KR20180012407A - Novel intermediate and improved process for the preparation of iobitridol using thereof - Google Patents

Abstract

The present invention relates to a novel method for producing iobitridol represented by chemical formula 1, 1-N,3-N-bis(2,3-dihydroxypropyl)-5-[3-hydroxy-2-(hydroxymethyl)propanamido]-2,4,6-triiodo-1-N,3-N-dimethylbenzene-1,3-dicarboxamide, which is a component for a contrast medium, and novel intermediates for the same. According to the present invention, desired entecavir can be produced economically and easily from the novel intermediates at a high yield.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention [0001] The present invention relates to a novel intermediate and an iobitricol,

The present invention relates to a novel process for the preparation of the contrast agent iobitridol and useful intermediates used therein.

(2,3-dihydroxypropyl) -5- [3-hydroxy-2- (hydroxymethyl) -1H-pyrazole- Propanamido] -2,4,6-triiodo-1-N, 3-N-dimethylbenzene-1,3-dicarboxamide is one of the most widely used nonionic, hypotonic iodine contrast agents in the world .

[Chemical Formula 1]

The above compound has been reported to synthesize the compound according to the method summarized in the following reaction formula.

<Reaction Scheme 1>

Although the above method is widely used in industry, there are some problems. The intermediate compound 6 is synthesized from a carboxylic acid compound, 1) there is a problem that the protecting group of the compound 5 is deprotected by an acid generated by SOCl ₂ , and the number of equivalents of thionyl chloride must be increased There is a problem. Therefore, there is a problem that 2) anhydrous reaction conditions should be made during the reaction, so that the tools and reagents used for the experiment must be dried for at least 1 hour. 3) There is a problem that the yield is also lowered in the reaction for producing triol.

On the other hand, Chinese Patent Publication CN 103254095 (hereinafter referred to as Patent Document 0001) discloses a method for directly producing iovitryptol from a compound represented by the following Chemical Formula 2 as shown in Reaction Scheme 2 below.

<Reaction Scheme 2>

However, also in the method disclosed in the above-mentioned prior art, there is a problem that a coupling reaction of an amine and an acid chloride must be performed in order to prepare an intermediate, and a loss of at least 25% due to a deprotection problem occurs.

Chinese Patent Publication CN 103254095

Therefore, an object of the present invention is to provide a novel process for producing iovitryptol in high yield in an industrially easy manner, and a novel intermediate compound to be used therefor.

In order to achieve the above object,

(1) reacting a diethylbis (hydroxymethyl) malonate compound of the following formula (3) with an acid catalyst and cyclohexanone to obtain a diastereomer compound of the following formula (4);

(2) subjecting the diastereomer compound of formula (4) to a de-esterification reaction in the presence of a base to obtain a di-acid compound of formula (5);

(3) a step of dicarboxylating the diacid compound of formula (5) in the presence of pyridine to obtain a monoacid compound of formula (6);

(4) reacting a monoacid compound of formula (6) with thionyl chloride to obtain an acyl chloride compound of formula (7);

(5) reacting an acyl chloride compound of formula (7) with an amido isophthaloyl chloride compound in a dimethylacetamide solvent to obtain a triamide compound of formula (8);

(I), wherein R &lt; 1 &gt; and R &lt; 2 &gt;

[Chemical Formula 1]

(3)

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

(7)

[Chemical Formula 8]

The present invention also provides a diastereomer compound represented by the following formula (4), which is used as an intermediate in the preparation of the Iobitridol of the above formula (1).

[Chemical Formula 4]

The present invention also provides a triamide compound of formula 8, which is used as an intermediate in the preparation of Iobitridol of formula 1 above.

[Chemical Formula 8]

According to the method of the present invention, the contrast agent iovitriol can be produced economically and easily from novel intermediates at a high yield.

The process for preparing iovitryptole according to the present invention is characterized in that a ketone compound is introduced as a protecting group to prepare a compound of formula (4) having a ketal structure, and a triamide compound (compound of formula (8) .

