KR20220139775A - Preparing method of iopamidol - Google Patents

Abstract

The present invention relates to a method for preparing iopamidol, comprising the steps of: avoiding N-acylation by first introducing an acyl group into serinol; using ammonium hydroxide (NH_4OH) for hydrolysis; and separating and purificating products by recrystallization in all processes to obtain iopaidol in high yield and purity without resin. Iopamidol is an iodized contrast agent that is widely used in X-ray imaging diagnostic technology and thus can be usefully utilized in diagnosing a patient's disease in the field of radiology or nuclear medicine.

Description

Preparation method of iopamidol {Preparing method of iopamidol}

The present invention relates to a method for preparing a novel iopamidol and the like.

In a medical diagnosis process using X-rays, many human tissues are invisible due to the low density and thickness difference of human tissues. Therefore, in order to obtain a clearer image for confirming the accuracy of diagnosis, it is necessary to introduce a “contrast agent,” a substance that changes the absorbency of X-rays.

Molecules with high atomic numbers increase photoelectric effects with X-rays. The spectral range of absorption frequencies of X-rays by molecules depends primarily on the arrangement of extra nuclear electrons. The frequency of X-rays used for medical diagnosis is tuned to the X-ray absorption spectra of barium atoms (Ba) and iodine atoms (I). Thus, these two molecules produce high-density shadows during X-ray imaging.

Iodized contrast agents are a class of compounds widely used in X-ray imaging diagnostic technology, and currently second-generation non-ionic contrast agents are mainly used in clinical practice. These include iopamidol, iohexol, iopromide, iomeprol, iopentol, ioversol, and the like, and the contrast agent is trii It has an odized aromatic nucleus.

The abundance of iodine in nature is low. This means that iodine and related compounds used as iodization reagents are relatively expensive. In other words, there is a need for research on a method for preparing a contrast agent to achieve a high yield, reasonable consumption of an iodization reagent, and a reasonable cycle time.

As a prior art, WO 0050385 discloses 5-amino-2,4,6-triiodo-N1,N3-alkylisophthalamide by introducing serinol into 5-amino-2,4,6-triiodoisophthalyl dichloride and reacting it with a suitable protecting agent. A method for preparing Iopamidol by removing all acyl groups present in the compound after acylation of the amino group at position 5 is disclosed. However, the method requires a two-step synthesis method of introduction of an acylation protecting group and a subsequent removal process, and has a problem in that a large amount of resin is used to separate the final compound.

Therefore, the present inventors avoid the N-acylation reaction by first introducing an acyl group into serinol (serinol, 2-amino-1,3-propanediol), and do not require a resin by separating and purifying the product by recrystallization in all processes. , completed the present invention by studying a method for producing Iopamidol with a high yield.

WO 0050385

An object of the present invention is to provide a method for producing Iopamidol.

Another object of the present invention is to provide a contrast medium composition comprising the compound prepared by the above method or a pharmaceutically acceptable salt thereof.

However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problems, and other problems not mentioned will be clearly understood by those skilled in the art from the following description.

In order to solve the above problems, the present invention provides a method for preparing a compound represented by the following formula (1) comprising the following steps.

(1) preparing a compound represented by the formula (5) from the compound represented by the following formula (2); and

(2) acetopropionyl chloride and ammonium hydroxide (NH ₄ OH) are sequentially added to the compound represented by the following formula (5) to obtain a compound represented by the formula (1).

[Formula 1]

;

;

[Formula 2]

;

;

[Formula 5]

,

,

In one embodiment of the present invention, R in the above formula may be a substituted or unsubstituted acyl group.

In another embodiment of the present invention, step (1) may be to prepare a compound represented by the formula (5) by adding a compound represented by the following formula (4) to the compound represented by the formula (2).

[Formula 4]

.

.

As another embodiment of the present invention, the compound represented by Formula 4 may be prepared from Formula 3 below.

[Formula 3]

.

.

