KR102702677B1 - Process for Preparation of Fimasartan and Intermediate for Preparing the Same - Google Patents

Abstract

The present invention relates to a simple and economical method for producing fimasartan and its manufacturing intermediate.

Description

{Process for Preparation of Fimasartan and Intermediate for Preparing the Same}

The present invention relates to a method for producing fimasartan and its manufacturing intermediate. More specifically, the present invention relates to a method for simply and economically producing fimasartan and its manufacturing intermediate.

Fimasartan, of the following chemical formula 1, is known as a blood pressure lowering agent of the angiotensin II receptor blocker (ARB) series.

[Chemical Formula 1]

A method for manufacturing fimasartan is disclosed in Korean Patent No. 10-521980, as shown in the following Reaction Scheme 1, by reacting a compound of Chemical Formula 2 with an amine in the presence of N-hydroxybenzotriazole (HOBt), N-methylmorpholine (NMM), and dicyclohexylcarbodiimide (DCC) to obtain a compound of Chemical Formula 3, reacting a compound of Chemical Formula 3 with a compound of Chemical Formula 4 in the presence of lithium hydride to obtain a compound of Chemical Formula 5, and then subjecting the compound of Chemical Formula 5 to a thioamidation reaction using Lawesson's reagent, followed by removal of a protecting group.

[Reaction Formula 1]

However, the above manufacturing method has a problem in that a large amount of N,N'-dicyclohexyl urea (DCU) is produced as a reaction by-product from N,N'-dicyclohexylcarbodiimide (DCC), which has a high moisture-absorbing property and is therefore difficult to filter using a general centrifuge.

In addition, Lawson's reagent is expensive, difficult to separate, and produces a large amount of hydrogen sulfide ( _H2S ) as a reaction byproduct during manufacturing, which poses environmental problems.

Therefore, there has been an urgent need for the development of a method for producing fimasartan in high yield through an economical and simple process without producing urea, a reaction by-product.

Republic of Korea Patent No. 10-521980

One object of the present invention is to provide a method for producing fimasartan simply and economically.

Another object of the present invention is to provide a method for producing a compound of chemical formula 3, which is an intermediate for producing fimasartan, in high yield while suppressing the production of urea as a reaction by-product.

Another object of the present invention is to provide a process for commercially producing fimasartan tromethamine salt dihydrate.

One embodiment of the present invention relates to a method for producing fimasartan of the following chemical formula 1, wherein the method of the present invention comprises:

(i) a step of obtaining a compound of the following chemical formula 3 by subjecting the compound of the following chemical formula 2 to an amidation reaction with dimethylamine hydrochloride in the presence of N,N'-diisopropylcarbodiimide, N-hydroxysuccinimide and a base;

(ii) a step of subjecting a compound of the following chemical formula 3 to an N-alkylation reaction with a compound of the following chemical formula 4 in the presence of a base to obtain a compound of the following chemical formula 5;

(iii) a step of subjecting a compound of the following chemical formula 5 to a thioamidation reaction with a P ₂ S ₅ -pyridine reagent to obtain a compound of the following chemical formula 6; and

(iv) a step of deprotecting a compound of the following chemical formula 6 in the presence of an acid.

[Chemical formula 2]

[Chemical Formula 3]

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical formula 6]

[Chemical Formula 1]

Hereinafter, the manufacturing method of the present invention will be described in more detail with reference to the following reaction scheme 2. The method described in the following reaction scheme 2 is merely an example of a representatively used method, and the reaction reagents, reaction conditions, etc. may be changed at any time depending on the case.

[Reaction Formula 2]

Step 1: Synthesis of the compound of chemical formula 3

The compound of chemical formula 3 can be prepared by an amidation reaction of the compound of chemical formula 2 with dimethylamine hydrochloride in the presence of N,N'-diisopropylcarbodiimide (DIC), N-hydroxysuccinimide (NHS) and a base.

The molar ratio of the compound of chemical formula 2 and N,N'-diisopropylcarbodiimide (DIC) is preferably 1:1 to 1:3, and more preferably 1:2.

The molar ratio of the compound of chemical formula 2 and N-hydroxysuccinimide (NHS) is preferably 1:1 to 1:2, and more preferably 1:1.3.

As the above base, triethylamine, trimethylamine, triisopropylamine, diisopropylethylamine, etc. can be used, and triethylamine is preferred.

The molar ratio of the compound of chemical formula 2 and the base is preferably 1:1 to 1:5, and more preferably 1:3.

The reaction solvent is dichloromethane, acetone, DMF alone or a mixture thereof, and it is preferable to use the reaction solvent in a volume ratio (ml/g) of about 5 to 20 times the weight of the compound of chemical formula 2 used, more preferably 10 times.

