KR20110086293A - New preparation of 2-(2-n-butyl-4-hydroxy-6-methyl-pyrimidine-5-yl)-n,n-dimethylacetamide - Google Patents

Abstract

PURPOSE: A novel method for preparing 2-(2-n-butyl-4-hydroxy-6-methyl-pyrimidine-5-yl)-N,N-dimethylacetamide is provided to suppress urea by-product production and t improve production yield. CONSTITUTION: A method for preparing 2-(2-n-butyl-4-hydroxy-6-methyl-pyrimidine-5-yl)-N,N-dimethylacetamide of chemical formula 1 comprises: a step of reacting a compound of chemical formula 3 with 2-(2-n-butyl-4-hydroxy-6-methyl-pyrimidine-5-yl)-acetic acid of chemical formula 2 under the presence of base; and a step of reacting with dimethylacmine. The base is triethyl amine, trimethyl amine, triisopropyl amine or diisopropyl ethyl amine. The compound of chemical formula 3 is ethyl chloroformate.

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-pyrimidine-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).

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, when the pentanamidine hydrochloride and dimethylacetyl succinate are reacted under a base such as potassium hydroxide, as shown in [Scheme 2], the terminal functional group of the methyl ester form of dimethyl acetyl succinate 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. At this time, by converting the carboxyl group, which is a terminal functional group, into an imide group with N-hydroxybenzotriazole, N-methylmorpholine, dicyclohexylcarbodiimide, and the like, the moisture is absorbed into the reaction byproduct, and thus, general centrifugation is performed. The disadvantage is that large amounts of urea are produced which are 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 a) 2- (2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl) -acetic acid of the following [Formula 2] and the following compound of the formula [3] are reacted under a base b) reacting the product of step a) with dimethylamine to form 2- (2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl) -N, N- Provided are methods for preparing dimethyl acetamide.

[Formula 1]

[Formula 2]

(3)

Where

R is C1-6 alkyl or C3-6 cycloalkyl, phenyl or benzyl,

X is chloro, bromo or iodo.

In the production method of the present invention, the compound of [Formula 2] may be purchased by commercially available or manufactured by a known method, for example, the method described in Korean Patent Registration No. 10-0521980.

In the preparation method of the present invention, the compound of Formula 3 may be purchased commercially or known methods (Justus Liebigs Annalen der Chemie, 1880, vol. 205, p. 231, or Gazzetta Chimica Italiana, 1920, vol. 50). II, p. 10). The compound is ethyl chloroformate, methylchloroformate, isopropylchloroformate, phenylchloroformate, benzylchloroformate, ethyl bromoformate, methyl bromoformate, isopropyl Bromoformate and the like are preferred, and ethylchloroformate is even more preferred.

In the production method of the present invention, the molar ratio of the compound of [Formula 2] and [Formula 3] of step a) may be 1: 1 to 5, more preferably 1: 2 to 3, more preferably 1: 2.5 More preferred.

In addition, in the preparation method of the present invention, the molar amount of the compound and base of step a) may be used in various molar ratios, but the same amount is preferable to minimize the generation of impurities.

In step a) of the production method of the present invention, the addition of the base and the compound of the formula [3] to the solution containing the compound of the formula [2], after the base addition, the compound of the formula [3] may be sequentially added and reacted, It is also possible to maintain a certain time between the addition of a base and the addition of a compound. For example, after the base is stirred in the solution containing the compound of Formula 2 for 30 minutes, the compound of Formula 3 may be added and reacted thereto. However, the present invention is not limited to such an addition order.

In the process of the invention, the base of step a) is preferably triethyl amine, trimethyl amine, triisopropyl amine or diisopropyl ethylamine.

In the production method of the present invention, the reaction temperature of step a) is preferably reacted at -10 to 35 ° C, and the reaction temperature can be changed during the reaction. In addition, the reaction time is preferably 10 minutes to 3 hours, but may vary depending on the reaction temperature. For example, after reacting at -10 to 5 ° C for 30 minutes, the reaction temperature can be increased to 25 ° C and then reacted.

In the preparation method of the present invention, in step b), the product of step a) may be a compound that is isolated separately or used in an in-situ state.

In the preparation method of the present invention, the dimethylamine of step b) may be prepared by the reaction of dimethylamine hydrochloride and triethylamine. The molar ratio of dimethylamine hydrochloride and triethylamine is preferably the same amount, preferably 1 to 5 times, more preferably 2 to 3.5 times the molar amount of the compound.

In the preparation method of the present invention, the reaction temperature of step b) is preferably 20 ° C. to the boiling point (reflux temperature) of the reaction solvent, and the reaction temperature may be changed during the reaction and may vary depending on the reaction solvent. The reaction time is preferably 1 to 24 hours, but may vary depending on the reaction temperature, the reaction solvent and the like. For example, when the reaction solvent is dichloromethane, it may be reacted at about 50 to 60 ℃ about 12 hours.

