Preparation method of iopamidol

Abstract

The present invention provides a method for preparing a compound of formula (II), wherein the method comprises: (i) reacting a compound of formula (I) with pyridine and 2-acetoxypropionyl chloride (APC) to obtain a compound of formula (II), wherein the compound of formula (I) has the following structure.

Description

Technical Field

[0001] The present invention relates to X-ray contrast agents and in particular to a method of producing iodinated X-ray contrast agents. The method of the present invention offers certain advantages over known such methods. Background Art

[0002] The use of iopamidol as a contrast agent (e.g. in X-ray imaging) is well established. Iopamidol has the following structure and is referred to herein as the compound of formula (III):

[0003]

[0004] The manufacture of iopamidol comprises producing formula (III) compound, and then preparing the preparation as contrast agent.This compound is usually prepared in multi-step synthesis, and is then purified before being used in preparation.In each synthesis step, it is important to optimize the productive rate and minimize the generation of impurities.For the step using expensive reagents, it is particularly important to optimize the use of these reagents.Iodination reagent is expensive, and therefore triiodination of aromatic ring is an important step, usually carried out in the later stage of whole synthesis.In this step, it is particularly important to obtain the high productive rate with a small amount of impurities and the minimum loss of iodination reagent.

[0005] Iopamidol has previously been used by e.g. Figure 1 The reaction scheme in painted For example, this method is described in WO 02 / 44132 A1. The disadvantage of this method is that it requires the use of solvents such as N,N-dimethylacetamide (DMAc) and harmful and corrosive chemicals such as SOCl2.

[0006] Iopamidol has also been previously Figure 2 1,3-ABA). 1,3-ABA is then iodinated using iodine monochloride. The free hydroxyl groups in the resulting compound are protected in several different ways, such as with acetone to obtain acetals, with anhydrides to obtain esters, or with alkyl or aryl phosphonates to obtain phosphates. The protected intermediate is then N-acylated with 2-acetoxypropionyl chloride (APC), deprotected, and hydrolyzed to provide iopamidol.

[0007] There is a need for improved methods of producing iopamidol. The method of the present invention satisfies this need.

[0008] The present invention provides advantages over the above methods for producing iopamidol. For example, the method of the present invention can be carried out in solvents that are readily available, unrestricted, and more environmentally friendly than previously used solvents. In addition, the method of the present invention can be carried out with fewer process steps than previous methods, which provides significant cost savings. In particular, compared to Figure 2 Compared to the reaction scheme shown, the method of the present invention avoids the need for a protection step prior to the reaction with APC. Summary of the Invention

[0009] In one aspect, the present invention provides a method for preparing a compound of formula (II):

[0010]

[0011] The method includes:

[0012] (i) reacting a compound of formula (I) with pyridine and 2-acetoxypropionyl chloride (APC) to obtain a compound of formula (II), wherein the compound of formula (I) has the following structure:

[0013]

[0014] In another aspect, the present invention provides a compound or formulation produced by the method of the present invention.

[0015] The present invention also provides the use of the compound of formula (II) as an intermediate in the method for producing iopamidol of formula (III):

[0016]

[0017] Compared with previous methods, the present invention has advantages. Avoid using OH-protecting groups, which will introduce other protection steps and potential other deprotection steps in the reaction sequence. Also avoid using high boiling point solvents such as DMAc or DMF that are subject to the strict restrictions of the REACH Directive, which then suppress the formation of some impurities. In addition, the method provides short reaction times, without using expensive and poisonous catalysts such as DMAP or the like. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 and Figure 2 A previous method for making iopamidol is depicted.

[0019] Figure 3 A reaction scheme is shown with steps that can be performed in the process of the present invention. DETAILED DESCRIPTION

[0020] The present invention relates to a process for preparing a compound of formula (II):

[0021]

[0022] The method comprises: (i) reacting a compound of formula (I) with pyridine and 2-acetoxypropionyl chloride (APC) to obtain a compound of formula (II), wherein the compound of formula (I) has the following structure:

[0023]

[0024] The method may further comprise the step (ii): reacting the compound of formula (II) with a hydrolyzing agent to obtain a compound of formula (III):

[0025]

[0026] Reaction schemes showing steps that can be carried out in the process of the present invention are listed in Figure 3 middle.

[0027] The starting compounds of the process of the invention may be prepared in any suitable manner.

[0028] For example, N,N'-substituted 5-amino-1,3-benzenedicarboxamides (eg, compounds shown below as formula (IV)) are known as intermediates in the synthesis of iopamidol.

