Preparation method and use of an iopromide intermediate

Abstract

The present invention relates to a preparation method and use of an iopromide intermediate, specifically to a preparation method of a compound of formula III, 3-(3-(chlorocarbonyl)-2,4,6-triiodo-5-(2-methoxyacetamido)benzamido)propane-1,2-diyl diacetate, and its use for preparing iopromide. The preparation method provided by the present invention has the advantages of simple operation, high yield and suitability for industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of drug synthesis, and relates to a preparation method and use of an iopromide intermediate. Specifically, it relates to a preparation method of diethyl 3-(3-(chlorocarbonyl)-2,4,6-triiodo-5-(2-methoxyacetamido)benzamido)propane-1,2-diacetate and its use for preparing iopromide. Background Art

[0002] Iopromide is a non-ionic iodine-containing contrast agent developed by Schering AG of Germany. Its chemical name is N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-5-[(methoxyacetyl)amino]-N-methyl-1,3-benzenedicarboxamide, and its structure is shown in Formula I. It can be used for angiography, renal arteriography, urography, contrast-enhanced examination of CT, and body cavity display (including arthrography, hysterosalpingography, fistulography).

[0003]

[0004] The preparation methods of iopromide are disclosed in US Patent US4364921, PCT Patent WO2009134030, Chinese Applications CN102351735, CN102964269, CN102015624, etc.

[0005] US Patent US4364921 discloses three preparation routes, and the reaction routes are as follows:

[0006] Route 1:

[0007]

[0008] Route 2:

[0009]

[0010] Route 3:

[0011]

[0012] In the above Route 1, during the process of preparing the compound of Formula 3 from the compound of Formula 2, it is easy to generate the bis-acylation by-product (bismer) shown in Formula 18;

[0013]

[0014] Although the above Routes 2 and 3 can avoid the generation of the bis-acylation by-product shown in Formula 18, the by-products in the iodination reaction step are numerous, the purity is low, and the separation and purification are difficult, which is not conducive to industrial production.

[0015] Therefore, it is particularly important to find a new preparation method of iopromide and its related intermediates that is more suitable for industrial production. Summary of the Invention

[0016] On the one hand, the present invention provides a preparation method of a compound of formula III, which is an intermediate of iopromide. The chemical name of the compound of formula III is: diethyl 3-(3-(chlorocarbonyl)-2,4,6-triiodo-5-(2-methoxyacetamido)benzamido)propane-1,2-diacetate; the preparation method of the compound of formula III includes the following steps:

[0017] (d) The compound of formula VI reacts with acetic anhydride to obtain the compound of formula V;

[0018] (e) The compound of formula V reacts with methoxyacetyl chloride to obtain the compound of formula IV;

[0019] (f) The compound of formula IV undergoes a reaction to obtain the compound of formula III.

[0020] The preparation process of the compound of formula III is as follows:

[0021]

[0022] In some embodiments, for the preparation method of the compound of formula III of the present invention, step (d) is carried out in the presence of acetic anhydride, a solvent and a catalyst.

[0023] In some embodiments, for the preparation method of the compound of formula III of the present invention, the solvent in step (d) is selected from ethanol, isopropanol, dichloromethane, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, toluene, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, isopropyl ether and dioxane; preferably 2-methyltetrahydrofuran, cyclopentyl methyl ether and tetrahydrofuran; more preferably tetrahydrofuran.

[0024] In some embodiments, for the preparation method of the compound of formula III of the present invention, the catalyst in step (d) is selected from triethylamine, pyridine, 4-dimethylaminopyridine (DMAP), 2,6-dimethylpyridine, 2,6-di-tert-butyl-4-methylpyridine, N-methylmorpholine, 1,8-diazabicycloundec-7-ene (DBU), triethylenediamine (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and tetramethylethylenediamine (TMPDA); preferably DBU and 4-dimethylaminopyridine; more preferably 4-dimethylaminopyridine.

[0025] In some embodiments, the method for preparing the compound of formula III of the present invention, wherein the molar ratio of the compound of formula VI to acetic anhydride in step (d) is 1:1 to 5; preferably 1:2 to 4; more preferably 1:3 to 4.

[0026] In some embodiments, the method for preparing the compound of formula III of the present invention, wherein the molar volume ratio of the compound of formula VI to the solvent in step (d) is 1 mmol: 0.5 to 2 mL; preferably 1 mmol: 0.5 to 1 mL; more preferably 1 mmol: 0.7 to 1 mL.

