KR101226332B1 - New preparation of 2-(2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl)-N,N-dimethylacetamide - Google Patents

Abstract

상기 식에서, R¹은 C₁~C₆인 직쇄 또는 측쇄 알킬이거나 C₃~C₆인 시클로 알킬이다.The present invention is reacted in the presence of a base compound and the pentanamidine (pentanamidine) or a salt thereof in the presence of a base 2- (2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl) Provided are methods for preparing -N, N-dimethyl acetamide.
(2)

Wherein R ¹ is C ₁ to C ₆ straight or branched alkyl or C ₃ to C ₆ cyclo alkyl.

Description

New Preparation of 2- (2-N-Butyl-4-hydroxy-6-methyl-pyrimidin-5-yl) -N, N-dimethylacetamide {New preparation of 2- (2-n-butyl -4-hydroxy-6-methyl-pyrimidin-5-yl) -N, N-dimethylacetamide}

The present invention relates to a process for the preparation of 2- (2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl) -N, N-dimethylacetamide.

Fimasartan is 2-n-butyl-5-dimethylaminothiocarbonylmethyl-6-methyl-3-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl ] Pyrimidin-4 (3H) -one {2-n-Butyl-5-dimethylaminothiocarbonylmethyl-6-methyl-3-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] pyrimidin -4 (3H) -one}, which has the following structural formula and is known as an antihypertensive agent of the Angiotensin II Receptor Blocker (ARB) family.

[Pimasaltan]

The method for preparing fimasartan is described in Korean Patent No. 10-521980, [Compound 1] and 4- [2 '-(N-triphenylmethyltetrazol-5-ylphenyl] benzyl, prepared as intermediates of fimasartan. A method is described in which bromide is reacted in the presence of a base, the obtained product is thioamidated using a Lassson's Reagent, and then the protecting group is removed under acidic conditions to produce fimasaltan (Scheme 1).

[Reaction Scheme 1]

This patent also describes a process for preparing compounds of Formula 1, which are useful intermediates of fimasartan, as shown in Scheme 2 below.

Scheme 2

However, as in [Scheme 2], when pentanamidine hydrochloride and dimethylacetylsuccinate are reacted under a base such as potassium hydroxide, the terminal functional group of the methyl ester form of dimethylacetylsuccinate is inevitably selected by the base during the reaction. Hydrolysis results in the product of the terminal functional group of formula (b) in the form of a carboxylic acid. Therefore, when the carboxyl group, which is a terminal functional group, is converted to an imide group with N-hydroxybenzotriazole, N-methylmorpholine, and dicyclohexyl carbodiimide, moisture is absorbed as a reaction by-product, and thus, general centrifugation is performed. The disadvantage is that urea is produced which is difficult to filter.

It is an object of the present invention to prepare 2- (2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl) -N, N-dimethylacetamide with suppressed urea by-product generation and improved production yield. To provide a method.

The present invention is reacted with the following compound [Formula 2] and pentanamidine (pentanamidine) or salts thereof in the presence of a base [Formula 1] compound 2- (2-n-butyl-4-hydroxy-6-methyl-pyri Provided are methods for preparing midin-5-yl) -N, N-dimethyl acetamide.

 [Formula 1]

[Formula 2]

Wherein R ¹ is C ₁ to C ₆ straight or branched alkyl or C ₃ to C ₆ cyclo alkyl.

In the present invention, pentanamidine or a salt thereof may be commercially available or prepared by a known method. Salts include hydrochloride, bromate, and the like, with hydrochloride being preferred.

In the present invention, the compound of [Formula 2] may be commercially available, or may be prepared by reacting the following [Formula 3] and [Formula 4] in the presence of a base.

(3)

[Formula 4]

Where

R ¹ is C ₁ to C ₆ straight or branched alkyl or C ₃ to C ₆ cycloalkyl,

X is F, Cl, Br or I.

In the above [Formula 2] compound preparation method, the compound [Formula 3] is preferably R ¹ is methyl or ethyl, the compound [Formula 4] is preferably X is Cl (chloro). In addition, the base in the reaction is preferably sodium ethoxide or sodium methoxide.

In the method for preparing the compound of Formula 1, the molar ratio of the compound of Formula 2 to pentanamidine or salts thereof has various values, but is preferably 1: 0.9 to 2, more preferably 1: 1 to 1.5. .

