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

A technology of dimethylacetamide and n-butyl, which is applied in the field of preparing 2--N,N-dimethylacetamide, can solve problems such as difficulty in centrifugation and filtration, achieve easy industrial application, economical preparation method, and increase yield rate effect

Active Publication Date: 2012-09-12
BORYUNG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Therefore, when N-hydroxybenzotriazole, N-methylmorpholine, or dicyclohexylcarboimide (carboimide) are used to convert the terminal functional group, that is, the carboxyl group, into an imine group, there are problems associated with the production of by-product urea. Disadvantage, urea is not easy to pass through the usual centrifugal filtration due to its high moisture absorption characteristics

Method used

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

Examples

Experimental program
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Effect test

preparation example 1

[0063] Preparation Example 1: Preparation of 2-(N,N-dimethylaminocarbonylmethyl)-methyl acetoacetate

[0064] In an ice bath, methyl acetoacetate (11.61 g, 0.1 mol) was dissolved in methanol (60 mL), and sodium methoxide (5.67 g, 0.105 mol) was added thereto, followed by stirring for 30 minutes. 2-Chloro-N,N-dimethylacetamide (12.40 g, 0.1 mol) was added dropwise thereto over 30 minutes, and the ice bath was removed, followed by stirring under reflux for 5 hours. The reaction mixture was cooled to 20° C., the solvent was removed under vacuum, and 100 mL of chloroform and 100 mL of purified water were added thereto, followed by stirring and separating the organic layer. The organic layer was concentrated, and the residue was purified by chromatography using a 1:2 (v / v) mixed solution of ethyl acetate and n-hexane to provide 12.06 g (yield: 57.1%) of a pale yellow transparent oil.

[0065] 1 H-NMR (200MHz, CDCl 3 )d 2.40(s, 1H), 2.91(s, 3H), 3.04(s, 3H), 3.10-2.75(m, 2H), 3.7...

preparation example 2

[0066] Preparation Example 2: Preparation of 2-(N,N-dimethylaminocarbonylmethyl)-ethyl acetoacetate

[0067] In an ice bath, ethyl acetoacetate (16.92 g, 0.130 mol) was dissolved in absolute ethanol (90 mL), and sodium ethoxide (9.78 g, 0.137 mol) was added thereto, followed by stirring for 30 minutes. 2-Chloro-N,N-dimethylacetamide (16.13 g, 0.130 mol) was added dropwise thereto, and the ice bath was removed, followed by stirring at room temperature for 15 hours. The solvent was removed under reduced pressure, and 150 mL of chloroform and 150 mL of purified water were added thereto, followed by stirring and separating the organic layer. The organic layer was concentrated, and the residue was purified by chromatography using a 1:5 (v / v) mixed solution of ethyl acetate and n-hexane to provide 12.96 g (yield: 41.0%) of a colorless transparent oil.

[0068] 1 H-NMR (200MHz, CDCl 3 )d 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) ,...

Embodiment 1

[0069] Example 1: Preparation of 2-(2-n-butyl-4-hydroxyl-6-methyl-pyrimidin-5-yl) using 2-(N,N-dimethylaminocarbonylmethyl)-methyl acetoacetate -N,N-Dimethylacetamide

[0070] Pentaneamidine hydrochloride (5.96 g, 43.6 mmol) was dissolved in 60 mL of ethanol, and 2-(N,N-dimethylaminocarbonylmethyl)-methyl acetoacetate obtained in Preparation Example 1 was added thereto ( 8.77g, 43.6mmol) and potassium hydroxide (2.88g, 43.6mmol), then stirred at 25°C for 15 hours. Concentration was performed under vacuum, and 50 mL of chloroform and 50 mL of purified water were added to the concentrate, followed by stirring and standing to separate an organic layer. The organic layer was concentrated, and 10 mL of ethyl acetate and 50 mL of hexane were added thereto, followed by reflux, cooling and filtration. The obtained filtrate was washed with 10 mL of a 1:5 (v / v) mixed solvent of ethyl acetate:hexane, and then dried to provide 7.7 g (30.6 mmol, yield: 70%) of the title compound as a whi...

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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

technical field [0001] The invention relates to a method for preparing 2-(2-n-butyl-4-hydroxyl-6-methyl-pyrimidin-5-yl)-N,N-dimethylacetamide. Background technique [0002] Chemically defined as 2-n-butyl-5-dimethylaminothiocarbonylmethyl-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4- Fimasartan of the base]methyl]pyrimidin-4(3H)-one has the following structural formula and is known as a hypotensive agent of the angiotensin II receptor blocker (ARB) class. [0003] [Fimasartan] [0004] [0005] A method for preparing Fimasartan is described in Korean Patent No. 10-521980, wherein a compound of formula 1 prepared as an intermediate of Fimasartan is reacted with 4-[2'-(N-triphenyl ylmethyltetrazol-5-ylphenyl]benzyl bromide, the resulting product was thioamidated using Lawson's reagent, and the protecting group was removed under acidic conditions to prepare Fimasartan (Scheme 1) . [0006] [Reaction Scheme 1] [0007] [0008] In addition, Korean Patent No. 10-521980...

Claims

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Application Information

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IPC IPC(8): C07D239/36C07D239/34C07C235/12
CPCC07D239/36C07D403/10C07C231/12C07C235/74
Inventor 金知汉李濬光柳炳旭崔沃卿金学元李宜和
Owner BORYUNG PHARMA CO LTD
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