[0027] In some embodiments, the method for preparing the compound of formula III of the present invention, wherein the temperature for carrying out the reaction in step (d) is selected from 60 to 100 °C; preferably 60 to 80 °C; more preferably 65 to 70 °C.

[0028] In some embodiments, the method for preparing the compound of formula III of the present invention, wherein step (d) further includes a post-treatment step: the reaction solution after reacting the compound of formula VI with acetic anhydride is concentrated under reduced pressure, and further recrystallized to obtain the compound of formula V.

[0029] In some embodiments, the method for preparing the compound of formula III of the present invention, wherein the solvent for recrystallization in the post-treatment step of step (d) is selected from dichloromethane, dichloroethane, ethyl acetate, isopropyl acetate, toluene, xylene, cumene, acetone, methyl tert-butyl ether and isopropyl ether; preferably ethyl acetate and toluene; more preferably toluene.

[0030] In some embodiments, the method for preparing the compound of formula III of the present invention, wherein the volume molar ratio of the solvent for recrystallization to the compound of formula VI in the post-treatment step of step (d) is 1 to 4 mL: 1 mmol; preferably 2 to 4 mL: 1 mmol; more preferably 2 to 3 mL: 1 mmol.

[0031] In some embodiments, the method for preparing the compound of formula III of the present invention, wherein the temperature for concentration under reduced pressure in the post-treatment step of step (d) is selected from 40 to 70 °C; preferably 40 to 60 °C; more preferably 50 to 60 °C.

[0032] In some embodiments, the method for preparing the compound of formula III of the present invention, wherein the heating temperature for recrystallization in the post-treatment step of step (d) is selected from 60 to 100 °C; preferably 60 to 80 °C; more preferably 70 to 80 °C.

[0033] In some embodiments, the method for preparing the compound of formula III of the present invention, wherein step (e) is carried out in the presence of methoxyacetyl chloride and a solvent.

[0034] In some embodiments, a method for preparing the compound of formula III of the present invention, wherein the solvent in step (e) is selected from tetrahydrofuran, acetone, acetonitrile, ethyl acetate, isopropyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, toluene; preferably ethyl acetate and acetonitrile; more preferably acetonitrile.

[0035] In some embodiments, a method for preparing the compound of formula III of the present invention, wherein the molar ratio of the compound of formula V to methoxyacetyl chloride in step (e) is 1:1 to 3; preferably 1:2 to 3; more preferably 1:2 to 2.5.

[0036] In some embodiments, a method for preparing the compound of formula III of the present invention, wherein the molar volume ratio of the compound of formula V to the solvent in step (e) is 1 mmol: 1 to 5 mL; preferably 1 mmol: 2 to 4 mL; more preferably 1 mmol: 2.5 to 3 mL.

[0037] In some embodiments, a method for preparing the compound of formula III of the present invention, wherein the temperature for carrying out the reaction in step (e) is selected from 60 to 100 °C; preferably 70 to 90 °C; more preferably 75 to 80 °C.

[0038] In some embodiments, a method for preparing the compound of formula III of the present invention, wherein after the reaction in step (e) is completed, the reaction solution can be directly subjected to the reaction of step (f) without post-treatment.

[0039] In some embodiments, a method for preparing the compound of formula III of the present invention, wherein step (f) is carried out in the presence of thionyl chloride and a solvent.

[0040] In some embodiments, a method for preparing the compound of formula III of the present invention, wherein the solvent in step (f) is selected from tetrahydrofuran, acetone, acetonitrile, ethyl acetate, isopropyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, toluene; preferably ethyl acetate and acetonitrile; more preferably acetonitrile.

[0041] In some embodiments, a method for preparing the compound of formula III of the present invention, wherein the molar ratio of the compound of formula IV to thionyl chloride in step (f) is 1:1 to 3; preferably 1:2 to 3; more preferably 1:2 to 2.5.

[0042] In some embodiments, a method for preparing the compound of formula III of the present invention, wherein the molar volume ratio of the compound of formula IV to the solvent in step (f) is 1 mmol: 1 to 4 mL; preferably 1 mmol: 2 to 4 mL; more preferably 1 mmol: 2 to 3 mL.

[0043] In some embodiments, for the method for preparing the compound of formula III of the present invention, the temperature for carrying out the reaction in step (f) is selected from 60 to 120 °C; preferably 80 to 100 °C; more preferably 80 to 90 °C.