In the production method of the present invention, the reaction solvent of step a) and step b) may use a conventional organic solvent, for example, dichloromethane, chloroform, tetrahydrofuran and the like. In addition, the amount of the reaction solvent may be used within the range used by a conventional organic manufacturer in a conventional reaction, it is preferable to use about 5 to 40 times the volume ratio (g / ml) per use weight of the compound. 15 to 30 times are preferred, about 20 times more preferred.

In addition, the present invention provides a method for preparing fimasartan using the compound of [Formula 1] prepared by the method of preparing the compound of [Formula 1]. For example, the method for preparing fimasartan using the compound of [Formula 1] prepared according to the present invention may be prepared using the method described in Korean Patent No. 10-0521980.

The production method of the present invention has the effect of improving the production yield while suppressing the generation of urea by-products produced by the existing production method, which was difficult to remove during the purification process. Therefore, the manufacturing method of the present invention is very economical and industrial application is easier than the existing manufacturing method.

The present invention is explained in more detail 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, Acros, Daejeong, or Samjeon, unless otherwise specified, and the ¹ H-NMR data are measured by a JNM-LA400 (JEOL) machine. to be.

< Manufacturing example > 2- (2-n-butyl-4-hydroxy-6- Methylpyrimidine -5-yl) acetic acid {2- (2-n-butyl-4-hydroxy-6-methylpyrimidin-5-yl) acetic acid } Manufacturing

Dissolve 1.78 kg of pentaneamidine hydrochloride and 1.89 kg of dimethylacetyl succinate in 5.5 L of methanol, add 1.31 kg of potassium hydroxide, stir at room temperature for 15 hours, add 20 L of water, cool the reaction temperature to 0 ° C, and 4N hydrochloric acid. The pH was acidified to 4 by addition of aqueous solution. The resulting solid was filtered and dried to yield 1.57 kg (70%) of the title compound.

¹ H-NMR (300MHz, CDCl ₃ ) δ 0.90 (t, 3H), 1.21 ~ 1.35 (m, 2H), 1.54 ~ 1.64 (m, 2H), 2.16 (s, 3H), 2.45 ~ 2.53 (t, 3H ), 3.38 (s, 2H), 12.41 (brs, 1H)

< Example > 2- (2-n-butyl-4-hydroxy-6- methyl -Pyrimidin-5-yl) -N, N- Dimethyl Acetate Preparation of Amides

Dichloromethane was prepared by preparing 5 g (22.3 mmol) of 2- (2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl) -acetic acid and 7.8 mL (55.7 mmol) of triethylamine. After dissolving in 100mL, the mixture was cooled to 0 ° C and stirred for 30 minutes. Ethylchloroformate 5.5 mL (55.7 mmol) was added dropwise to this solution for 5 minutes, and the reaction temperature was adjusted to 25 ° C. and stirred for 30 minutes. 5.5 g (66.9 mmol) of dimethylamine hydrochloride and 9.5 mL (66.9 mmol) of triethylamine were added to the solution, and the mixture was refluxed at 55 ° C. for 12 hours, cooled to 25 ° C., and 50 mL of purified water was added thereto to give 1 N sodium hydroxide solution. The solution was basified to pH 9 by addition. The organic layer was separated and the aqueous layer was extracted with 50 mL of dichloromethane. The combined organic layers were washed with 50 mL of brine and dried over anhydrous sodium sulfate. After filtration it was concentrated under reduced pressure. The concentrate was crystallized using ethyl acetate and n-hexane to give 5.2 g (yield: 93%) of a white title compound.

¹ H-NMR (300 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 (7)

a) reacting 2- (2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl) -acetic acid of the following Chemical Formula 2 and the following Chemical Formula 3 under a base;
b) reacting the product of step a) with dimethylamine to form 2- (2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl) -N, N-dimethyl Process for preparing acetamide.
[Formula 1]

(2)

(3)

Where
R is C1-6 alkyl or C3-6 cycloalkyl, phenyl or benzyl,
X is chloro, bromo or iodo. The process of claim 1, wherein the base of step a) is triethyl amine, trimethyl amine, triisopropyl amine or diisopropyl ethylamine. The method according to claim 1, wherein the compound of [Formula 3] of step a) is ethyl chloroformate. The method of claim 1, wherein the molar ratio of the compound of Formula 2 and the compound of Formula 3 is 1: 2 to 3. The method according to claim 1, wherein the use equivalent of the compound of [Formula 3] and the base of step a) is the same. The method of claim 1, wherein the dimethylamine of step b) is prepared by the reaction of dimethylamine hydrochloride and triethylamine. A method for preparing fimasartan using the compound of [Formula 1] according to any one of claims 1 to 6.