In the method for preparing a compound of the present invention, the base is preferably potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide or sodium ethoxide, and more preferably sodium hydroxide and potassium hydroxide. The amount of base used is preferably 1: 1 to 2 moles relative to moles of pentanamidine or salts thereof.

In the Formula 1 compound production method of the present invention, [formula 2] compound is preferably R ¹ is methyl or ethyl, it is further more preferably methyl.

In the method of preparing the compound of Formula 1, the reaction temperature is preferably about 5 ° C to 45 ° C, more preferably about 20 ° C to 30 ° C, and the reaction time may be reacted for 1 to 48 hours. However, this may vary depending on the reaction temperature, the reaction solvent, or the use of a catalyst.

In the method for preparing a compound of the present invention, the reaction solvent is preferably a polar solvent, a solvent such as ethanol, methanol, acetonitrile or a mixed solvent thereof may be used, and ethanol is more preferable. The amount of the reaction solvent may be used within the range used by a conventional organic manufacturer in a conventional reaction, but it is preferable to use about 5 to 40 times the volume ratio (g / ml) per use weight of pentanamidine or its salt, 9 to 20 times are preferred, and 9 to 12 times are even more preferred.

In addition, the present invention provides a method for producing pimasaltan, including the method for preparing the compound of [Formula 1] of the present invention. For example, the method for preparing fimasartan of the present invention is a method for preparing [Formula 1] of the present invention and 2- (2-n-butyl-4-hydroxy-6-methyl as described in Korean Patent No. 10-0521980. -Pyrimidin-5-yl) -N, N-dimethylacetamide as a starting material for preparing fimasartan.

The production method of the present invention has the effect of suppressing the generation of urea by-products, which are difficult to remove during the purification process by being produced in the existing production method, and at the same time improve the production yield. Therefore, the manufacturing method of the present invention is very economical and industrial application is easier than the existing manufacturing method.

The invention is further illustrated by the following examples. The following non-limiting examples are intended to illustrate the present invention in more detail, and merely illustrate the manufacturing method of the present invention, and do not limit the scope of the present invention.

In addition, the reagents and solvents mentioned below are purchased from Aldrich, or Acros, Daejeong, Samjeon, unless otherwise specified, and the ¹ H-NMR data is JNM-LA400 (JEOL), GEMINI 200 (VERIAN). It is the value measured with the machine of g).

< Manufacturing example  1> 2- (N, N- Dimethylaminocarbonylmethyl ) -Acetoacetic acid Methyl ester  Produce

Methyl acetoacetate (11.61 g, 0.1 mol) was dissolved in methanol (60 mL) in an ice bath, and then sodium methoxide (5.67 g, 0.105 mol, 1.05 equiv) was added and stirred for 30 minutes. 2-chloro-N, N-dimethylacetamide (12.40 g, 0.1 mol, 1.0 equiv) was added dropwise for 30 minutes, then the ice bath was removed and stirred at reflux for 5 hours. After cooling to 20 ° C., the solvent was removed in vacuo, and 100 mL of chloroform and 100 mL of purified water were added thereto, followed by stirring to separate an organic layer. The organic layer was concentrated and the residue was purified by chromatography using a mixed solution of 1: 2 = ethyl acetate: n-hexane (v / v) to give 12.06 g of a pale yellow transparent oil (yield 57.1%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ 2.40 (s, 1H), 2.91 (s, 3H), 3.04 (s, 3H), 3.10 ~ 2.75 (m, 2H), 3.75 (s, 1H), 4.15 ( m, 1H)

< Manufacturing example  2> 2- (N, N- Dimethylaminocarbonylmethyl ) -Acetoacetic acid Ethyl ester  Produce

Ethyl acetoacetate (16.92 g, 0.130 mol) was dissolved in ethanol (90 mL) dried in an ice bath, and sodium ethoxide (9.78 g, 0.137 mol, 1.05 equiv) was added and stirred for 30 minutes. 2-chloro-N, N-dimethylacetamide (16.13 g, 0.130 mol, 1.0 equiv) was added dropwise, the ice bath was removed and stirred at room temperature for 15 hours. After removing the solvent under reduced pressure, 150 mL of chloroform and 150 mL of purified water were added thereto, followed by stirring to separate an organic layer. The organic layer was concentrated and the residue was purified by chromatography using a mixed solution of 1: 5 = ethyl acetate: n-hexane (v / v) to give 12.96 g of a colorless transparent oil (yield 41.0%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.08 (t, 3H), 1.20 (t, 3H), 1.30 (t, 3H), 2.40 (s, 2H), 2.80 (dd, 1H), 3.04 (dd, 1H), 3.34 (m, 4H), 4.17 (t, 2H), 4.20 (m, 1H)