The reaction temperature is preferably 0 to 35°C, and the reaction time is preferably 1 to 5 hours.

The compound of formula 2 is commercially available or can be readily prepared by methods known in the art.

The post-treatment process after the reaction is performed by filtering the generated solid and recrystallizing the filtrate with isopropyl alcohol, and a compound of chemical formula 3 with a purity of 95% or higher can be obtained by simple filtration and recrystallization.

The manufacturing step of the compound of the above chemical formula 3 can suppress urea byproducts generated in existing methods, and reduce production costs by simplifying the post-treatment process with a simple filtration and crystallization process after the reaction.

Step 2: Synthesis of the compound of chemical formula 5

The compound of chemical formula 5 can be prepared by N-alkylating the compound of chemical formula 3 with the compound of chemical formula 4 in the presence of a base.

As the above base, carbonate, amide salt, hydroxy salt, etc. of an alkali metal can be used, and lithium hydroxide (LiOH) is most preferable.

The molar ratio of the compound of chemical formula 3 and the base is preferably 1:1 to 1:2, and more preferably 1:1.1.

It is preferable to use a mixed solvent of dimethylformamide and toluene as the reaction solvent, and the mixing ratio of dimethylformamide and toluene is preferably 1:9 to 1:30, and 1:9 is more preferable.

The reaction temperature is preferably 50 to 70°C, and the reaction time is preferably 15 to 30 hours.

Step 3: Synthesis of the compound of chemical formula 6

The compound of chemical formula 6 can be prepared by thioamidation reaction of the compound of chemical formula 5 with a P ₂ S ₅ -pyridine reagent.

The molar ratio of the compound of chemical formula 5 and the P ₂ S ₅ -pyridine reagent is preferably 1:1 to 1:3. 1:1.2 is more desirable.

The above P ₂ S ₅ -pyridine reagent can be easily prepared by the method described in the literature [ J. Org . Chem . 2011, 76 , 1546-1553].

Toluene, xylene and Any organic solvent may be used, with toluene being preferred.

The post-reaction post-treatment process can be performed by adding purified water, going through an extraction process, removing pyridine, a reaction by-product of the P ₂ S ₅ -pyridine reagent, etc. from the aqueous layer, and concentrating the organic layer.

The reaction temperature is preferably 80 to 120°C, and the reaction time is preferably 1 to 5 hours.

Lawesson's reagent, which is used in the conventional thioamidation reaction, has low stability at high temperatures above 110°C and is easily decomposed. In contrast, P ₂ S ₅ -pyridine reagent has excellent stability even at high temperatures above 110°C, and thus, in the present invention, the thioamidation reaction can be carried out in a short period of time by heating and refluxing in an organic solvent such as toluene and xylene, which have high boiling points. In addition, after completion of the reaction, purified water is added to the reaction solution to easily remove pyridine, which is a reaction by-product of the P ₂ S ₅ -pyridine reagent, thereby eliminating the need for a column chromatogram process.

Step 4: Chemical Formula 1 Of the fimasartan Synthesis

Fimasartan of chemical formula 1 can be prepared by deprotection reaction of compound of chemical formula 6 in the presence of acid.

As the above acid, hydrochloric acid, acetic acid, trifluoroacetic acid, etc. can be used, and hydrochloric acid is preferred.

The molar ratio of the compound of chemical formula 6 to the acid is preferably 1:1 to 1:10, and more preferably 1:1.

Organic solvents such as alcohol and tetrahydrofuran can be used as reaction solvents, with methanol being preferred.

The reaction temperature is preferably 60 to 70°C, and the reaction time is preferably 3 to 6 hours.

One embodiment of the present invention relates to a method for producing fimasartan tromethamine salt dihydrate by adding tromethamine and water to fimasartan of chemical formula 1 manufactured above.

The method for producing fimasartan tromethamine salt dihydrate according to the present invention is

(v) a step of dissolving fimasartan and tromethamine in an organic solvent;

(vi) a step of adding water; and

(vii) a step of stirring the reactants and filtering the solid produced.

As the above organic solvent, at least one selected from the group consisting of methanol, ethanol, 2-propanol, acetonitrile, and acetone can be used.

In the above step (vi), it is preferable to use purified water, and the amount of water used is preferably 0.1 to 10 times the volume ratio (ml/g) per weight of the compound of chemical formula 1.

One embodiment of the present invention relates to a method for producing a compound of the following chemical formula 3, wherein the method of the present invention comprises:

(i) a step of subjecting a compound of the following chemical formula 2 to an amidation reaction with dimethylamine hydrochloride in the presence of N,N'-diisopropylcarbodiimide, N-hydroxysuccinimide and a base.