In another embodiment of the present invention, in step (2), acetopropionyl chloride is added to the compound represented by Formula 5 to prepare a compound represented by Formula 6 as an intermediate.

[Formula 6]

.

.

In another embodiment of the present invention, the compound represented by Formula 4 is the following Compound 4-1, the compound represented by Formula 5 is the following Compound 5-1, and the compound represented by Formula 6 is the following Compound 6 It can be -1.

[Compound 4-1]

;

;

[Compound 5-1]

;

;

[Compound 6-1]

.

.

In another embodiment of the present invention, the compound represented by Formula 4 is the following Compound 4-2, the compound represented by Formula 5 is the following Compound 5-2, and the compound represented by Formula 6 is the following Compound 6 It can be -2.

[Compound 4-2]

;

;

[Compound 5-2]

;

;

[Compound 6-2]

.

.

In another embodiment of the present invention, R may be an acetyl group or a pivaloyl group.

In another embodiment of the present invention, the acetopropionyl chloride may be a (S)-stereoisomer.

In addition, the present invention provides a contrast medium composition comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof prepared by the above preparation method.

[Formula 1]

.

.

The present invention relates to a method for producing iopamidol, etc., wherein an acyl group is first introduced into serinol to avoid the N-acylation reaction, and hydrolyzed using ammonium hydroxide (NH ₄ OH), and all By separating and purifying the product by recrystallization in the process, Iopamidol can be obtained in high yield and purity without resin. The Iopamidol is an iodized contrast agent that is widely used in X-ray imaging diagnostic technology, and can be usefully used in diagnosing a patient's disease in radiology or nuclear medicine.

As a result of studying a novel method for preparing Iopamidol, the present inventors first protected the serinol salt by acylation, and then converted the serinol salt having an acyl protecting group to 5-amino-2,4,6-triiodo isophthalate. After treatment with one dichloride (ATIPA-Cl), when preparing Iopamidol through acetopropionyl chloride (APC) coupling and hydrolysis with ammonium hydroxide, Iopami in high yield and purity It was confirmed that stones could be obtained.

Accordingly, the method for preparing Iopamidol of the present invention is shown in Scheme 1 below.

[Scheme 1]

On the other hand, the conventional method for preparing Iopamidol is shown in Scheme 2 below.

[Scheme 2]

The prior art converts 5-amino-2,4,6-triiodo isophthaloyl dichloride (ATIPA-Cl) to tetraacetate and introduces a (S)-acetoxypropanoyl group followed by sodium hydroxide (NaOH) As to produce the final compound by hydrolysis, in this process, the overall yield is 60%, but there was a problem in that it was separated and recrystallized using an excessive ion exchange resin column.

On the other hand, in the present invention, the overall yield is 80% (R = Ac), 74% (R = Pv) from the starting material of [Scheme 1], and an acyl protecting group is first introduced into serinol, which is a side reaction of the prior art, N- The acylation reaction can be avoided, the product is separated and purified by recrystallization in all processes, and there is a technical feature of not using a resin.

In the present invention, the term “substitution” refers to a reaction in which an atom or group included in the molecule of a compound is replaced with another atom or group of atoms.

As used herein, the term “acyl group” includes an acyl group derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acid or sulfonic acid, and includes alkanoyl, such as acetyl, propionyl, pivaloyl, and the like; aralkanoyl such as phenylacetyl and the like; aroyl, such as benzoyl, tolyl, and the like; aryloxyalkanoyl such as POA (phenoxyacetyl) and the like; alkoxycarbonyls such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC (tert-butoxycarbonyl), 2-iodoethoxycarbonyl and the like; aralkoxycarbonyls such as CBZ (carbobenzoxy) and the like; arylsulfonyl, such as Mtr (4-methoxy-2,3,6-trimethylbenzenesulfonyl) and the like. In the present invention, the acyl group may be preferably an acetyl group or a pivaloyl group, which can protect the amino group against chemical reactions, but can be used as a protecting group that is easy to remove after the desired chemical reaction is carried out elsewhere in the molecule. have.

