Method for preparing iopamidol

Abstract

The present invention provides a method for preparing a compound of formula (II), comprising the step of: (i) reacting a compound of formula (I), having the structure: [Formula 1] JPEG2023531544000014.jpg5138

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to x-ray contrast agents, and in particular to a method for producing iodinated x-ray contrast agents.The method of the present invention offers certain advantages over known such methods. [Background technology]

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

[0003] [ka] It is referred to as a compound of the formula:

[0004] The manufacture of iopamidol requires the production of a compound of formula (III) followed by the preparation of a formulation for use as an imaging agent. Typically, the compound is produced in a multi-step synthesis and then purified before use in a formulation. At each synthetic step, it is important to optimize the yield and minimize the production of impurities. In steps where expensive reagents are used, it is particularly important to optimize the use of such reagents. Iodinating reagents are expensive, and therefore triiodination of the aromatic ring is a critical step and is generally performed at a later stage in the overall synthesis. In this step, it is particularly important to obtain a high yield with few impurities and to minimize the consumption of the iodinating agent.

[0005] Iopamidol has previously been produced by a process such as that depicted in the reaction scheme of Figure 1. Such a process is described, for example, in WO 02 / 44132. This process has the disadvantage of requiring the use of solvents such as N,N-dimethylacetamide (DMAc) and hazardous, corrosive chemicals such as SOCl.

[0006] Iopamidol has also been previously produced by the method represented in the reaction scheme of FIG. 2. In this reaction scheme, the alkyl ester of 5-nitroisophthalic acid is first reacted with 2-amino-1,3-propanediol (serinol) to obtain the compound 5-amino-N,N'-bis(1,3-dihydroxypropan-2-yl)isophthalamide (also known as 1,3-ABA). Then, 1,3-ABA is iodinated using iodine monochloride. The free hydroxyl groups in the resulting compound are protected in several different ways, for example, by converting them to acetals using acetone, to esters using acid anhydrides, or to phosphate esters using alkyl phosphates or aryl phosphates. The protected intermediate is then N-acylated with 2-acetoxypropanoyl chloride (APC), deprotected, and hydrolyzed to obtain iopamidol.

[0007] An improved method is needed for the production of iopamidol. The method of the present invention meets this need.

[0008] The present invention provides advantages over the above-described method for producing iopamidol. For example, the method of the present invention is more user-friendly than those previously used, has no limitations, and can be carried out in environmentally friendly solvents. In addition, the method of the present invention can be carried out in fewer process steps than previous methods, resulting in significant cost savings. In particular, compared to the reaction scheme shown in FIG. 2, the method of the present invention avoids the need for a protection step before reacting with APC. SUMMARY OF THE INVENTION

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

[0010]

Chemical formula

[0011]

Chemical formula

[0012] In another aspect, the present invention provides a compound or formulation produced by the method of the present invention.

[0013] The present invention also relates to formula (III):

[0014]

Chemical formula

[0015] The present invention has advantages compared to conventional methods. In the reaction sequence, the use of OH - protecting groups that would introduce an additional protection step and possibly an additional deprotection step is avoided. The use of high - boiling solvents such as DMAc or DMF, which are subject to strict regulations under the REACH Directive, is also avoided, thereby inhibiting the formation of certain impurities. Furthermore, the method does not use expensive and toxic catalysts such as DMAP and shortens the reaction time.

Brief Description of the Drawings

[0016]

Figure 1

Figure 2

Figure 3

Embodiments for Carrying Out the Invention

[0017] The present invention relates to formula (II):

[0018] [[ID=5--]]

Chemical formula

[0019]

Chemical formula

[0020] This method further includes (ii) reacting the compound of formula (II) with a hydrolyzing agent to obtain a compound of formula (III):

[0021]

Chemical formula

[0022] A reaction scheme showing the steps that can be performed in the method of the present invention is presented in Figure 3.

[0023] The starting compound of the method of the present invention can be prepared by any suitable method.

[0024] For example, N,N'-substituted 5-amino-1,3-benzenedicarboxamides (e.g., shown below as compounds of formula (IV)) are known as intermediates in the synthesis of iopamidol. These compounds can be used to prepare the compound of formula (I) by iodination. In the following formula, R represents a 1,3-dihydroxy-2-propyl group (R = -CH(CH2OH)2) or a 2,3-dihydroxy-1-propyl group (R = -CH2CH(OH)CH2(OH)).

[0025]

Chemical formula

[0026] The compound of formula (IV) can be prepared starting from dimethyl 5-nitro-1,3-benzenedicarboxylate (shown below as the compound of formula (V)) and amidating the ester groups, for example, using 2-amino-1,3-dihydroxypropane (commonly known as serinol) or 1-amino-2,3-dihydroxypropane (commonly known as isoserinol), and then reducing the 5-nitro group of the resulting N,N'-bis-substituted 5-nitro-1,3-benzenedicarboxamide. Alternatively, the reduction reaction step can be carried out first, followed by the amidation reaction step.