The iovitriol of Formula 1 of the present invention can be prepared by performing the reaction as shown in Reaction Scheme 3 below.

<Reaction Scheme 3>

The process for preparing the iovitri stearate of the present invention as shown in Reaction Scheme 3 will be described step by step as follows.

<Step 1>

In step 1 according to the present invention, diethyl malonate of formula (2) is reacted with formaldehyde to obtain diethyl bis (hydroxymethyl) malonate of formula (3).

<Step 2>

 In Step 2, the ketone compound is reacted with diethylbis (hydroxymethyl) malonate of Formula 3 obtained in Step 1 to introduce a ketal protecting group.

The ketone compound may be any one of cyclohexanone, 3-pentanone, acetone and 4-heptanone, preferably cyclohexanone, have.

In the case of using 3-pentanone among the above-mentioned ketone compounds, the yield is somewhat lower than that of the reaction using cyclohexanone, and the yield is somewhat lower than that of the cyclohexanone. When acetone is used, the reaction is more favorable in the decarboxylation reaction, It may not proceed. Cyclohexanone can be the most preferable protecting group because the reaction condition is intense and the dicarboxylation reaction occurs well and is relatively stable to the acid and easily obtainable.

The protecting group used in the present invention plays a role as a more stable protecting group than isobutyraldehyde, so that the synthetic intermediates are stable and easy to handle, and are cheaper than conventional isobutylaldehyde, so that they are useful for mass production in an economical aspect, and the yield is remarkably improved.

The reaction may be carried out in an organic solvent at 70 to 80 ° C for 11 to 13 hours, and the organic solvent used may be benzene, toluene, or xylene.

By such a method, the ketal compound of formula (4) can be obtained in a yield of 97% or more.

<Step 3>

In step 3, the diacid compound of formula (5) can be obtained from the diastereomer compound (compound of formula (4)) in which the ketal protecting group is introduced in step (2).

This reaction is a reaction in which a hydroxyl ion attacks a carbonyl group of an ester using a base to de-esterify it to form a carboxylate, and then an acid is added to synthesize a di-acid again.

By the above reaction, the diacid compound of Chemical Formula 5 can be obtained in a yield of 95% or more.

<Step 4>

Step 4 is a step of obtaining a monocarboxylic acid of formula (6) from a dicarboxylic acid compound of formula (5) obtained in step (3) through a decarboxylation reaction.

The reaction can be simply decarboxylated using pyridine as a solvent and base without the use of other reagents. The monocarboxylic acid of formula (6) can be obtained in a yield of 93% or more by the above method.

<Steps 5 to 6>

In steps 5 to 6, mono acid (compound of formula 6) is synthesized with acid chloride (compound of formula 7) and then reacted with an amine compound, so that the acid chloride of formula 7 is unstable, The following reaction can proceed without separation.

The compound of formula (6) introduced with the ketone protecting group of step 2 above has a higher number of carbon atoms than the known compound in the reaction using thionyl chloride, so thionyl chloride is more stable in the acid generated by the reaction with water, Can proceed.

In the presence of the hydrochloride in which thionyl chloride is produced by the reaction with water in the presence of the above-mentioned reaction, it can be seen that the reaction of the kettle type protecting group, which can be broken by the acid, does not occur and the reaction proceeds.

By the above method, the compound of formula (8) can be obtained in a yield of 85% or more.

<Steps 7 to 8>

In Steps 7 to 8, the acid chloride portion of the compound of Formula 8

N- methyl-1,2-dihydroxypropylamine is reacted, then sulfuric acid is used to remove the protecting group and then iobitridol is synthesized using resin.

By the above process, the iovitriol of formula (1) can be obtained in a yield of 98% or more.

According to the process for preparing iovitri stones according to the present invention, the iovitriol can be synthesized at a yield (71%) higher than the final yield according to the process for producing the Chinese patent (CN 103254095).

The present invention will now be described in more detail with reference to the following examples, but the present invention is not limited thereto.