As used herein, the term “diagnosis” refers to determining the susceptibility of an individual to a specific disease or disorder, determining whether an individual currently has a specific disease or disorder, or having a specific disease or disorder determining a subject's prognosis, or therametrics (eg, monitoring the subject's condition to provide information about the efficacy of treatment).

As used herein, the term "contrast agent" refers to a substance administered in the body to strongly and specifically contrast or image cancer cells in a living body, and currently in medical and diagnostic fields, images of tissues and cells It is widely used for reinforcement. The term "contrast agent" of the present invention is not limited to the range of conventionally known CT, PET, or MRI contrast agents, and is used to include an imaging agent for ultrasound image analysis, an imaging agent for fluorescence image analysis, and the like.

The composition of the present invention may be administered orally or parenterally in a pharmaceutically effective amount according to a desired method, and the term “pharmaceutically effective amount” of the present invention means a disease with a reasonable benefit/risk ratio applicable to medical treatment. It means an amount sufficient to treat the drug and does not cause side effects, and the effective dose level includes the patient's health condition, severity, drug activity, drug sensitivity, administration method, administration time, administration route, and excretion rate; It may be determined according to factors including the duration of treatment, combination or concurrent drugs, and other factors well known in the medical field.

As used herein, the term “individual” may be a mammal, such as a rat, livestock, mouse, or human, preferably a human.

The composition of the present invention may be formulated in various forms for administration to an individual, and a representative formulation for parenteral administration is an injection formulation, preferably an isotonic aqueous solution or suspension. Formulations for injection may be prepared according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. For example, each component may be dissolved in saline or buffer to be formulated for injection. In addition, formulations for oral administration include, for example, ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups and wafers. , sucrose, mannitol, sorbitol, cellulose and/or glycine) and glidants (eg silica, talc, stearic acid and its magnesium or calcium salts and/or polyethylene glycol). The tablet may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and optionally starch, agar, alginic acid or It may further contain disintegrating agents, such as sodium salts thereof, absorbents, colorants, flavoring agents and/or sweetening agents. The formulation may be prepared by conventional mixing, granulating or coating methods.

The present invention can apply various transformations and can have various embodiments. Hereinafter, specific embodiments are illustrated in the drawings and described in detail in the detailed description. However, this is not intended to limit the present invention to specific embodiments, and should be understood to include all modifications, equivalents, and substitutes included in the spirit and scope of the present invention. In describing the present invention, if it is determined that a detailed description of a related known technology may obscure the gist of the present invention, the detailed description thereof will be omitted.

Example 1. Preparation of 1,3-dialkoxypropane-2-aminium salt

For the preparation of Iopamidol of the present invention, a method for preparing 1,3-dialkoxypropane-2-aminium salt is shown in [Scheme 3] below.

[Scheme 3]

Preparation of 1,3-diacetoxypropane-2-aminium salt (Compound 4-1)

A solution of serinol salt (compound 3 , 1.00 g, 7.84 mmol) in acetyl chloride (1.67 mL) was added and stirred at 90° C. for 3 hours. After completion of the reaction (monitored by TLC), the solution was evaporated under reduced pressure in vacuo to give the compound (1.66 g, 96%) as a white solid.

m.p. 103~104℃

¹ H-NMR (400 MHz, CD ₃ OD) δ4.38-4.23 (m, 4H), 3.79 (s, 1H), 2.12 (s, 6H)

¹³ C NMR (100 MHz, CD ₃ OD) 171.87, 62.38, 50.74, 20.51

LRMS Calcd. for C ₇ H ₁₃ NO ₄ [M+H] ⁺ : 175.08; found 176.0

Preparation of 1,3-bis(pivalooxy)propane-2-iminium salt (Compound 4-2)

A solution of serinol salt (Compound 3 , 2.06 g, 16.15 mmol) in pivaloyl chloride (4.4 mL) was stirred at 90° C. for 3 hours. After completion of the reaction (monitored by TLC), the solution was evaporated under reduced pressure in vacuo to give the compound (4.61 g, 96%) as a white solid.