[0044] In some embodiments, for the method for preparing the compound of formula III of the present invention, step (f) further includes a post-treatment step: concentrating the reaction solution after the reaction under reduced pressure, and further performing slurrying to obtain the compound of formula III.

[0045] In some embodiments, for the method for preparing the compound of formula III of the present invention, the solvent used for slurrying in the post-treatment step of step (f) is selected from acetonitrile, ethyl acetate, acetone, dichloromethane, toluene, and tetrahydrofuran; preferably ethyl acetate and toluene; more preferably ethyl acetate.

[0046] On the other hand, the present invention also provides a method for preparing iopromide, comprising the following steps:

[0047] (a) Reacting compound 4 with 3-amino-1,2-propanediol to obtain a compound of formula VIII;

[0048] (b) Subjecting the compound of formula VIII to a reduction reaction to obtain a compound of formula VII;

[0049] (c) Subjecting the compound of formula VII to an iodination reaction to obtain a compound of formula VI;

[0050] (d) Reacting the compound of formula VI with acetic anhydride to obtain a compound of formula V;

[0051] (e) Reacting the compound of formula V with methoxyacetyl chloride to obtain a compound of formula IV;

[0052] (f) Reacting the compound of formula IV to obtain a compound of formula III;

[0053] (g) Reacting the compound of formula III with methylaminoglycerol to obtain a compound of formula II;

[0054] (h) Subjecting the compound of formula II to a hydrolysis reaction to obtain iopromide.

[0055] The preparation process of the iopromide is as follows:

[0056]

[0057] In some embodiments, for the method for preparing iopromide of the present invention, step (a) is carried out in the presence of 3-amino-1,2-propanediol and a solvent, and the solvent is selected from methanol, acetonitrile, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, and N,N-dimethylacetamide; preferably N,N-dimethylformamide.

[0058] In some embodiments, the method for preparing iopromide of the present invention, wherein step (a) further comprises a post-treatment step: adding hydrochloric acid to the reaction solution after the reaction is completed, cooling and stirring for crystallization.

[0059] In some embodiments, the method for preparing iopromide of the present invention, wherein step (b) is carried out in the presence of a reducing agent and a solvent, the reducing agent is selected from Raney nickel / hydrazine hydrate and palladium carbon / hydrazine hydrate, and the solvent is selected from one or more of water, methanol, ethanol, isopropanol and tetrahydrofuran; preferably, the reducing agent is selected from palladium carbon / hydrazine hydrate, and the solvent is selected from water.

[0060] In some embodiments, the method for preparing iopromide of the present invention, wherein step (b) further comprises a post-treatment step: filtering the reaction solution after the reaction is completed, and adding hydrochloric acid to the filtrate and stirring to obtain a solution of the compound of formula VII.

[0061] In some embodiments, the method for preparing iopromide of the present invention, wherein step (c) is carried out in the presence of an iodinating agent and a solvent, the iodinating agent is selected from iodic acid, N-iodosuccinimide and NaICl2; the solvent is selected from one or more of water, methanol, ethanol, isopropanol and tetrahydrofuran; preferably, the iodinating agent is selected from NaICl2, and the solvent is selected from water.

[0062] In some embodiments, the method for preparing iopromide of the present invention, wherein step (c) can be directly reacted in the solution after the completion of step (b).

[0063] In some embodiments, the method for preparing iopromide of the present invention, wherein steps (d), (e) and (f) are as described in the method for preparing the compound of formula III above.

[0064] In some embodiments, the method for preparing iopromide of the present invention, wherein step (g) is carried out in the presence of methylaminoglycerol and a solvent, the solvent is selected from dichloromethane, acetonitrile, tetrahydrofuran, N,N-dimethylformamide and N,N-dimethylacetamide; preferably acetonitrile.

[0065] In some embodiments, the method for preparing iopromide of the present invention, wherein step (h) is carried out in the presence of a base and a solvent, the base is selected from sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide; the solvent is selected from water, methanol, ethanol and isopropanol; preferably, the base is selected from sodium hydroxide, and the solvent is selected from water.

[0066] In some embodiments, the method for preparing iopromide of the present invention, wherein after the completion of step (g), the reaction can be directly carried out in step (h) without post-treatment.

[0067] In some embodiments, the method for preparing iopromide of the present invention, wherein step (h) further comprises a post-treatment step: adding hydrochloric acid to the reaction solution after the reaction is completed, decolorizing with activated carbon, filtering, nanofiltrating, and drying to obtain iopromide.