[0029] These compounds can be used to prepare compounds of formula (I) by iodination. In the following formula, R represents 1,3-dihydroxy-2-propyl (R = -CH (CH2OH)2) or 2,3-dihydroxy-1-propyl (R = -CH2CH(OH)CH2(OH).

[0030]

[0031] The compound of formula (IV) can be prepared starting from dimethyl 5-nitro-1,3-phthalate (hereinafter shown as the compound of formula (V)), for example, by amidating the ester group with 2-amino-1,3-dihydroxypropane (commonly known as serinol) or with 1-amino-2,3-dihydroxypropane (commonly known as isoserinol), and then reducing the 5-nitro group of the resulting N,N'-disubstituted 5-nitro-1,3-phthalamide. Alternatively, the reduction reaction step can be performed first, followed by the amidation reaction step.

[0032]

[0033] The amidation reaction in this method is typically carried out in the presence of a protic organic solvent (such as a lower alkanol) at a temperature of about 65° C. to about 150° C. using at least a stoichiometric amount of serine or isoserine (i.e., at least two moles of serine or isoserine per mole of dimethyl 5-nitro-1,3-phthalate). Further details of this method are provided in WO 02 / 44125 A1 and WO 00 / 29372 A1.

[0034] N, N'-substituted 5-amino-1,3-benzenedicarboxamides (e.g., compounds of formula (IV)) can also be prepared as described in WO00 / 29372. For example, a di-lower alkyl 5-nitroisophthalate can be reacted with at least two molar equivalents of a compound of formula RNH2 (e.g., wherein R is CH2CH(OH)CH2OH or CH(CH2OH)2) in a solvent containing a lower aliphatic alcohol containing a basic catalyst to obtain a solution containing 5-nitro-N, N'-bis(R)-isophthalamide, and the solution is catalytically hydrogenated without isolating the 5-nitro-N, N'-bis(R)-isophthalamide to obtain a solution of 5-amino-N, N'-bis(R)-isophthalamide.

[0035] Further details of the method of the invention are provided below.Any feature provided below may be used in combination with any other feature provided below.

[0036] In this method, the compound of formula (I) reacts with pyridine and APC in a solvent in step (i). The solvent in step (i) can be any suitable solvent, such as an aprotic solvent. The solvent in step (i) can be at least one of toluene, tetrahydrofuran (THF), acetonitrile, diethyl ether, methyl ethyl ketone, diglyme, glyme, dioxane, methylene chloride, chloroform, ethyl acetate, benzene, diisopropyl ether and acetone. The solvent in step (i) can be at least one of toluene, THF and acetonitrile. The solvent in step (i) can be acetonitrile.

[0037] Step (i) of the method can be carried out at any suitable temperature. For example, step (i) can be carried out at a temperature of 5°C to 75°C, 15°C to 65°C, 15°C to 50°C, 15°C to 30°C, 40°C to 60°C, or 20°C to 30°C.

[0038] In step (i) of the method, APC can be added to a mixture of at least the compound of formula (I) and pyridine. In step (i) of the method, APC can be added to a mixture of at least the compound of formula (I) and pyridine over a period of 0 to 10 hours, 0.5 to 6 hours, or 1 to 3 hours. The APC can be added in a first amount, followed by cooling and then adding the APC in a second amount, wherein the first and second amounts can be the same or different. Cooling can occur to a temperature of 10 to 40° C. or to ambient temperature.

[0039] Pyridine has three important functions. First, the main function of pyridine is to act as a base when HCl is generated during the reaction. Free HCl will cause degradation of the compound of formula (II). Second, pyridine is a cosolvent in the reaction. The compound of formula (II) is difficult to dissolve in most organic solvents (including acetonitrile), but is soluble in pyridine. Third, pyridine is used as a catalyst in the reaction. When APC is added to the reaction mixture, it will first react with pyridine to form an acylpyridinium complex. The acylpyridinium complex will then react with the free hydroxyl-(OH) and amine (NH2) groups in the compound of formula (I) to ultimately obtain the compound of formula (II).

[0040] After the addition of APC, the resulting reaction mixture can be maintained at a temperature of 5° C. to 75° C., 5° C. to 70° C., 5° C. to 95° C., 15° C. to 75° C., 15° C. to 65° C., 15° C. to 60° C., 15° C. to 50° C., 15° C. to 30° C., 40° C. to 60° C., 20° C. to 40° C., or 20° C. to 30° C. The resulting reaction mixture can be maintained at any of these temperatures for up to 24 hours or for 2 to 12 hours.

[0041] The compound of formula (II) produced in step (i) of the process can be reacted in step (ii) of the process without isolation. In particular, the compound of formula (II) produced in step (i) does not need to be purified before further reaction.

