.

Clause 13. the method of clause 11 or 12, wherein the C-VI reaction mixture is stirred with the anion exchange resin suspended in aqueous methanol to separate organic impurities.

Clause 14. the method of clause 13, wherein the anion exchange resin is a polystyrene-based resin, a polyacrylate-based resin, preferably a styrene-divinylbenzene copolymer-based resin.

Clause 15. the method of any one of clauses 11 to 14, wherein the C-VI is directly isolated and purified by precipitation from the reaction mixture by adding an organic solvent selected from methanol, ethanol, n-propanol, 2-propanol, or a combination thereof at pH 5-7.

Clause 16. the method of any one of clauses 11 to 15, wherein the precipitated C-VI is crystallized from a solvent mixture consisting of water, acetone, and acetic acid.

Clause 17. the method of any one of clauses 1 to 16, wherein in step 5C-VI is reacted with an alkylating agent incorporating a 2, 3-dihydroxypropyl group in the presence of 2-methoxyethanol (0-99%) in the presence of an inorganic base in an organic solvent selected from N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methyl-2-pyrrolidone, ethylene glycol, propylene glycol, glycerol, methanol, or a combination thereof.

Clause 18. the method of clause 17, wherein the alkylating agent that introduces a 2, 3-dihydroxypropyl group is selected from the group consisting of 3-halopropane-1, 2-diol and glycidol.

Clause 19. the method of clause 17 or 18, wherein the alkylating agent that introduces a 2, 3-dihydroxypropyl group is a 3-halopropane-1, 2-diol.

Clause 20. the method of any one of clauses 17 to 19, wherein the alkylating agent introduced with a 2, 3-dihydroxypropyl group is added to the stirred reaction mixture in one or more portions during the reaction.

Clause 21. the method of any one of clauses 17 to 20, wherein the reaction temperature is from 10 ℃ to 60 ℃.

Clause 22. the method of any one of clauses 17 to 21, wherein the inorganic base is selected from the group consisting of alkali metal hydroxides and alkaline earth metal hydroxides.

Clause 23. the method of any one of clauses 17 to 22, wherein the inorganic base is lithium hydroxide, calcium hydroxide, sodium hydroxide, potassium hydroxide, or a mixture thereof.

Clause 24. the method of any one of clauses 17 to 23, wherein the reaction to prepare iomenol is carried out in the presence of a metal halide in addition to the inorganic base.

Clause 25. the method of clause 24, wherein the metal halide is selected from CaCl₂、ZnCl₂、MgCl₂、CaBr₂、ZnBr₂And MgBr₂。

Clause 26. a method of preparing C-III, as shown in the following scheme:

[ chemical formula 5]

Wherein the crude product C-III is purified by crystallization in a solvent comprising methanol or a mixture of methanol and water (methanol: 1-99% by weight) at 20 ℃ to 100 ℃.

Clause 27. a crystal of a C-III methanol solvate having the formula:

[ chemical formula 6]

Characterized by a powder X-ray diffraction pattern having four or more 2 θ ± 0.2 peaks and selected from about 12.2 °, 12.8 °, 15.0 °, 21.1 °, 21.4 °, 22.7 °, 24.6 °, 25.3 °, 27.2 °, 31.0 °, 31.2 °, 33.4 °, and 33.9 °, wherein the measurement of said crystal is made at a temperature of about 293K.

Clause 28. a crystal of a C-III methanol solvate having the formula:

[ chemical formula 7]

Characterized in that the unit cell parameters at T293K are substantially equal to: 17.000(1) for a, 13.896(1) for b, 12.597(1) for c, 2975.9 for unit cell volume V³And an orthogonal space group Pbca.

clause 29. a method of preparing C-IV, as shown in the following scheme:

[ chemical formula 8]

Wherein C-III is chlorinated with thionyl chloride under reflux conditions in a solvent comprising ethyl acetate and/or toluene in the presence or absence of a catalytic amount of N, N-dimethylformamide.

Clause 30. the method of clause 29, wherein the crude C-IV is purified using an anion exchange resin to remove organic impurities, wherein the resin is a polystyrene-based resin, a polyacrylate-based resin, preferably a styrene-divinylbenzene copolymer-based resin.

Clause 31. a method of preparing C-V, as shown in the following scheme:

[ chemical formula 9]

wherein C-IV is coupled to malonic acid in the presence of phosphorus trichloride or to activated malonic acid.

Clause 32. the method of clause 31, wherein C-IV is coupled with activated malonic acid.