[0068] On the other hand, the present invention provides the use of the method for preparing the compound of formula III below in the preparation of iopromide, which is characterized by comprising:

[0069] (d) Reacting the compound of formula VI with acetic anhydride to obtain the compound of formula V;

[0070] (e) Reacting the compound of formula V with methoxyacetyl chloride to obtain the compound of formula IV;

[0071] (f) Reacting the compound of formula IV to obtain the compound of formula III.

[0072] The preparation process of the compound of formula III is as follows:

[0073]

[0074] In some embodiments, steps (d), (e) and (f) of the method for preparing the compound of formula III in the above use are as described in the method for preparing the compound of formula III above.

[0075] In the present invention, methoxyacetyl chloride, 3-amino-1,2-propanediol and methylaminoglycerol can all be obtained through commercial channels.

[0076] In the present invention, compound 4 can be obtained through commercial channels.

[0077] In the present invention, unless otherwise specified, the term "room temperature" refers to 20 - 25 °C.

[0078] In the method for preparing the iopromide intermediate compound of formula III provided by the present invention, the acetylation reaction occurs after the nitro reduction reaction and the benzene ring triiodination reaction, avoiding the generation of deacetylation by-products. In the method for preparing iopromide provided by the present invention, multiple steps can adopt tandem reactions, that is, the intermediate does not need to be purified and can be directly used for the next step reaction; even if post-treatment purification is required, the operation is simple. The method for preparing iopromide and its intermediate provided by the present invention has the advantages of simple operation, high yield, and suitability for industrial production. Detailed Description of the Invention

[0079] The following examples further illustrate the technical solutions of the present invention in a non-limiting and detailed manner. They should not be considered as limiting the scope of the present invention, but only as exemplary illustrations and typical representatives of the present invention. Solvents, reagent kits, raw materials, etc. used in the present invention are all commercially available chemically pure or analytically pure products.

[0080] Example 1: Preparation of Compound VIII

[0081]

[0082] Under N2 protection, 200 g of 3-amino-1,2-propanediol and 105 mL of N,N-dimethylformamide were added to a dry reaction flask, and the mixture was stirred and heated to 60 °C. After reaching the temperature, Compound 4 (200 g) was added in batches. After the addition was completed, the internal temperature was maintained at 70 - 80 °C for reaction for 6 hours. TLC was used to monitor until Compound 4 was completely reacted. The temperature was lowered to an internal temperature of 20 - 30 °C, and dilute hydrochloric acid (prepared by dissolving 128 g of concentrated hydrochloric acid in 2 kg of water) was added while controlling the internal temperature below 40 °C. The temperature was further lowered to an internal temperature of 0 - 5 °C and stirred for crystallization for 42 hours. Then, it was filtered by centrifugation and dried to obtain 232 g of Compound VIII, with a yield of 92%.

[0083] Example 2: Preparation of Compound VI

[0084]

[0085] 500 g of purified water, 100 g of Compound VIII, 6 g of palladium-carbon (5%), and 34.6 g of hydrazine hydrate (80%) were added to a reaction flask respectively. After the addition was completed, the temperature of the feed liquid was controlled at 60 - 85 °C and stirred for reaction for 6 hours. After the reaction was completed, the temperature was lowered to 30 - 35 °C and filtered. 70.4 g of hydrochloric acid was added to the filtrate and stirred for 10 minutes to obtain a solution of Compound VII.

[0086] The solution of Compound VII and 500 g of sodium chloride iodine monochloride solution (40%) were added to the reaction flask under stirring, and the temperature of the feed liquid was controlled at 75 - 85 °C and stirred for reaction for 5 hours. After the reaction was completed, the temperature was lowered to 15 - 20 °C and stirred for crystallization for 1 hour, then filtered and dried to obtain 200 g of Compound VI, with a yield of 90%.

[0087] Example 3: Preparation of Compound V

[0088]

[0089] 56 mL of tetrahydrofuran, 25 g of acetic anhydride, and 5 mg of 4-dimethylaminopyridine were added to a reaction flask. Compound VI (50 g) was added under stirring, and the mixture was refluxed at 65 - 70 °C. TLC was used to track until the reaction was complete. Then, it was concentrated under reduced pressure at 50 - 60 °C, 173.2 mL of toluene was added, and recrystallization was carried out at 70 - 80 °C for more than 2 hours. After cooling to room temperature, it was filtered to obtain 55 g of Compound V, with a yield of 97%.