[Example]

Example  One. Diethyl  1,5- Dixo Spyro [5.5] Undecan -3,3- Dicarboxylate  (Compound of formula 4)

(1-1). Preparation of diethyl bis (hydroxymethyl) malonate (compound of formula 3)

Formaldehyde (60 g, 2 mol) is dissolved in distilled water containing 8 g of potassium bicarbonate. This solution is dropwise funneled and purged with diethyl malonate (compound of formula 1, 160 g, 1 mol) in Ar gas and then dropwise at 30 ° C for 1 hour. This solution is extracted three times with organic layer using 100 ml of diethyl ether and 320 ml of saturated ammonium sulfate, and then 20 g of anhydrous sodium sulfate is added and dried for 1 hour. This solution is filtered to remove sodium sulfate. This solution is distilled under reduced pressure. The resulting solid is dried at 40C. Add 50 mL of isopropyl ether to this solid. Keep the solution at 50C until all solids are dissolved. Transfer the solution to an Erlenmeyer flask and recrystallize at 0 ° C for 1 hour. Filter the resulting solid. The remaining solvent is removed using a vaccum pump. 158 g of the desired product (compound of formula (III)) was produced.

^{1 H NMR (400 MHz, CDCl} 3) δ4.26-4.21 (q, J = 7.2 Hz, 4H), 4.10 (s, 2H), 4.08 (s, 2H), 1.28-1.24 (t, J = 7.1 Hz , 6H).

(1-2). Preparation of diethyl 1,5-dioxaspiro [5.5] undecane-3,3-dicarboxylate (compound of formula 4)

(17 mL, 0.16 mol) and p- toluenesulfonic acid (0.52 g, 0.0023 mol) are added to 100 mL of benzene after the addition of diethyl bis (hydroxymethyl) malonate (compound of formula 3, 12 g, 0.0075 mol) The solution is stirred under argon gas purging under reflux conditions for 13 hours. After cooling the solution to room temperature, the water produced during the reaction is removed using a Dean stark trap. After cooling the solution to room temperature, benzene is distilled off under reduced pressure, and then extracted with 50 mL of ethyl acetate and saturated aqueous sodium bicarbonate solution three times with an organic layer, followed by distillation under reduced pressure. The remaining solvent is removed using a vaccum pump. 15.8 g of the desired product (compound of formula (IV)) was produced.

^{1 H NMR (400 MHz, CDCl} 3) d4.27 (s, 4H), 4.24-4.19 (q, J = 7.1 Hz, 4H), 1.73-1.70 (t, J = 5.8 Hz, 4H), 1.53-1.48 (m, 4H), 1.40-1.36 (m, 2H), 1.26-1.23 (t, J = 7.2 Hz, 6H).

Example  2. 2,4,6- Tree iodo -5- (1,5- Dioxaspiro [5.5] undecane -3- Carboxamido ) Isophthaloic Dichloride  (Compound of formula 8)

(2-1). Preparation of 1,5-dioxaspiro [5.5] undecane-3,3-dicarboxylic acid (compound of formula 5)

Dissolve diethyl 1,5-dioxaspiro [5.5] undecane-3,3-dicarboxylate (compound of formula 4, 3 g, 0.01 mol) in 20 mL of ethyl alcohol and add 11 mL of 3.25 N sodium hydroxide. The solution is stirred under Ar gas purging at room temperature for 3 hours. Ethyl alcohol is distilled off under reduced pressure and the pH is adjusted to 3 using 2N hydrochloric acid at 0C. Extract 3 times with organic layer using 20 mL of diethyl ether and distill off under reduced pressure. The remaining solvent is removed using a vaccum pump. 2.32 g of the desired product (compound of formula 5) was produced.

^{1 H NMR (400 MHz, DMSO} ) δ13.18 (s, 2H), 4.12 (s, 4H), 1.64-1.61 (t, J = 3.5 Hz, 4H), 1.42-1.41 (m, 4H), 1.35- 1.33 (m, 2H).