Clause 33. the method of clause 32, wherein as the activated malonic acid, an active ester or mixed anhydride thereof can be used, which is preferably prepared in situ by adding dicyclohexylcarbodiimide/N-hydroxybenzotriazole and/or dicyclohexylcarbodiimide/hydroxysuccinimide and/or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, HCl/N-hydroxybenzotriazole and/or 1-propanephosphonic acid cyclic anhydride.

Clause 34. the method of any one of clauses 31 to 33, wherein the reaction is carried out in freshly distilled tetrahydrofuran or methyltetrahydrofuran.

Clause 35. the method of any one of clauses 31 to 34, wherein the crude product C-V is purified by stirring in a solvent comprising tetrahydrofuran, methyltetrahydrofuran, diethyl ether, dioxane, or a mixture thereof.

Clause 36. the method of any one of clauses 31 to 35, wherein the C-V is not dried and is used directly in the next reaction step.

Clause 37. a method of preparing C-VI, as shown in the following scheme:

[ chemical formula 10]

Wherein C-V is reacted with 3-amino-propane-1, 2-diol in an organic solvent in the presence of a base at 2 ℃ to 25 ℃.

Clause 38. the method of clause 37, wherein the organic solvent is N, N-dimethylformamide in the presence of trimethylamine.

Clause 39. the method of clause 37 or 38, wherein the C-VI reaction mixture is stirred with the anion exchange resin suspended in aqueous methanol to separate organic impurities.

Clause 40. the method of clause 39, wherein the anion exchange resin is a polystyrene-based resin, a polyacrylate-based resin, preferably a styrene-divinylbenzene copolymer-based resin.

Clause 41. the method of any one of clauses 37 to 40, wherein C-VI is directly isolated and purified by precipitation from the reaction mixture at pH5-7 by addition of an organic solvent selected from methanol, ethanol, n-propanol, 2-propanol, or a combination thereof.

Clause 42. the method of any one of clauses 37 to 41, wherein the precipitated C-VI is crystallized from a solvent mixture consisting of water, acetone, and acetic acid.

Clause 43. a process for preparing iomenol, as shown in the following scheme:

[ chemical formula 11]

Wherein C-VI is reacted with an alkylating agent incorporating 2, 3-dihydroxypropyl groups in the presence of 2-methoxyethanol (0-99%) in the presence of an inorganic base in an organic solvent selected from the group consisting of N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methyl-2-pyrrolidone, ethylene glycol, propylene glycol, glycerol, methanol or a combination thereof.

Clause 44. the method of clause 43, wherein the alkylating agent that introduces a 2, 3-dihydroxypropyl group is selected from the group consisting of 3-halopropane-1, 2-diol and glycidol.

Clause 45. the method of clauses 43 or 44, wherein the alkylating agent that introduces a 2, 3-dihydroxypropyl group is a 3-halopropane-1, 2-diol.

Clause 46. the method of any one of clauses 43 to 45, wherein the alkylating agent introduced with the 2, 3-dihydroxypropyl group is added to the stirred reaction mixture in one or more portions during the reaction.

Clause 47. the method of any one of clauses 43 to 46, wherein the reaction temperature is from 10 ℃ to 60 ℃.

Clause 48. the method of any one of clauses 43 to 47, wherein the inorganic base is selected from the group consisting of alkali metal hydroxides and alkaline earth metal hydroxides.

Clause 49. the method of any one of clauses 43 to 48, wherein the inorganic base is lithium hydroxide, calcium hydroxide, sodium hydroxide, potassium hydroxide, or a mixture thereof.

Clause 50. the method of any one of clauses 43 to 49, wherein the reaction to produce iomenol is carried out in the presence of a metal halide in addition to the inorganic base.

Clause 51. the method of clause 50, wherein the metal halide is selected from CaCl₂、ZnCl₂、MgCl₂、CaBr₂、ZnBr₂And MgBr₂。

Clause 52. a process for preparing iomenol, as shown in the following scheme:

[ chemical formula 12]

Clause 53. the method of clause 52, wherein C-VI is protected with 2, 2-dimethoxypropane in N, N-dimethylformamide in the presence of an acidic catalyst.

Clause 54. the method of clauses 52 or 53, wherein the C-VI diacetone compound is crystallized from the reaction mixture by adding water.

Clause 55. the method of any one of clauses 52 to 54, wherein the crystals of C-VI diacetone compound are obtained in high purity (+ 98%) and high yield (+ 92%).