< Example  1> 2- (N, N- Dimethylaminocarbonylmethyl ) -Acetoacetic acid Methyl ester To  2- (2-n-butyl-4-hydroxy-6- methyl -Pyrimidin-5-yl) -N, N- Of dimethylacetamide  Produce

Pentaneamidine hydrochloride (5.96 g, 43.6 mmol, 1.0 equiv) was dissolved in 60 mL ethanol, and 2- (N, N-dimethylaminocarbonylmethyl) -acetoacetic acid methyl ester (8.77 g, obtained in Production Example 1) was dissolved. 43.6 mmol, 1.0 equiv) and potassium hydroxide (2.88 g, 43.6 mmol, 1.0 equiv) were added and stirred at 25 ° C. for 15 h. Concentrated using a vacuum, 50mL of chloroform and 50mL of purified water were added thereto, stirred, and left to stand to separate an organic layer. The organic layer was concentrated, 10 mL of ethyl acetate and 50 mL of hexane were added, refluxed, cooled, and filtered. 1: 5 = ethylacetate: hexane (v / v) was washed with 10 mL of a mixed solvent and dried to give 7.7 g (30.6 mmol) of the title compound in the form of a white powder (yield 70%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.93 (t, 3H), 1.40 (m, 2H), 1.72 (m, 2H), 2.34 (s, 3H), 2.62 (t, 2H), 2.96 (s, 3H), 3.16 (s, 3H), 3.56 (s, 2H)

< Example  2> 2- (N, N- Dimethylaminocarbonylmethyl ) -Acetoacetic acid Ethyl ester To  2- (2-n-butyl-4-hydroxy-6- methyl -Pyrimidin-5-yl) -N, N- Of dimethylacetamide  Produce

Pentaneamidine hydrochloride (6.83 g, 50.0 mmol, 1.0 equiv) was dissolved in 70 mL ethanol, and then 2- (N, N-dimethylaminocarbonylmethyl) -acetoacetic acid ethyl ester (10.76 g, obtained in Production Example 2) 50.0 mmol) and potassium hydroxide (3.30 g, 50.0 mmol) were added and stirred at 25 ° C. for 4 hours. Concentrated using a vacuum, 50mL of chloroform and 50mL of purified water were added thereto, stirred, and left to stand to separate an organic layer. The organic layer was concentrated, 70 mL of hexane was added thereto, refluxed, cooled, and the solid was filtered. The solid was washed with 10 mL of hexane and dried to give 6.56 g (23.5 mmol) of the title compound as a white powder (yield 47.0%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.93 (t, 3H), 1.40 (m, 2H), 1.72 (m, 2H), 2.34 (s, 3H), 2.62 (t, 2H), 2.96 (s, 3H), 3.16 (s, 3H), 3.56 (s, 2H)

Claims (9)

The compound of Formula 2 is reacted with a pentanamidine or a salt thereof in the presence of a base, and thus 2- (2-n-butyl-4-hydroxy-6-methyl-pyrimidine-5 is a compound of Formula 1; -Yl) -N, N-dimethyl acetamide.
[Formula 1]

(2)

Wherein R ¹ is C ₁ to C ₆ straight or branched alkyl or C ₃ to C ₆ cyclo alkyl. The method of claim 1, wherein the pentanamidine salt is pentanamidine hydrochloride. The method of claim 1, wherein the molar ratio of the compound of Formula 2 and pentanamidine or a salt thereof is 1: 1 to 1.5. The method according to claim 1, wherein the base is potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide or sodium ethoxide. The method of claim 1, wherein R ^{1 in} [Formula 2] is methyl or ethyl. The method of claim 1, wherein the compound of [Formula 2] is prepared by reacting the following [Formula 3] compound and [Formula 4] in the presence of a base.
(3)

[Chemical Formula 4]

In this formula,
R ¹ is C ₁ to C ₆ straight or branched alkyl or C ₃ to C ₆ cycloalkyl,
X is F, Cl, Br or I. 7. The method of claim 6, wherein R ^{1 in} [Formula 3] is methyl or ethyl. The method of claim 6, wherein the base is sodium methoxide or sodium ethoxide. A method for producing fimasaltan comprising the method of any one of claims 1 to 8.