[0027]

Chemical formula

[0028] The amidation reaction in such a process is usually carried out using at least a stoichiometric amount of serinol or isoserinol (i.e., at least 2 moles of serinol or isoserinol per mole of dimethyl 5-nitro-1,3-benzenedicarboxylate) in the presence of a protic organic solvent such as a lower alkanol and at a temperature of about 65 °C to about 150 °C. Further details regarding such a process are described in WO 02 / 44125 pamphlet and WO 00 / 29372 pamphlet.

[0029] N,N'-substituted 5-amino-1,3-benzenedicarboxamides (for example, the compound of formula (IV)) can also be prepared as described in WO 00 / 29372 pamphlet. For example, in a solvent containing a lower aliphatic alcohol containing a basic catalyst, di-lower alkyl 5-nitroisophthalate is reacted with at least 2 molar equivalents of a compound of formula RNH2 (for example, where R is CH2CH(OH)CH2OH or CH(CH2OH)2) to obtain a solution containing 5-nitro-N,N'-bis(R) isophthalamide. Without isolating 5-nitro-N,N'-bis(R) isophthalamide, the solution may be hydrogenated catalytically to obtain a solution of 5-amino-N,N'-bis(R)-isophthalamide.

[0030] Further details of the method of the present invention are presented below. Any of the features presented below can be combined with any other feature presented below.

[0031] In this method, in step (i), the compound of formula (I) is reacted with pyridine and APC in a solvent. The solvent in step (i) may 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.

[0032] Step (i) of this method can be carried out at any suitable temperature. For example, step (i) may 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.

[0033] In step (i) of the method, the APC may be added to a mixture of at least the compound of formula (I) and pyridine. In step (i) of the method, the APC may be added to a mixture of at least the compound of formula (I) and pyridine over 0 to 10 hours, 0.5 to 6 hours or 1 to 3 hours. The APC may be added in a first amount, followed by cooling and subsequent addition of a second amount of APC, and the first and second amounts may be the same or different. When cooling, it may be to a temperature of 10 to 40 °C or to ambient temperature.

[0034] Pyridine has three important functions. First, the main function of pyridine is to act as a base so that HCl is generated during the reaction. Free HCl causes the decomposition of the compound of formula (II). Second, pyridine is a co-solvent in the reaction. The compound of formula (II) is difficult to decompose in most organic solvents including acetonitrile, but is soluble in pyridine. Third, pyridine acts as a catalyst in the reaction. When the APC is added to the reaction mixture, the APC first reacts with pyridine to form an acylpyridinium complex. The acylpyridinium complex then reacts with the free hydroxyl-(OH) group and amine (NH2) group of the compound of formula (I) to finally obtain the compound of formula (II).

[0035] After the addition of the APC, the resulting reaction mixture may 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 may be maintained at any of these temperatures for up to 24 hours or for 2 to 12 hours.

[0036] The compound of formula (II) produced in step (i) of the method may be reacted in step (ii) of the method without being isolated. In particular, it is not necessary to purify the compound of formula (II) produced in step (i) before further reaction.

[0037] Step (ii) of this method can be carried out at any suitable temperature. For example, step (ii) may 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°C to 50°C, 40°C to 60°C or 20°C to 40°C.

[0038] Step (ii) of this method can be carried out under acidic conditions or basic 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.

[0039] In this method, the hydrolyzing agent can be used together with water in step (ii) to control the pH between 12 and 14. The hydrolyzing agent can 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 to approximately 13.5.

[0040] The hydrolyzing agent in step (ii) may be an aqueous base solution or a basic ion exchange resin. The hydrolyzing agent in step (ii) may be an aqueous NaOH solution, an aqueous KOH solution or ammonia, and / or combinations thereof. In particular, the hydrolyzing agent in step (ii) may be an aqueous NaOH solution.

[0041] The compound of formula (III) may be purified. It is desirable to purify the compound of formula (III) to obtain 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, namely, desalting (e.g., electrodialysis or ion exchange resin), distillation, one or more columns (e.g., using Amberlite XAD1600N), evaporation of water, crystallization can be used in any combination. For example, the compound of formula (III) can be purified according to the method described in US Patent Application Publication No. 2011 / 017673.

[0042] Using the compound of formula (III), a formulation for use, for example, as a contrast agent can be prepared. The formulation can be prepared by dissolving the compound of formula (III) in a solvent (such as water). This enables the formulation to be injected into a subject.