Clause 56. the method of any one of clauses 52 to 55, wherein the C-VI diacetone compound is reacted with an alkylating agent incorporating a 2, 3-dihydroxypropyl group in the presence of an inorganic base in an organic solvent selected from N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methyl-2-pyrrolidone, ethylene glycol, propylene glycol, glycerol, methanol, or a combination thereof, and/or in a mixture of an organic solvent and methoxyethanol (0-99%).

Clause 57. the method of any one of clauses 52 to 56, wherein the alkylating agent that introduces a 2, 3-dihydroxypropyl group is selected from the group consisting of 3-halopropane-1, 2-diol and glycidol.

Clause 58. the method of any one of clauses 52 to 57, wherein the alkylating agent that introduces a 2, 3-dihydroxypropyl group is a 3-halopropane-1, 2-diol.

Clause 59. the method of any one of clauses 52 to 58, wherein the alkylating agent introduced with a 2, 3-dihydroxypropyl group is added to the stirred reaction mixture in one or more portions during the reaction.

clause 60. the method of any one of clauses 52 to 59, wherein the reaction temperature is from 10 ℃ to 60 ℃.

Clause 61. the method of any one of clauses 52 to 60, wherein the inorganic base is selected from the group consisting of alkali metal hydroxides and alkaline earth metal hydroxides.

Clause 62. the method of any one of clauses 52 to 61, wherein the inorganic base is lithium hydroxide, calcium hydroxide, sodium hydroxide, potassium hydroxide, or a mixture thereof.

clause 63. the method of any one of clauses 52 to 62, wherein the reaction to prepare iomenol diacetone compound is carried out in the presence of a metal halide in addition to the inorganic base.

Clause 64. the method of clause 63, wherein the metal halide is selected from CaCl₂、ZnCl₂、MgCl₂、CaBr₂、ZnBr₂And MgBr₂。

clause 65. the method of any one of clauses 52 to 64, wherein the iodometritol diacetone compound is obtained by crystallization from an organic solvent selected from methanol, ethanol, n-propanol, 2-propanol, or a combination thereof.

Clause 66. the method of any one of clauses 52 to 65, wherein the iomesol is obtained by deprotecting iomesol diacetone compound in the presence of a strong acid in an aqueous or methanol or ethanol solution or in methanol-water or ethanol-water.

Clause 67. a process for purifying iomenol, wherein crude iomenol is purified by crystallization in the presence of water in (i) a binary or ternary solvent mixture of an alcohol selected from 2-methoxyethanol, 1-methoxy-2-propanol and an alcohol selected from methanol, ethanol, 2-propanol, n-butanol and/or 2-butanol, (ii) diethylene glycol and/or triethylene glycol, or (iii) 2-ethoxyethanol and/or 1-methoxy-2-propanol.

Clause 68. a method of purifying iomenol from a saturated or supersaturated solution of said compound, said method comprising:

Step 1: suspending the deionized iomesol in a solvent mixture comprising one or more organic solvents and water,

Step 2: heating and/or sonicating the mixture to completely dissolve the mixture,

And step 3: the solution continues to be subjected to the same or different heating and/or sonication to deposit crystals,

And 4, step 4: the solvent or solvent mixture is added continuously during the crystallization, or the solvent or solvent mixture is added in individual portions (increasing the yield from 40-50% to 70-85%),

And 5: the resulting crystals were collected on a filter.

clause 69. the method of clause 68, wherein the heating in step 2 and/or step 3 and/or step 4 is performed using microwaves.

Clause 70. the method of any one of clauses 68 or 69, wherein the organic solvent in step 1 and step 4 comprises one or more C₁-C₆Straight or branched chain or alkoxy alkanol, C₂-C₈Aliphatic ethers, C₄-C₆Cyclic ethers and/or glycols.

Clause 71. the method of any one of clauses 68 to 70, wherein the organic solvent in step 1 and step 4 is selected from the group consisting of methanol, ethanol, n-propanol, 2-propanol, n-butanol, isobutanol, sec-butanol, tert-butanol, pentanol including isopentanol, hexanol, 2-methoxyethanol, 2-ethoxyethanol, 1-methoxy-2-propanol, 2-isopropoxyethanol, ethylene glycol, diethylene glycol, and triethylene glycol.

Clause 72. the method of any one of clauses 68 to 71, wherein the solvent mixture in step 1 and step 4 comprises up to 20% water.

clause 73. the method of any one of clauses 68 to 72, wherein the crystallization process in step 3 can be initiated by adding seeds of iomenol crystals while or after the temperature is increased.

Clause 74. the method of any one of clauses 68 to 73, wherein tromethamine (trometamol) is used to buffer the pH during crystallization.