[0042] Step (ii) of the method can be carried out at any suitable temperature. For example, step (ii) can be carried out at a temperature of 5°C to 95°C, 5°C to 70°C, 15°C to 75°C, 15°C to 60°C, 15 to 50°C, 40°C to 60°C, or 20°C to 40°C.

[0043] Step (ii) of the method can be carried out under acidic or alkaline conditions. When carried out under acidic conditions, any suitable acid can be used. For example, sulfuric acid and / or hydrochloric acid can be used as the hydrolyzing agent.

[0044] In this method, a hydrolyzing agent may be used together with water in step (ii) to control the pH between 12 and 14. A hydrolyzing agent may be used together with water in step (ii) to control the pH between 12.8 and 13.7 or between 13 and 13.6 or about 13.5.

[0045] The hydrolyzing agent in step (ii) can be an aqueous base or a basic ion exchange resin. The hydrolyzing agent in step (ii) can be aqueous NaOH, aqueous KOH or ammonia and / or a combination thereof. In particular, the hydrolyzing agent in step (ii) can be aqueous NaOH.

[0046] The compound of formula (III) can be purified. It is desirable to purify the compound of formula (III) to a purity of at least 90%, at least 95%, or at least 99.8%. Purification can be achieved using any suitable purification method. One or more of the following purification methods can be used in any combination: desalination (e.g., electrodialysis or ion exchange resins), distillation, one or more columns (e.g., using Amberlite XAD1600N), water evaporation, crystallization. For example, the compound of formula (III) can be purified according to the method described in US 2011 / 017673 A1.

[0047] The compound of formula (III) can be used to prepare a formulation, for example as a contrast agent. The formulation can be prepared by dissolving the formulation in a solvent (e.g., water). This allows the formulation to be injected into a subject.

[0048] In addition to the solvent, the formulation may further include one or more of a buffer, a complexing agent, and a pH regulator. The buffer may be tromethamine. The complexing agent may be calcium disodium EDTA. The pH regulator may be hydrochloric acid and / or sodium hydroxide. The formulation may include a compound of formula (III), water, tromethamine, calcium disodium EDTA, and hydrochloric acid and / or sodium hydroxide.

[0049] The present invention also relates to compounds and / or formulations produced by the methods of the present invention. The present invention also relates to uses of the compounds and / or formulations produced by the methods of the present invention. In particular, the compounds and / or formulations can be used as contrast agents (e.g., in a subject).

[0050] The present invention also relates to the use of the compound of formula (II) as an intermediate in the production method of iopamidol.

[0051] Example

[0052] The present invention is described with reference to the following examples.

[0053] Example 1

[0054] 5-Amino-N,N'-bis(1,3-dihydroxypropan-2-yl)-2,4,6-triiodoisophthalamide (30.0 g; 42.6 mmol), acetonitrile (93.0 g), and pyridine (18.5 g; 234 mmol) were added to a reactor under magnetic stirring. The reaction medium was heated to 67°C, and (S)-2-acetoxypropanoyl chloride (22.0 ml; 174 mmol) was added over 60 minutes. The reaction mixture was cooled to 35°C, and a further amount of (S)-2-acetoxypropanoyl chloride (9.2 ml; 72.7 mmol) was added over 60 minutes, then left to stir for a further 18 hours. Water (150 ml) was added, followed by the cautious addition of 50% NaOH (54.4 g; 680 mmol). The pH was then adjusted to 13.5 using a further amount of 50% NaOH and stirred for 45 minutes. The reaction mixture was neutralized to pH 7.0 using 35% HCl, and the organic solvent was distilled off under reduced pressure to obtain iopamidol with an HPLC purity of 91.6%.The iopamidol product can be further purified using conventional purification methods.

[0055] Example 2

[0056] 5-Amino-N,N'-bis(1,3-dihydroxypropan-2-yl)-2,4,6-triiodoisophthalamide (30.1 g; 42.7 mmol), acetonitrile (93.0 g), and pyridine (20.4 g; 258 mmol) were added to a reactor with magnetic stirring. The reactor temperature was set to 67.5°C, and (S)-2-acetoxypropionyl chloride (31.2 ml; 246 mmol) was added over 60 minutes. Four hours after the addition, the reactor was cooled to ambient temperature, and water (150 ml) was added, followed by the careful addition of 50% NaOH (54.4 g; 680 mmol). The pH was then adjusted to 13.5 using an additional amount of 50% NaOH and stirred for 30 minutes. The reaction mixture was neutralized to pH 6.5 using 35% HCl, and the organic solvent was distilled off under reduced pressure to yield iopamidol with a purity of 91.2%. The iopamidol product can be further purified using conventional purification methods.