[0043] In addition to the solvent, the formulation may further contain one or more of a buffering agent, a complexing agent, and a pH adjuster. The buffering agent may be tromethamine. The complexing agent may be calcium disodium EDTA. The pH adjuster may be hydrochloric acid and / or sodium hydroxide. The formulation may contain the compound of formula (III), water, tromethamine, calcium disodium EDTA, and hydrochloric acid and / or sodium hydroxide.

[0044] The present invention also relates to the compounds and / or formulations produced by the methods described according to the present invention. The present invention also relates to the use of the compounds and / or formulations produced by the methods of the present invention. In particular, the present compounds and / or the present formulations can be used as contrast agents (for example, in a subject).

[0045] The present invention also relates to the use of the compound of formula (II) as an intermediate in a method for producing iopamidol.

Examples

[0046] The present invention will be described with reference to the following examples.

[0047] [Example 1] 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 the reactor with magnetic stirring. The reaction medium was heated to 67 °C and (S)-2-acetyloxypropanoyl chloride (22.0 ml; 174 mmol) was added over 60 minutes. The reaction mixture was cooled to 35 °C, an additional amount of (S)-2-acetyloxypropanoyl chloride (9.2 ml; 72.7 mmol) was added over 60 minutes, and then the mixture was allowed to stand with stirring for a further 18 hours. Water (150 ml) was added, followed by careful addition of 50% NaOH (54.4 g; 680 mmol). An additional amount of 50% NaOH was then used to adjust the pH to 13.5 and the mixture was 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.

[0048] [Example 2] 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 the reactor with magnetic stirring. The temperature of the reactor was set to 67.5 °C and (S)-2-acetyloxypropanoyl chloride (31.2 ml; 246 mmol) was added over 60 minutes. Four hours after the addition, the reactor was cooled to ambient temperature, water (150 ml) was added, followed by careful addition of 50% NaOH (54.4 g; 680 mmol). An additional amount of 50% NaOH was then used to adjust the pH to 13.5 and the mixture was 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 obtain iopamidol with a purity of 91.2%. The iopamidol product can be further purified using conventional purification methods.

[0049] [Example 3] 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 the reactor with magnetic stirring. The temperature of the reactor was set at 60 °C, and (S)-2-acetyloxypropanoyl chloride (30.6 ml; 242 mmol) was added over 60 minutes. Five hours after the addition, the reactor was cooled to ambient temperature, water (150 ml) was added, and then 50% NaOH (53.2 g; 665 mmol) was carefully added. Then, an additional amount of 50% NaOH was used to adjust the pH to 13.5 and stirred for 30 minutes. 35% HCl was used to neutralize the reaction mixture to pH 7.0, and the organic solvent was distilled off under reduced pressure to obtain iopamidol with a purity of 92.5%. The iopamidol product can be further purified using conventional purification methods.

[0050] [Example 4] 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 the reactor with magnetic stirring. The temperature of the reactor was set at 25 °C, and (S)-2-acetyloxypropanoyl 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 bring the pH to 11.7. Then, the pH was adjusted to 13.6 by carefully adding additional 50% NaOH. After stirring for 30 minutes, 35% HCl was used to adjust the pH to 6.9, 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 the solution was further purified by passing it through a column with Amberlite XAD1600N, and then water was evaporated to obtain iopamidol with a purity of 98.2%.

[0051] [Example 5] 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) were added to a round-bottom flask with magnetic stirring. (S)-2-Acetoxypropanoyl chloride (4.04 ml; 31.9 mmol) was added over 60 minutes and the reaction mixture was left to stand with stirring at ambient temperature for 18 hours. Water (40 ml) and methanol (40 ml) were added and the pH was adjusted to 13.5 by adding 25% NaOH and maintained. After stirring for 30 minutes, the reaction mixture was neutralized to pH 7 with acetic acid and concentrated under reduced pressure to give iopamidol as a dark brown residue with an HPLC purity of 57%. The iopamidol product can be further purified using conventional purification methods.

[0052] [Example 6] 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) were added to a round-bottom flask with magnetic stirring. (S)-2-Acetoxypropanoyl chloride (4.04 ml; 31.9 mmol) was added over 60 minutes and the reaction mixture was left to stand with stirring at ambient temperature for 18 hours. Water (50 ml) and methanol (20 ml) were added and the pH was adjusted to 13.5 by adding 25% NaOH and maintained. After stirring for 30 minutes, the reaction mixture was neutralized to pH 7 with acetic acid and concentrated under reduced pressure to give iopamidol as a yellow residue with an HPLC purity of 74%. The iopamidol product can be further purified using conventional purification methods.