Clause 75. the method of any one of clauses 68 to 74, wherein steps 2,3, and 4 are performed at a temperature of 70 ℃ to 140 ℃ and a pressure of 0 bar to 10 bar.

Clause 76. the method of any one of clauses 68 to 75, wherein the concentration of iomesol as starting material in step 1 and step 4 is 10 w/v% to 60 w/v%.

Effects of the invention

The present invention provides an efficient process for the preparation of iomenol and its intermediates of the present invention in high yield. In addition, the invention also provides effective purification of high-purity iomesol and each intermediate thereof.

Drawings

FIG. 1 shows an overview of the thermogravimetric analysis of C-III methanol solvate in example 3.

FIG. 2 shows the X-ray powder diffraction pattern of C-III methanol solvate in example 3.

FIG. 3 shows the mass spectrum of C-III methanol solvate in example 3.

FIG. 4 shows the IR spectrum of C-III methanol solvate in example 3.

Detailed Description

Step 1

[ chemical formula 13]

Current purification of crude intermediates C-III is not sufficiently effective to remove impurities that result in the formation of large amounts of pentaiodide impurities in the final step of the synthesis of iomesol; thus, we have developed crystallization of C-III in methanol via formation of C-III methanol solvate.

The upper diagram shows the synthetic route of intermediates C-III. Iodinating an aqueous solution of an ammonium salt of a 5-amino-isophthalic acid mono-primary amide in water with a sodium iodide dichloride solution at a temperature of 75 ℃ to 80 ℃. The collected product was washed and purified by conversion to C-III sodium salt, followed by precipitation to C-III. The C-III obtained is dried.

C-III was purified by additional purification in methanol. The aim is to obtain C-III with an HPLC purity of more than 99.0%. The high purity of C-III is crucial to minimize impurities in all synthesis steps leading to ioimenol API, mainly to reduce the hypoiodinated impurities (mono-and divalent) and chlorine impurities. The present inventors have found that purification in methanol is effective. During analysis of purified and dried C-III, we found that dried C-III consistently contained 1% -2% residual solvent. We hypothesize that methanol may be present in the C-III molecule as part of the C-III solvate due to the large excess of methanol used in the purification process. This assumption is confirmed to be correct as shown in the working examples shown below.

Recrystallization of C-III from methanol as described gives C-III methanol solvate. To our knowledge (Reaxys and SciFinder databases), this is a completely new molecule that has not been reported or published anywhere in the scientific journal or patent literature, and we will be the first to claim for it. As is apparent from NMR analysis in the working examples below, the molar ratio of C-III to methanol is about 1: 0.94. The production of C-III methanol solvate may result in significantly purer C-III and therefore may minimize impurities that may cause separation problems in subsequent steps of the preparation of iomenol. The C-III methanol solvate was more crystalline than the crude C-III as confirmed by XRD in the following working examples. The precise structure and other properties are further supported by numerous analytical methods (melting point, density, TGA, MS, FTIR). See the working examples below.

Step 2

[ chemical formula 14]

The impurities from steps C-IV not only result in lower yields and higher amounts of impurities, which negatively affect the impurity distribution of the intermediates in the next step, but also negatively affect the filterability of the intermediates in the next step. Generally, the best way how to prepare intermediates in high purity and yield is to use pure starting materials. Preparation of 3-amino-5- (aminocarbonyl) -2,4, 6-triiodobenzoyl chloride (C-IV) can be prepared by treating 3-amino-5- (aminocarbonyl) -2,4, 6-triiodobenzoic acid C-III with thionyl chloride (U.S. patent No. 5,698,739, carboxamide non-ionic contrast medium) or as (U.S. patent No. 8,680,334, method for preparing iomesol). Both methods give intermediates C-IV of low purity (about 92%), both of which are described below. We have developed the preparation of intermediates C-IV with higher chromatographic purity (96-99% area). Unlike the above-mentioned processes (both patents), our strategy is based on obtaining C-IV of significantly higher purity, thus reducing the transfer of impurities to the subsequent steps. Generally, a higher purity of the starting material also has a positive influence on the yield in the subsequent steps of the preparation of iomesol.

Step 3

[ chemical formula 15]

3,3' - [ (1, 3-dioxo-1, 3-propanediyl) diimino ] bis [5- (aminocarbonyl) -2,4, 6-triiodobenzoyl chloride ] (C-V) can be prepared by treating 3-amino-5- (aminocarbonyl) -2,4, 6-triiodobenzoyl chloride (C-IV) with malonyl dichloride as described in patent US 5,698,739 (carboxamide non-ionic contrast medium) or patent US 8,680,334 (method for preparing iomesol). None of these patented synthetic methods provides the highly pure intermediates C-V. Moreover, the environmental burden of the chemicals used in both patents is enormous. We developed two new methods for intermediates C-V:

1) when the crude product is roughly washed with Tetrahydrofuran (THF), it is based on a method using phosphorus trichloride.