(2-2). Preparation of 1,5-dioxaspiro [5.5] undecane-3-carboxylic acid (compound of formula 6)

1,5-dioxaspiro [5.5] undecane-3,3-dicarboxylic acid (compound of formula 5, 1 g, 0.004 mol) is dissolved in 40 mL of pyridine. The solution is stirred under argon gas purging at 90 C for 2 hours. After cooling the solution to room temperature, distill off the pyridine, add 20% excess of 10% potassium hydroxide, and wash twice with 50 mL of diethyl ether. Add an excess amount of diethyl ether to the aqueous layer and adjust the pH to 2 using 12 N hydrochloric acid at 0 ° C. The organic layer was extracted three times with 50 mL of diethyl ether and then distilled under reduced pressure. The remaining solvent is removed using a vaccum pump. 0.74 g of the desired product (compound of formula (VI)) was produced.

^{1 H NMR (400 MHz, CDCl} 3) δ4.12-4.04 (m, 4H), 2.81-2.75 (m, 1H), 1.79-1.76 (t, J = 5.5 Hz, 2H), 1.73-1.70 (t, J = 5.7 Hz, 2H), 1.55-1.46 (m, 4H), 1.42-1.39 (m, 2H).

(2-3). Preparation of 1,5-dioxaspiro [5.5] undecane-3-carbonyl chloride (compound of formula 7)

1,5-Dioxaspiro [5.5] undecane- 3-carboxylic acid SOCl 2 was dissolved (the compound of formula 6) 0.5 g (2.5 mmol) in 5 mL cyclohexane 0.6 mL (7.5 mmol) and pyridine (0.4 mL, 5 mmol) are added. The solution is stirred under Ar gas purging at 75 C for 6 hours. Pyridine is distilled off under reduced pressure. The remaining solvent is removed using a vaccum pump. The resulting crude product (compound of formula 7) was subjected to the following reaction without further separation.

(2-4). 2,4,6-Triiodo-5- (1,5-dioxaspiro [5.5] undecane-3-carboxamido) isophthaloyl dichloride Manufacturing

5-amino-2,4,6-triiodoisophthaloyl dichloride (1 g, 1.7 mmol) was dissolved in 3 mL of dimethylacetamide and the solution of 1,5-dioxaspiro [5.5] undecane-3-carbonyl chloride g, 2.5 mmol) is added via cannula. The solution is stirred under argon gas purging at room temperature for 12 hours. Dimethylacetamide was distilled off under reduced pressure, and extracted with ethyl acetate (20 mL) three times with organic layer. The remaining reactants were separated by silica gel column (hexane: ethyl acetate = 3: 1) to obtain 2,4,6-triiodo-5- (1,5-dioxaspiro [5.5] undecane-3-carboxamido) isophthaloyl dichloride. The remaining solvent is removed using a vaccum pump. 1.66 g of the desired product (compound of formula 8) was produced.

¹ H NMR (400 MHz, CDCl ₃ )? 4.57-4.54 (dd, J = 11.3, 6.4 Hz, 1H), 4.35-4.30 (dd, J = 11.2, 10.2 Hz, 1H), 3.90-3.87 J = 11.5, 3.9 Hz, 1H ), 3.64-3.59 (dd, J = 11.2, 9.8 Hz, 1H), 2.86-2.79 (m, 1H), 2.29-2.18 (m, 4H), 1.72-1.50 (m, 6H).

Example  3. Iovit tree stone  (Compound of Formula 1)

(3-1). Protected iovitri stones ( N ₁ , N ₃ -bis (2,3-dihydroxypropyl) -2,4,6-triiodo- N ₁ , N ₃ -dimethyl- Dioxaspiro [5.5] undecane-3-carboxamido) isophthalamide) (Compound of Formula 9)

The compound of formula (8) (2 g, 0.0023 mol) was dissolved in 12 mL of isopropyl alcohol, and triethylamine (0.83 mol) was added to the solution. g, 0.0084 mol). N- methyl-1,2-dihydroxypropylamine (0.89 g, 0.0085 mol) is dropwise added to this solution using a dropping funnel for 1 hour. The solution is stirred under Ar gas purging at room temperature for 3 hours. The resulting solid is filtered and the filtrate is filtered under reduced pressure. This solid is recrystallized with H ₂ O. The remaining solvent is removed using a vaccum pump. The resulting crude product (compound of formula 9) underwent the following reaction without further separation.