m.p. 156~159℃

¹ H-NMR (400 MHz, CD ₃ OD) δ4.34-4.25 (m, 4H), 3.86-3.82 (m, 1H), 1.25 (s, 18H)

¹³ C NMR (100 MHz, CD ₃ OD) δ179.04, 62.30, 50.47, 39.91, 27.42

LRMS Calcd. for C ₁₃ H ₂₅ NO ₄ [M+H] ⁺ : 259.18 ; found 260.1

Example 2. Preparation of Iopamidol

The method for preparing Iopamidol of the present invention using the 1,3-dialkoxypropane-2-aminium salt is shown in [Scheme 4] below.

[Scheme 4]

Preparation of ((5-amino-2,4,6-triiodoisophthaloyl)bis(azanediyl))bis(propane-2,1,3-triyl)tetraacetate (Compound 5-1)

To a solution of 5-amino-2,4,6-triiodoisophthaloyl dichloride (ATIPA-Cl, compound 2 , 1.00 g, 1.68 mmol) in DMF (3.4 mL), acetyl serinol salt (compound 4-1 , 790 mg, 3.7 mmol) and TEA (1 mL, 7.06 mmol) were added. Stirred at room temperature for 24 hours. After completion of the reaction (monitored by TLC), the residue was recrystallized from ethanol to give the compound (1.39 g, 94%) as a white solid.

m.p. 155~160℃

HPLC Purity: 97.20%

¹ H-NMR (400 MHz, CD ₃ OD) δ 4.53-4.49 (m, 2H), 4.37-4.24 (m, 8H), 2.09 (s, 6H, rotamer A), 2.07 (s, 6H, rotamer B) .

¹³ C NMR (100 MHz, CD ₃ OD) δ 172.73, 172.49, 149.87, 149.71, 79.34, 63.58, 63.52, 20.89, 20.88.

LRMS Calcd. for C ₂₂ H ₂₆ I ₃ N ₃ O ₁₀ [M+H] ⁺ : 872.88; found 873.7.

(S)-((5-(2-acetoxypropanamido)-2,4,6-triiodoisophthaloyl)bis(azanediyl))bis(propane-2,1,3-triyl) Preparation of tetra acetate (compound 6-1)

((5-amino-2,4,6-triiodoisophthaloyl)bis(azanediyl))bis(propane-2,1,3-triyl)tetraacetate (Compound 5 ) in DMAc (575 μL) (S) -1 -chloro-1-oxopropan-2-ylacetate (250 μL, 1.61 mmol) was added to the (S)-1-chloro-1-oxopropan-2-ylacetate (250 μL, 1.61 mmol) solution and stirred at room temperature for 12 hours. After completion of the reaction (monitored by TLC), the mixture was extracted with saturated NaHCO ₃ aqueous solution and DCM. The organic layer was MgSO ₄ After removal of water and concentration in vacuo, the compound (1.05 g, 93%) was obtained as a white solid.

m.p. >250℃

HPLC Purity: 97.35%

¹ H-NMR (400 MHz, CD ₃ OD) δ 5.37-5.32 (m, 1H), 4.54-4.51 (m, 2H), 4.36-4.24 (m, 8H), 2.18 (d, J = 4.68 Hz, 1.5 H, rotamer A), 2.17 (d, J = 4.68 Hz, 1.5H, rotamer B), 2.07 (s, 12H), 1.64 (d, J = 7.0 Hz, 3H).

¹³ C-NMR (100 MHz, CD ₃ OD) δ 172.49, 172.08, 171.81, 171.62, 151.33, 144.04, 98.86, 89.91, 71.42, 71.39, 63.56, 63.49, 20.86, 18.16.

LRMS Calcd. for C ₂₇ H ₃₂ I ₃ N ₃ O ₁₃ [M+H] ⁺ : 986.91; found 987.9.