[0090] Example 4: Preparation of Compound III

[0091]

[0092] 18.3 g of thionyl chloride and 1.3 mL of N,N-dimethylformamide were added to a reaction flask. Under nitrogen protection, 13.8 g of methoxyacetic acid was added dropwise at room temperature. The reaction was carried out until no obvious gas was generated, then the temperature was raised to 40 - 50 °C and reacted for 2 hours, and then the temperature was raised to 70 - 80 °C and reacted until no obvious gas was generated to obtain 16.6 g of methoxyacetyl chloride.

[0093] 55 g of the compound of formula V, 16.6 g of methoxyacetyl chloride and 191 mL of acetonitrile were added to a reaction flask, and the temperature was raised to an internal temperature of 75 - 80 °C and reacted for 4 hours to obtain a solution of the compound of formula IV.

[0094] The temperature of the reaction solution was lowered to 50 - 60 °C, 18.3 g of thionyl chloride was added to the reaction solution of the compound of formula IV in the previous step, and the reaction was carried out at 80 - 90 °C. TLC was used to monitor until the remaining amount of the compound of formula IV was ≤1%. The temperature was lowered to room temperature, the acetonitrile was concentrated under reduced pressure, 222 mL of ethyl acetate was added for pulping, and 50 g of the compound of formula III was obtained by filtration with a yield of 81%.

[0095] Example 5: Preparation of Iopromide

[0096]

[0097] 127 mL of acetonitrile, 14 g of methylaminoglycerol and 50 g of the compound of formula III were successively added to a reaction flask, and the internal temperature was controlled at 25 - 40 °C and stirred for reaction. After the reaction was completed, filtration was carried out, the mother liquor was concentrated to dryness, 100 g of an aqueous solution containing 9.9 g of sodium hydroxide (the aqueous sodium hydroxide solution was pre-cooled) was added, and the reaction was stirred at room temperature for 4 hours. After the reaction was completed, dilute hydrochloric acid (prepared by dissolving 20.5 mL of concentrated hydrochloric acid in 250 g of water) was added, 5 g of activated carbon was used for decolorization, filtration was carried out, the filtrate was subjected to nanofiltration to remove salts, and spray drying was carried out to obtain 40 g of iopromide with a yield of 82%.

Claims

1. A preparation method of iopromide, comprising the following steps: (a) Reacting compound 4 with 3 - amino - 1,2 - propanediol to obtain a compound of formula VIII; (b) Subjecting the compound of formula VIII to a reduction reaction to obtain a compound of formula VII; (c) Subjecting the compound of formula VII to an iodination reaction to obtain a compound of formula VI; (d) Reacting the compound of formula VI with acetic anhydride to obtain a compound of formula V; (e) Reacting the compound of formula V with methoxyacetyl chloride to obtain a compound of formula IV; (f) Reacting the compound of formula IV to obtain a compound of formula III; (g) Reacting the compound of formula III with methylaminoglycerol to obtain a compound of formula II; (h) Subjecting the compound of formula II to a hydrolysis reaction to obtain iopromide; The preparation process of the iopromide is as follows: Among them, After the reaction in step (e) is completed, the reaction solution is directly subjected to the reaction in step (f) without post - treatment.

2. The preparation method of iopromide according to claim 1, wherein, Step (d) is carried out in the presence of acetic anhydride, a solvent and a catalyst; the solvent in step (d) is selected from tetrahydrofuran.

3. The preparation method of iopromide according to claim 2, wherein, The catalyst in step (d) is selected from 4 - dimethylaminopyridine.

4. The preparation method of iopromide according to claim 2, wherein, The molar ratio of the compound of formula VI to acetic anhydride in step (d) is 1:3 - 4.

5. The preparation method of iopromide according to claim 1, wherein, Step (e) is carried out in the presence of methoxyacetyl chloride and a solvent; the solvent in step (e) is selected from acetonitrile.

6. The preparation method of iopromide according to claim 5, wherein, The molar ratio of the compound of formula V to methoxyacetyl chloride in step (e) is 1:2 - 2.

5.

7. The preparation method of iopromide according to claim 1, wherein, Step (f) is carried out in the presence of thionyl chloride and a solvent; the solvent in step (f) is selected from acetonitrile.

8. The preparation method of iopromide according to claim 7, wherein, The molar ratio of the compound of formula IV to thionyl chloride in step (f) is 1:2 - 2.5.

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