[Chemical formula 2]

[Chemical Formula 3]

A detailed description of the method for producing the compound of the above chemical formula 3 is identical to the first step described above in relation to the method for producing the above fimasartan, and therefore, a detailed description is omitted to avoid duplication.

According to the manufacturing method of the present invention, fimasartan and its manufacturing intermediate can be manufactured using inexpensive raw materials in a simple process while suppressing the production of urea by-products. In addition, the reaction time can be shortened and the post-treatment process can be simplified. Therefore, the manufacturing method of the present invention can be effectively applied to the commercial production process of fimasartan.

Hereinafter, the present invention will be described more specifically by examples. It will be apparent to those skilled in the art that these examples are only for the purpose of explaining the present invention and that the scope of the present invention is not limited to these examples.

Manufacturing example 1 : 2 -Butyl-1,6- Dehydro -4- methyl -6- Ox -5- Pyrimidine acetic acid manufacturing

95 g of 2-n-butyl-5-ethoxycarbonylmethyl-4-hydroxy-6-methylpyrimidine, 240 mL of methanol, and 700 mL of tetrahydrofuran were added. 1,000 g of a 10% aqueous sodium hydroxide solution was added and stirred at room temperature for 3 hours. After cooling the reaction solution to 0 to 5 °C, the pH was adjusted to 4.0 with a 10% aqueous hydrochloric acid solution, stirred for 1 hour, and the resulting solid was filtered and washed with purified water. After vacuum drying at 50 to 55 °C for 12 hours, 79 g (yield 95%) of 2-butyl-1,6-dihydro-4-methyl-6-ox-5-pyrimidineacetic acid was obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 3.33 (s, 2H), 2.43 (m, 2H), 2.10 (s, 3H), 1.57 (m, 2H), 1.26 (m, 2H), 0.85 ( t, 3H)

Example 1 : 2 -(2-n-butyl-4-hydroxy-6- Methylpyrimidine -5-days)- N,N - Manufacture of dimethylacetamide

79 g of 2-butyl-1,6-dihydro-4-methyl-6-ox-5-pyrimidineacetic acid obtained in Manufacturing Example 1, 57 g of dimethylamine hydrochloride, 53 g of N-hydroxysuccinimide, 89 g of N,N'-diisopropylcarbodiimide, 96 g of triethylamine, and 800 mL of dichloromethane were added and stirred at 30 to 35 °C for 3 hours. The reaction solution was cooled to 0 to 5 °C and stirred for 2 hours. The resulting solid was filtered and recrystallized from isopropyl alcohol, and then dried in vacuum at 50 to 55 °C for more than 12 hours to obtain 75 g (yield 85%) of 2-(2-n-butyl-4-hydroxy-6-methylpyrimidin-5-yl)-N,N-dimethylacetamide.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 3.40 (s, 2H), 3.03 (s, 3H), 2.78 (s, 3H), 2.45 (m, 2H), 2.05 (s, 3H), 1.58 ( m,2H), 1.26(m, 2H), 0.85(t, 3H)

Example 2 : 2 -n-butyl-5- Dimethylaminocarbonylmethyl -6- methyl -3-[[2′-(N- Triphenylmethyltetrazole -5-day) Preparation of biphenyl-4-yl]methyl]-pyrimidin-4(3H)-one

75 g of 2-(2-n-butyl-4-hydroxy-6-methylpyrimidin-5-yl)-N,N-dimethylacetamide obtained in Example 1, 180 g of 5-(4'-bromomethyl-1,1'-biphenyl-2-yl)-1-triphenylmethyl-1H-tetrazole, 75 mL of dimethylformamide, 680 mL of toluene, and 8 g of lithium hydroxide were added and stirred at 60 to 65 °C for 24 hours. The resulting solid was filtered and washed with toluene. Vacuum drying at 50 to 55 °C for more than 12 hours yielded 153 g (yield 70%) of 2-n-butyl-5-dimethylaminocarbonylmethyl-6-methyl-3-[[2′-(N-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]-pyrimidin-4(3H)-one.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.89 (m, 1H), 7.44 (m, 2H), 7.31 (m, 4H), 7.24 (m, 6H), 7.07 (m, 2H), 6.91 (m, 8H), 5.16(s, 2H), 3.61(s, 2H), 3.14(s, 3H), 2.95(s, 3H), 2.50(m, 2H), 2.32(s, 3H), 1.57(m, 2H) ), 1.25(m, 2H), 0.83(t, 3H)

Example 3 : 2 -n-butyl-5- Dimethylaminothiocarbonylmethyl -6- methyl -3-[[2′-(1H- tetrazole -5-day)biphenyl-4-yl] methyl ]-Pyrimidin-4(3H)-one (Pimasartan) Preparation