[0057] Example 3

[0058] 5-Amino-N,N'-bis(1,3-dihydroxypropan-2-yl)-2,4,6-triiodoisophthalamide (30.0 g; 42.6 mmol), acetonitrile (93.0 g), and pyridine (18.5 g; 234 mmol) were added to a reactor with magnetic stirring. The reactor temperature was set to 60°C, and (S)-2-acetoxypropionyl chloride (30.6 ml; 242 mmol) was added over 60 minutes. Five hours after the addition, the reactor was cooled to ambient temperature, and water (150 ml) was added, followed by the careful addition of 50% NaOH (53.2 g; 665 mmol). The pH was then adjusted to 13.5 using an additional amount of 50% NaOH and stirred for 30 minutes. The reaction mixture was neutralized to pH 7.0 using 35% HCl, and the organic solvent was distilled off under reduced pressure to yield iopamidol with a purity of 92.5%. The iopamidol product can be further purified using conventional purification methods.

[0059] Example 4

[0060] 5-Amino-N,N'-bis(1,3-dihydroxypropan-2-yl)-2,4,6-triiodoisophthalamide (40.0 g; 56.7 mmol), acetonitrile (124 g), and pyridine (20.7 g; 262 mmol) were added to a reactor under magnetic stirring. The temperature of the reactor was set to 25°C, and (S)-2-acetoxypropanoyl chloride (43.5 ml; 344 mmol) was added over 30 minutes. The reaction mixture was stirred at 25°C for 23 hours, and water (100 ml) was added. 50% NaOH (76.0 g; 950 mmol) was slowly added to the reaction mixture to obtain a pH of 11.7. The pH was then adjusted to 13.6 by carefully adding more 50% NaOH. After stirring for 30 minutes, the pH was adjusted to 6.9 using 35% HCl, and the organic solvent was distilled off under reduced pressure. The crude product was desalted using electrodialysis and ion exchange resins (Purolite PPC150 and Purolite A847) and further purified by passing the solution through a column with Amberlite XAD1600N, followed by evaporation of water to give iopamidol with 98.2% purity.

[0061] Example 5

[0062] Under magnetic stirring, a round-bottom flask was charged with 5-amino-N,N'-bis(1,3-dihydroxypropan-2-yl)-2,4,6-triiodoisophthalamide (3.53 g; 5.00 mmol), toluene (8.67 g), and pyridine (2.38 g; 30.0 mmol). (S)-2-Acetoxypropionyl chloride (4.04 ml; 31.9 mmol) was added over 60 minutes, and the reaction mixture was left to stir at ambient temperature for 18 hours. Water (40 ml) and methanol (40 ml) were added, and the pH was adjusted and maintained at 13.5 by the addition of 25% NaOH. After stirring for 30 minutes, the reaction mixture was neutralized to pH 7 with acetic acid and concentrated under reduced pressure to yield iopamidol with 57% HPLC purity as a dark brown residue. The iopamidol product can be further purified using conventional purification methods.

[0063] Example 6

[0064] Under magnetic stirring, a round-bottom flask was charged with 5-amino-N,N'-bis(1,3-dihydroxypropan-2-yl)-2,4,6-triiodoisophthalamide (3.53 g; 5.00 mmol), THF (8.88 g), and pyridine (2.38 g; 30.0 mmol). (S)-2-Acetoxypropionyl chloride (4.04 ml; 31.9 mmol) was added over 60 minutes, and the reaction mixture was left to stir at ambient temperature for 18 hours. Water (50 ml) and methanol (20 ml) were added, and the pH was adjusted and maintained at 13.5 by the addition of 25% NaOH. After stirring for 30 minutes, the reaction mixture was neutralized to pH 7 with acetic acid and concentrated under reduced pressure to yield iopamidol as a yellow residue with 74% HPLC purity. The iopamidol product can be further purified using conventional purification methods.

[0065] Those skilled in the art will appreciate that the examples were generally performed on a laboratory scale and that the conditions used may be adjusted when putting the invention into practice on an industrial scale.