[0053] Those skilled in the art will understand that the examples were carried out on a laboratory scale as usual and that the conditions used can be adapted when implementing the present invention on an industrial scale. The present invention includes the following aspects. <1> Formula (II):

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Claims

1. A method for preparing a compound of formula (II): 【Chemical 1】 comprising: (i) reacting a compound of formula (I) having the following structure: [Chemical Formula 2] with pyridine and 2 - acetyloxypropanoyl chloride (APC) to obtain a compound of formula (II).

2. (ii) further comprising reacting the compound of formula (II) with a hydrolyzing agent to obtain a compound of formula (III): 【Chemical Formula 3】 The method according to claim 1.

3. The method according to claim 1 or claim 2, wherein in step (i), the compound of formula (I) is reacted with pyridine and APC in a solvent.

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

5. The solvent in step (i) is (i) toluene, THF, acetonitrile, diethyl ether, methyl ethyl ketone, diglyme, glyme, dioxane, methylene chloride, chloroform, ethyl acetate, benzene, diisopropyl ether, or acetone, and / or a combination thereof, or (ii) toluene, THF, or acetonitrile, and / or a combination thereof, or (iii) acetonitrile, The method according to claim 4.

6. The method according to claim 2, wherein in step (ii), the hydrolyzing agent is used together with water to control the pH to (i) 12 - 14, or (ii) 12.8 - 13.7, or (iii) 13.

5.

7. The hydrolyzing agent in step (ii) is (a) an aqueous base solution or a basic ion - exchange resin, or (b) an aqueous NaOH solution, an aqueous KOH solution, or ammonia, and / or a combination thereof, or (c) an aqueous NaOH solution, The method according to claim 2 or claim 6.

8. Step (i) is carried out at a temperature of (a) 5°C - 75°C, or (b) 15°C - 65°C, or (c) 15°C - 50°C, or (d) 15°C - 30°C, or (e) 40°C - 60°C, or (f) 20°C - 30°C The method according to any one of claims 1 to 7.

9. Step (ii) is carried out at a temperature of (a) 5°C - 95°C, or (b) 5°C - 70°C, or (c) 15°C - 75°C, or (d) 15°C - 60°C, or (e) 15°C - 50°C, or (f) 40°C - 60°C, or (g) 20°C - 40°C The method according to any one of claims 2 to 8.

10. In step (i), the APC is added to a mixture of at least the compound of formula (I) and pyridine (i) over a period of more than 0 hours to 10 hours, and / or (ii) added in a first amount, followed by cooling and subsequent addition of a second amount of APC, where the first amount and the second amount may be the same or different, The method according to any one of claims 1 to 9.

11. In step (i), the APC is added to a mixture of at least the compound of formula (I) and pyridine (i) added over a period of 0.5 to 6 hours, the method according to claim 10.

12. In step (i), the APC is added to a mixture of at least the compound of formula (I) and pyridine (i) added over a period of 1 to 3 hours, the method according to claim 10 or 11.

13. In step (i), the APC is added to a mixture of at least the compound of formula (I) and pyridine, and in step (ii) of claim 10, the cooling is to a temperature of 10°C to 40°C, the method according to any one of claims 10 to 12

14. In step (i), the APC is added to a mixture of at least the compound of formula (I) and pyridine, and in step (ii) of claim 10, the cooling is to ambient temperature, the method according to any one of claims 10 to 13.

15. After the addition of the APC, the resulting reaction mixture is maintained at the temperature according to claim 8, the method according to any one of claims 9 to 14.

16. The resulting reaction mixture is maintained for up to 24 hours, the method according to claim 15.

17. The resulting reaction mixture is maintained for 2 to 12 hours, the method according to claim 15 or 16.

18. The compound of formula (II) produced in step (i) is reacted in step (ii) without being isolated, the method according to any one of claims 2 to 17.

19. The compound of formula (III) is purified, the method according to any one of claims 2 to 18.

20. The purification includes one or more of desalting, resin treatment, distillation, and crystallization, the method according to claim 19.

21. The compound of formula (III) is dissolved in a solvent to produce a formulation, the method according to any one of claims 2 to 20.

22. (i) the formulation further contains a solvent, and / or (ii) the formulation further comprises a buffering agent, and / or (iii) the formulation further comprises a complexing agent, and / or (iv) the formulation further comprises a pH adjuster, The method according to claim 21. **Claim 23** The method according to claim 22, wherein in (i) the solvent is water. **Claim 24** The method according to claim 22 or 23, wherein in (ii) the buffering agent is tromethamine. **Claim 25** The method according to any one of claims 22 to 24, wherein in (iii) the complexing agent is calcium disodium EDTA. **Claim 26** The method according to any one of claims 22 to 25, wherein in (iv) the pH adjuster is hydrochloric acid or sodium hydroxide.

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