[α] _D ²⁰ = -52.5°

(S)-N1,N3-bis(1,3-dihydroxypropan-2-yl)-5-(2-hydroxypropanamido)-2,4,6-triiodoisoflaamide (compound 1) Manufacturing

(S)-((5-(2-acetoxypropanamido)-2,4,6-triiodoisophthaloyl)bis(azanediyl))bis(propane-2, After dissolving 1,3-triyl)tetraacetate (Compound 6-1 , 1 g, 1.013 mmol), ammonium hydroxide solution (20 mL) was added, followed by stirring at 50 °C for 24 hours. After completion of the reaction (TLC monitoring), washed with DCM, recrystallized from IPA to obtain Iopamidol (Compound 1 , 732 mg, 93%) as a white solid.

HPLC Purity: 97.30%

¹ H-NMR (400 MHz, CD ₃ OD) δ 4.34-4.29 (m, 1H), 4.12-4.07 (m, 2H), 3.90-3.75 (m, 8H), 1.52 (d, J = 6.8 Hz, 3H) ).

¹³ C NMR (100 MHz, D ₂ O) δ 176.82, 176.60, 171.91, 171.83, 171.76, 149.15, 149.06, 142.19, 97.81, 97.68, 88.87, 68.10, 59.74, 53.14, 53.05, 52.99, 19.42.

LRMS Calcd. for C ₁₇ H ₂₂ I ₃ N ₃ O ₈ [M+H] ⁺ : 776.85; found 778.

[α] _D ²⁰ = -2.1°

((5-amino-2,4,6-triiodoisophthaloyl)bis(azanediyl))bis(propane-2,1,3-triyl)tetra(2,2-dimethylpropanoate) Preparation of (Compound 5-2)

To a solution of 5-amino-2,4,6-triiodoisophthaloyl dichloride (Compound 4-2 , 900 mg, 1.51 mmol) in DMF (3 mL), pivaloyl serinol salt (1.03 g, 3.47 mmol) ) and TEA (910 μL, 6.49 mmol) were added. Stirred at room temperature for 24 hours. After completion of the reaction (monitored by TLC), the residue was extracted with water and DCM, and the organic layer was dried to remove moisture from MgSO ₄ and concentrated in vacuo to obtain the compound (1.48 g, 94%) as a white solid.

m.p. 220~222℃

¹ H-NMR (400 MHz, CD ₃ OD) δ 4.52-4.47 (m, 2H), 4.37-4.26 (m, 8H), 1.23 (s, 18H, rotamer A) and 1.22 (s, 18H', rotamer B) )

¹³ C NMR (100 MHz, CD ₃ OD) δ 179.59, 179.56, 172.73, 149.70, 79.43, 72.72, 63.11, 63.07, 39.90, 27.66

LRMS Calcd. for C ₃₄ H ₅₀ I ₃ N ₃ O ₁₀ [M+H] ⁺ : 1041.06; found 1042.1

(S)-((5-(2-acetoxypropanamido)-2,4,6-triiodoisophthaloyl)bis(azanediyl))bis(propane-2,1,3-triyl) Preparation of tetrakis (2,2-dimethylpropanoate (Compound 6-2)

((5-amino-2,4,6-triiodoisophthaloyl)bis(azanediyl))bis(propane-2,1,3-triyl)tetrakis(2, To a solution of 2-dimethylpropanoate) (compound 5-2 , 1.0 g, 0.96 mmol) was added (S)-1-chloro-1-oxopropan-2-yl acetate (188 μL, 1.25 mmol) at room temperature stirred for 12 h. After completion of the reaction (monitored by TLC), the mixture was extracted with saturated NaHCO ₃ aqueous solution and DCM. The organic layer was dried with MgSO ₄ , and then concentrated in vacuo to obtain the compound (960 mg, 87%) as a white solid.