153 g of 2-n-butyl-5-dimethylaminocarbonylmethyl-6-methyl-3-[[2′-(N-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]-pyrimidin-4(3H)-one obtained in Example 2, 96 g of P ₂ S ₅ -pyridine reagent, and 1,500 mL of toluene were added and heated under reflux for 3 hours, cooled to room temperature, and washed with water. The organic layer was separated and concentrated, and 22 g of concentrated hydrochloric acid and 700 mL of methanol were added. The reaction solution was heated under reflux for 3 hours and cooled to room temperature. The reaction solution was concentrated, ethyl acetate was added, and stirred at room temperature for 6 hours. The resulting solid was filtered and washed with ethyl acetate. Vacuum drying at 50 to 55 ℃ for more than 12 hours was performed to obtain 85 g (yield 80%) of 2-n-butyl-5-dimethylaminothiocarbonylmethyl-6-methyl-3-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-pyrimidin-4(3H)-one.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.45 (m, 1H), 7.30 (m, 3H), 7.02 (m, 2H), 6.92 (m, 2H), 5.21 (s, 2H), 3.75 ( s, 2H), 3.46(s, 3H), 3.38(s, 3H), 2.57(m, 2H), 2.13(s, 3H), 1.53(m, 2H), 1.25(m, 2H), 0.79(t , 3H)

Example 4 : Pima saltan Tromethamine salt Production of dihydrate

Example 3 85 g of 2-n-butyl-5-dimethylaminothiocarbonylmethyl-6-methyl-3-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-pyrimidin-4(3H)-one, 21 g of tromethamine, and 900 mL of isopropanol were added and heated under reflux to dissolve. The reaction solution was cooled to 20 to 30 °C, and 160 mL of purified water was added to the reaction solution. The reaction solution was cooled to 0 to 5 °C and stirred for 2 hours. The produced solid was filtered and dried under vacuum at 50 to 55 °C for more than 12 hours to obtain 100 g (yield 90%) of pimasartan tromethamine salt dihydrate.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.50 (m, 1H), 7.33 (m, 3H), 7.02 (d, 2H), 6.94 (d, 2H), 5.21 (br, 2H), 3.75 ( s, 3H), 3.41(m, 12H), 2.58(m, 2H), 2.47(m,3H), 2.13(s, 3H), 1.53(m, 2H), 1.24(m, 2H), 0.78(t , 3H)

Moisture (KF method): 5.60%

Claims (9)

(i) a step of obtaining a compound of the following chemical formula 3 by subjecting the compound of the following chemical formula 2 to an amidation reaction with dimethylamine hydrochloride in the presence of N,N'-diisopropylcarbodiimide, N-hydroxysuccinimide and a base;
(ii) a step of subjecting a compound of the following chemical formula 3 to an N-alkylation reaction with a compound of the following chemical formula 4 in the presence of a base to obtain a compound of the following chemical formula 5;
(iii) a step of subjecting a compound of the following chemical formula 5 to a thioamidation reaction with a P ₂ S ₅ -pyridine reagent to obtain a compound of the following chemical formula 6; and
(iv) A method for producing fimasartan of the following chemical formula 1, comprising the step of deprotecting a compound of the following chemical formula 6 in the presence of an acid:
[Chemical formula 2]

[Chemical Formula 3]

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical formula 6]

[Chemical Formula 1]
A manufacturing method in claim 1, wherein in step (i), the base is triethylamine, trimethylamine, triisopropylamine or diisopropylethylamine. A manufacturing method in claim 1, wherein in step (ii), the base is a carbonate, amide salt or hydroxy salt of an alkali metal. A manufacturing method in claim 1, wherein the molar ratio of the compound of formula 5 and the P ₂ S ₅ -pyridine reagent in step (iii) is 1:1 to 1:3. A manufacturing method in claim 1, wherein the reaction temperature in step (iii) is 80 to 120°C. A manufacturing method in claim 1, wherein the acid in step (iv) is hydrochloric acid, acetic acid or trifluoroacetic acid. (v) a step of dissolving fimasartan and tromethamine manufactured by a manufacturing method according to any one of claims 1 to 6 in an organic solvent;
(vi) a step of adding water; and
(vii) A method for producing fimasartan tromethamine salt dihydrate, comprising the step of stirring the reactants and filtering the solid produced. A method for producing a compound of the following chemical formula 3, comprising the step of subjecting a compound of the following chemical formula 2 to an amidation reaction with dimethylamine hydrochloride in the presence of N,N'-diisopropylcarbodiimide, N-hydroxysuccinimide and a base:
[Chemical formula 2]

[Chemical Formula 3]
A manufacturing method in claim 8, wherein the base is triethylamine, trimethylamine, triisopropylamine or diisopropylethylamine.