Claims

1. A method for preparing a compound of formula (II): The method comprises: (i) reacting a compound of formula (I) with pyridine and 2-acetoxypropionyl chloride (APC) to obtain a compound of formula (II), wherein the compound of formula (I) has the following structure:

2. The method of claim 1, wherein the method further comprises: (ii) reacting the compound of formula (II) with a hydrolyzing agent to obtain a compound of formula (III):

3. The method of claim 1, wherein the compound of formula (I) is reacted with pyridine and APC in a solvent in step (i).

4. The method of claim 3, wherein the solvent is an aprotic solvent.

5. The method of claim 3, wherein the solvent in step (i) is: (i) toluene, THF, acetonitrile, diethyl ether, methyl ethyl ketone, diglyme, glyme, dioxane, dichloromethane, chloroform, ethyl acetate, benzene, diisopropyl ether or acetone and / or combinations thereof; or (ii) toluene, THF or acetonitrile and / or combinations thereof; or (iii) Acetonitrile.

6. The method of any one of claims 2-5, wherein the hydrolyzing agent is used with water in step (ii) to control the pH to: (i) between 12 and 14; or (ii) between 12.8 and 13.7; or (iii) about 13.

5.

7. The method of any one of claims 2 to 5, wherein the hydrolyzing agent in step (ii) is: (a) aqueous base or basic ion exchange resin; or (b) aqueous NaOH, aqueous KOH or ammonia and / or combinations thereof; or (c) Aqueous NaOH.

8. The method of any one of claims 1 to 5, wherein step (i) is performed at a temperature of: (a) 5°C to 75°C; or (b) 15°C to 65°C; or (c) 15°C to 50°C; or (d) 15°C to 30°C; or (e) 40°C to 60°C; or (f) 20°C to 30°C.

9. The method of claim 2, wherein step (ii) is performed at the following temperature: (a) 5°C to 95°C; or (b) 5°C to 70°C; or (c) 15°C to 75°C; or (d) 15°C to 60°C; or (e) 15°C to 50°C; or (f) 40°C to 60°C; or (g) 20°C to 40°C.

10. The method of claim 1, wherein in step (i), APC is added to a mixture of at least the compound of formula (I) and pyridine: (i) within a period of 0 to 10 hours; and / or (ii) in a first amount, followed by cooling and subsequently adding APC in a second amount, wherein the first amount and the second amount are the same or different.

11. The method of claim 10, wherein in step (i), APC is added to a mixture of at least the compound of formula (I) and pyridine: (i) within a period of 0.5 to 6 hours; and / or (ii) in a first amount, followed by cooling and subsequently adding APC in a second amount, wherein the first amount and the second amount are the same or different.

12. The method of claim 11, wherein in step (i), APC is added to a mixture of at least the compound of formula (I) and pyridine: (i) within a period of 1 to 3 hours; and / or (ii) in a first amount, followed by cooling and subsequently adding APC in a second amount, wherein the first amount and the second amount are the same or different.

13. The method of claim 10, wherein in step (i), APC is added to a mixture of at least the compound of formula (I) and pyridine: (i) within a period of 0 to 10 hours; and / or (ii) in a first amount, followed by cooling and subsequently adding APC in a second amount, wherein the first amount and the second amount are the same or different, wherein cooling is to a temperature of 10°C to 40°C.

14. The method of claim 13, wherein in step (i), APC is added to a mixture of at least the compound of formula (I) and pyridine: (i) within a period of 0 to 10 hours; and / or (ii) in a first amount, followed by cooling and subsequently adding APC in a second amount, wherein the first amount and the second amount are the same or different, and wherein cooling is to ambient temperature.

15. The process of any one of claims 9 to 14, wherein after the addition of the APC, the resulting reaction mixture is maintained at a temperature as defined in claim 8.

16. The process of claim 15, wherein after the addition of the APC, the resulting reaction mixture is maintained at a temperature as defined in claim 8 for up to 24 hours.

17. The process of claim 16, wherein after the addition of APC, the resulting reaction mixture is maintained at a temperature as defined in claim 8 for 2 to 12 hours.

18. The method of claim 2, wherein the compound of formula (II) produced in step (i) is reacted in step (ii) without isolation.

19. The method of claim 2, wherein the compound of formula (III) is purified.

20. The method of claim 19, wherein the purification comprises one or more of the following: desalting, resin treatment, distillation, and crystallization.

21. The method of claim 2, wherein the compound of formula (III) is dissolved in a solvent to prepare the formulation.

22. The method of claim 21, wherein: (i) the formulation further comprises a solvent; and / or (ii) the formulation further comprises a buffer; and / or (iii) the formulation further comprises a complexing agent; and / or (iv) The formulation further comprises a pH adjuster.

23. The method of claim 22, wherein the solvent is water.

24. The method of claim 22, wherein the buffer is tromethamine.

25. The method of claim 22, wherein the complexing agent is calcium disodium EDTA.

26. The method of claim 22, wherein the pH adjuster is hydrochloric acid or sodium hydroxide.

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