m.p. 129~132℃

¹ H-NMR (400 MHz, CD ₃ OD) δ 5.37-5.32 (m, 1H), 4.52-4.49 (m, 2H), 4.36-4.27 (m, 8H), 2.18 (d, J = 4.8 Hz, 1.5 H, rotamer A), 2.17 (d, J = 4.8 Hz, 1.5H, rotamer B), 1.63 (d, J = 7.0 Hz, 3H), 1.22 (s, 36H)

¹³ C NMR (100 MHz, CD ₃ OD) δ 179.47, 172.01, 171.73, 171.57, 171.50, 151.17, 151.12, 151.03, 150.97, 143.98, 98.98, 98.90, 98.81, 89.86, 71.34, 71.90, 39.99, 62.90, 62.85 27.64, 20.86, 18.19, 18.14

LRMS Calcd. for C ₃₉ H ₅₆ I ₃ N ₃ O ₁₃ [M+H] ⁺ : 1155.09; found 1156.7

[α] _D ²⁰ = -10°

(S)-N1,N3-bis(1,3-dihydroxypropan-2-yl)-5-(2-hydroxypropanamido)-2,4,6-triiodoisophthalamide (compound 1) Manufacturing

( S )-((5-(2-acetoxypropanamido)-2,4,6-triiodoisophthaloyl)bis(azanediyl))bis(propane-2, 1,3-Tryl)tetrakis(2,2-dimethylpropanoate (Compound 6-2 , 1 g, 1.013 mmol) was added with an aqueous ammonium hydroxide solution (20 mL) and stirred at 50° C. for 24 hours. After completion (TLC monitoring), washing with DCM and recrystallization from IPA gave Iopamidol (Compound 1 , 727 mg, 91%) as a white solid.

HPLC Purity: 97.30%

¹ H-NMR (400 MHz, CD ₃ OD) δ 4.34-4.29 (m, 1H), 4.12-4.07 (m, 2H), 3.90-3.75 (m, 8H), 1.52 (d, J = 6.8 Hz, 3H) ).

¹³ C NMR (100 MHz, D ₂ O) δ 176.82, 176.60, 171.91, 171.83, 171.76, 149.15, 149.06, 142.19, 97.81, 97.68, 88.87, 68.10, 59.74, 53.14, 53.05, 52.99, 19.42.

LRMS Calcd. for C ₁₇ H ₂₂ I ₃ N ₃ O ₈ [M+H] ⁺ : 776.85; found 778.

[α] _D ²⁰ = -2.1°

Comparative Experimental Example 1. Effect of introduction of an acyl group into a serinol salt

In order to confirm the effect of first acylating the serinol salt (Compound 3 ), 5-amino-2,4,6-triiodo isope directly without acylating the serinol salt according to a previously reported synthesis method (WO0050385) The yield and purity of compound 5-1 prepared by acylation after addition to taloyl dichloride (compound 2 ) and compound 5-1 according to an embodiment of the present invention were compared.

((5-Amino-2,4,6-triiodoisophthaloyl)bis(azanediyl))bis(propane-2,1,3-triyl)tetraacetate (Compound 5-1)

After dissolving 5-amino-2,4,6-triiodoisophthaloyl dichloride (ATIPA-Cl, Compound 2 , 1 g, 1.68 mmol) in dimethylacetamide (1.6 mL), 2-amino-1,3 -propandediol (serinol, 600 mg, 6.72 mmol) and triethylamine (1.29 mL) were added and stirred at 30 °C for 8 hours. The reaction was cooled and 4-dimethylaminopyridine (10 mg, 0.084 mmol) and acetic anhydride (950 μL) were added slowly. After the reaction was stirred for 2 hours, water was slowly added to terminate the reaction, and the solid was filtered, washed with water, and dried to obtain tetraacetate (Compound 5-1 , 1.23 g, 84%) as a white solid. HPLC Purity: 86.3%

The yield of compound 5-1 prepared without acylation of the serinol salt (compound 3) was 84% and the purity was 86.3%, but the yield of compound 5-1 prepared according to the present invention was 94% and the purity was 97.20%. , yield and purity were all high.