2) The method is based on the use of activated malonic acid, and its use ensures high purity and yield. Moreover, the environmental burden is greatly reduced. The activator is dicyclohexylcarbodiimide/N-hydroxybenzotriazole, dicyclohexylcarbodiimide/hydroxysuccinimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, HCl/N-hydroxybenzotriazole or 1-propanephosphonic acid cyclic anhydride.

For the route 1) above, 5-amino-2, 4, 6-triiodo-3-chlorocarbonyl benzamide (C-IV) is reacted with malonic acid and phosphorus trichloride (PCl) at 45 deg.C to 50 deg.C₃) Coupling in freshly distilled THF. The product 3,3' - [ (1, 3-dioxo-1, 3-propanediyl) diimino]Bis [5- (aminocarbonyl) -2,4, 6-triiodobenzoyl chloride (C-V) was filtered, washed with freshly distilled tetrahydrofuran and dried.

For the route 2) above, 3-amino-5- (aminocarbonyl) -2,4, 6-triiodobenzoyl chloride (C-IV) was coupled via malonic acid in the presence of the coupling agent 1-propanephosphonic acid cyclic anhydride.

Step 4

[ chemical formula 16]

The improved process for the intermediate C-VI (3,3' - [ (1, 3-dioxo-1, 3-propanediyl) diimino ] bis [5- (aminocarbonyl) -2,4, 6-triiodobenzoyl chloride ]) is based on amidation of C-V by 3-amino-propane-1, 2-diol in N, N-dimethylformamide at 2 ℃ to 25 ℃. The reaction mixture was purified by ion ex resin and precipitated and crystallized from an isopropanol-water mixture. The product was filtered, washed with acetone and dried.

Step 5

[ chemical formula 17]

Crude iomenol can be prepared by alkylating C-VI with 3-chloro-propane-1, 2-diol using a non-aqueous organic solvent in the presence of anhydrous calcium chloride and lithium hydroxide. This is achieved by adding 3-chloro-propane-1, 2-diol stepwise to the reaction mixture and lowering the reaction temperature.

The process for the preparation of crude iomeprol can be carried out by using various solvents such as 2-methoxyethanol, dimethylsulfoxide, N-dimethylformamide, N-methyl-2-pyrrolidone, ethylene glycol or propylene glycol. Lithium hydroxide, lithium hydroxide hydrate, calcium oxide or calcium hydroxide is used as the base. Anhydrous glycerol was used to improve the solubility of C-VI. Calcium chloride is used to reduce the over-alkylation reaction. The alkylating agent 3-chloro-1, 2-propanediol is added stepwise or in portions.

Step 6 to step 8

[ chemical formula 18]

We have developed a process for the preparation of protected C-VI (hereinafter referred to as "C-VI diacetone") using 2, 2-dimethoxypropane as the protecting agent. This method differs from the procedure described in US 5,698,739. C-VI diacetone compound, 5' - (malonylbis (azepinyl)) bis (N- ((2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) -2,4, 6-triiodoisophthalamide, was reacted with 3-chloro-propane-1, 2-diol in methanol at 10 ℃ to 60 ℃ in the presence of lithium hydroxide monohydrate, anhydrous calcium chloride and glycerol.

Alternatively, the synthesis of the C-VI diacetone compound starts as a one-pot process from C-V, wherein C-VI is not isolated, and the reaction is continued directly to obtain the C-VI diacetone compound.

Method for purifying iomesol

For the purification of crude iomeprol, crystallization can be used, and a preferred crystallization solvent is a solvent comprising 2-methoxyethanol to increase its yield. More preferably, the solvent used for crystallization is a binary or ternary solvent mixture of an alcohol selected from 2-methoxyethanol, methoxy-2-propanol and from methanol, ethanol, 2-propanol, n-butanol and/or 2-butanol.

Other preferred crystallization solvents include glycols such as diethylene glycol and triethylene glycol. 2-ethoxyethanol or 1-methoxy-2-propanol may also be used as crystallization solvent.

Furthermore, the presence of water in the crystallization solvent is very important for crystallization. The amount of water is preferably 1 to 10 v/v%.

Further, for crystallization, tromethamine is preferably included. The amount of tromethamine is preferably 0.1 to 0.5 w/v%.