(3-2). Preparation of iovitriglycol (compound of formula 1)

The protected iobitridol (compound of formula 9, 2g, 0.0023 mol) synthesized above was dissolved in H ₂ O and sulfuric acid (0.18 mL, 0.0034 mol) was added at 0 ° C. This solution is stirred for 1 hour. The solution is adjusted to pH 7 with aqueous sodium hydroxide solution and the H ₂ O is distilled off under reduced pressure. The resulting solid is dissolved in ethanol and the resulting solid is filtered. The temperature of the filtrate is lowered to 0 ° C. and the resulting solid is filtered again. Ethyl alcohol is distilled off under reduced pressure. After dissolving the solid in distilled water, add hydrogen ion type ion exchange resin and stir for 0.5 hour. Resin is filtered and the distilled water is distilled off under reduced pressure. The solid was dissolved in 20 mL of ethyl alcohol and stirred under reflux conditions for 5 hours under Ar gas purging. Add isopropyl alcohol slowly to this solution until the solution is free of suspended solids. The solution is cooled to room temperature and the resulting solid is filtered. This solid is washed with isopropyl alcohol and dried at 35 ° C for 3 hours. The remaining solvent is removed using a vaccum pump. 1.88 g of the desired product (compound of formula 1) was produced.

^{1 H NMR (400 MHz, D} 2 O) δ4.14 (s, 2H), 3.98-3.94 (m, 3H), 3.88-3.84 (m, 2H), 3.73-3.71 (m, 4H), 3.62-3.58 (m, 2H), 3.46-3.33 (m, 3H), 3.18-3.16 (m, 2H), 2.99-2.92 (m, 6H).

Comparative Example  One. Of the iovitri stones (compounds of formula I)  Produce.

In the process of the present invention, the iovitriol of formula (1) was synthesized in the same manner as in the examples of the present invention except that isobutyraldehyde (2-methylpropanal) was added instead of the ketone compound in the step 2 to synthesize an acetal protecting group.

Claims (5)

(1) reacting a diethyl bis (hydroxymethyl) malonate compound of Formula 3 with an acid catalyst and cyclohexanone to obtain a diastereomer compound of Formula 4;
(2) subjecting the diastereomer compound of formula (4) to a de-esterification reaction in the presence of a base to obtain a di-acid compound of formula (5);
(3) a step of dicarboxylating the diacid compound of formula (5) with pyridine to obtain a monoacid compound of formula (6);
(4) reacting a monoacid compound of formula (6) with thionyl chloride to obtain an acyl chloride compound of formula (7);
(5) reacting an acyl chloride compound of formula (7) with an amido isophthaloyl chloride compound in a dimethylacetamide solvent to obtain a triamide compound of formula (8);
A process for preparing an iovitrythol of formula (1), comprising:
[Chemical Formula 1]

(3)

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

(7)

[Chemical Formula 8]

3. The process according to claim 1, wherein the pyridine in step (3) is a solvent and is used as a base. The process according to claim 1, wherein the amide compound of formula (8) is reacted with N-methyl-1,2-dihydroxypropylamine to obtain a triamide compound of formula (9)
Removing the ketal group of formula (9) in an acidic condition;
&Lt; RTI ID = 0.0 &gt; 1. &Lt; / RTI &gt;
[Chemical Formula 9]

A compound represented by the following formula (4), which is used as an intermediate for the preparation of Iobitridol:
[Chemical Formula 4]

A compound represented by the following formula (8), which is used as an intermediate for the preparation of Iobitridol:
[Chemical Formula 8]