Comparative Experimental Example 2. Effect of Hydrolysis by Ammonium Hydroxide

In order to compare the effects of the base used in the last hydrolysis step, the yield and purity of Iopamidol prepared by hydrolysis with sodium hydroxide (NaOH) and Iopamidol according to an embodiment of the present invention were compared.

(S)-N1,N3-bis(1,3-dihydroxypropan-2-yl)-5-(2-hydroxypropanamido)-2,4,6-triiodoisoflaamide (compound 1) Manufacturing

(S)-((5-(2-acetoxypropanamido)-2,4,6-triiodoisophthaloyl)bis(azanediyl))bis in methanol and water (4.75 mL : 4.75 mL) (Propane-2,1,3-triyl)tetraacetate (Compound 6-1 , 1.4 g, 1.42 mmol) was dissolved, and 2M sodium hydroxide solution (6.2 mL) was added thereto, followed by stirring at 45 °C for 2 hours. After completion of the reaction (TLC monitoring), it was loaded onto an Amberlite (registered trademark) XAD-16.00 resin column and eluted with water. The eluate was evaporated, and the residue was recrystallized in ethanol to obtain Iopamidol (Compound 1 , 767 mg, 70%) as a white solid.

HPLC Purity: 95.2%

The yield of compound 1 prepared using sodium hydroxide (NaOH) was 70% and the purity was 95.2%, but the yield of compound 1 prepared according to the present invention was 93% and the purity was 97.30%, both of which were high in yield and purity. appear.

As described above in detail a specific part of the content of the present invention, for those of ordinary skill in the art, it is clear that this specific description is only a preferred embodiment, and the scope of the present invention is not limited thereby. something to do. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

Claims (9)

(1) preparing a compound represented by the formula (5) from the compound represented by the following formula (2); and
(2) by sequentially adding acetopropionyl chloride and ammonium hydroxide (NH ₄ OH) to the compound represented by Formula 5 to obtain a compound represented by Formula 1; including,
A method for preparing a compound represented by the following formula (1).
[Formula 1]

;
[Formula 2]

;
[Formula 5]

,
In the above formula, R is a substituted or unsubstituted acyl group.
According to claim 1,
In the step (1), the compound represented by Formula 5 is prepared by adding a compound represented by the following Formula 4 to the compound represented by Formula 2, wherein the compound represented by Formula 5 is prepared.
[Formula 4]

,
In the above formula, R is a substituted or unsubstituted acyl group.
3. The method of claim 2,
The compound represented by the formula (4) is characterized in that prepared from the following formula (3), the preparation method.
[Formula 3]

,
In the above formula, R is a substituted or unsubstituted acyl group.
According to claim 1,
In the step (2), acetopropionyl chloride is added to the compound represented by Formula 5 to prepare a compound represented by the following Formula 6 as an intermediate.
[Formula 6]

,
In the above formula, R is a substituted or unsubstituted acyl group.
5. The method of claim 4,
The compound represented by Formula 4 is the following compound 4-1,
The compound represented by Formula 5 is the following compound 5-1,
The compound represented by the formula (6) is the following compound 6-1, the manufacturing method.
[Compound 4-1]

;
[Compound 5-1]

;
[Compound 6-1]

.
5. The method of claim 4,
The compound represented by Formula 4 is the following compound 4-2,
The compound represented by Formula 5 is the following compound 5-2,
The compound represented by Formula 6 is the following compound 6-2, the preparation method.
[Compound 4-2]

;
[Compound 5-2]

;
[Compound 6-2]

.
According to claim 1,
Wherein R is an acetyl group (acetyl) or pivaloyl group (pivaloyl), characterized in that, the manufacturing method.
According to claim 1,
The acetopropionyl chloride is (S) - characterized in that the stereoisomer, the manufacturing method.
A contrast medium composition comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof prepared by the method of any one of claims 1 to 8.
[Formula 1]

.