WO2011090323A2 - Novel preparation method of 2-(2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl)-n,n-dimethylacetamide - Google Patents

Novel preparation method of 2-(2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl)-n,n-dimethylacetamide Download PDF

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WO2011090323A2
WO2011090323A2 PCT/KR2011/000401 KR2011000401W WO2011090323A2 WO 2011090323 A2 WO2011090323 A2 WO 2011090323A2 KR 2011000401 W KR2011000401 W KR 2011000401W WO 2011090323 A2 WO2011090323 A2 WO 2011090323A2
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formula
compound
methyl
preparation
base
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PCT/KR2011/000401
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French (fr)
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WO2011090323A3 (en
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Ji-Han Kim
Joon-Kwang Lee
Byoung-Wug Yoo
Ok-Kyoung Choi
Hak-Won Kim
Sun-Hwa Lee
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Boryung Pharmaceutical Co., Ltd
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Priority claimed from KR20100005945A external-priority patent/KR101058284B1/en
Application filed by Boryung Pharmaceutical Co., Ltd filed Critical Boryung Pharmaceutical Co., Ltd
Priority to CN201180004629.8A priority Critical patent/CN102666496B/en
Priority to IN2695DEN2012 priority patent/IN2012DN02695A/en
Publication of WO2011090323A2 publication Critical patent/WO2011090323A2/en
Publication of WO2011090323A3 publication Critical patent/WO2011090323A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to a method for preparing 2-(2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl)-N,N-dimethylacetamide.
  • Fimasartan chemically defined as 2-n-butyl-5-dimethylaminothiocarbonylmethyl-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]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.
  • ARB Angiotensin II Receptor Blocker
  • Fimasartan The method for preparing Fimasartan is described in Korean Patent No. 10-521980, wherein the compound of formula 1 prepared as an intermediate of Fimasartan is reacted with 4-[2'-(N-triphenylmethyltetrazol-5-ylphenyl]benzyl bromide in the presence of a base, the resulting product is subjected to thioamidation using a Lawesson's reagent, and the protective group is removed under acidic conditions to prepare Fimasartan (Reaction Scheme 1).
  • Korean patent No. 10-521980 describes a method for preparing the compound of formula 1 which is a useful intermediate of Fimasartan, as shown in the following Reaction Scheme 2.
  • An object of the present invention is intended to provide a method for preparing 2-(2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl)-N,N-dimethylacetamide, which is capable of suppressing the formation of a by-product urea and achieving an improved production yield.
  • the present invention provides a method for preparing 2-(2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl)-N,N-dimethylacetamide which is a compound of the following formula 1, comprising reacting a compound of the following formula 2 with pentanamidine or a salt thereof in the presence of a base (hereinafter, referred to as “first preparation method”).
  • R 1 represents C 1 -C 6 linear or branched alkyl or C 3 -C 6 cycloalkyl.
  • pentanamidine or a salt thereof is commercially available or may be prepared by a known method.
  • the salt includes hydrochloride, bromate, or the like, and hydrochloride is preferable.
  • the compound of formula 2 is a commercially available compound or may be prepared by a known method. And the compound of formula 2 is prepared by reacting the compound of the following formula 3 with the compound of the following formula 4 in the presence of a base.
  • the present invention includes this method for preparing the compound of formula 2.
  • R 1 represents C 1 -C 6 linear or branched alkyl or C 3 -C 6 cycloalkyl
  • X represents F, Cl, Br or I.
  • the compound of formula 3 is preferably a compound wherein R 1 represents methyl or ethyl,and the compound of formula 4 is preferably a compound wherein X represents Cl(chloro).
  • the base in the above reaction is preferably sodium ethoxide or sodium methoxide.
  • the molar ratio of the compound of formula 2:pentanamidine or a salt thereof may vary, but is preferably in the range of 1:0.9 to 2, and more preferably 1:1 to 1.5.
  • the base is preferably potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide or sodium ethoxide, and more preferably sodium hydroxide or potassium hydroxide.
  • the amount of the base used relative to pentanamidine or a salt thereof is preferably in the molar range of 1:1 to 2.
  • the compound of formula 2 is a compound wherein R 1 preferably represents methyl or ethyl,and more preferably methyl.
  • the reaction temperature is preferably in the range of about 5°C to 45°C, more preferably about 20°C to 30°C.
  • the reaction time is in the range of 1 hour to 48 hours and may vary depending on the reaction temperature, the reaction solvent or whether or not a catalyst is used.
  • the reaction solvent is preferably a polar solvent, and examples of the solvent that can be used in the present invention include ethanol, methanol, acetonitrile and a mixed solvent thereof. Ethanol is more preferable.
  • the amount of the reaction solvent is within the range which is used in a common reaction by ordinary organic manufacturers, it is preferable to use about a 5 to 40-fold volume (g/mL) of the reaction solvent per weight of pentanamidine or a salt thereof, preferably a 9 to 20-fold volume, and more preferably a 9 to 12-fold volume.
  • the present invention provides a method for preparing Fimasartan, comprising the first preparation method of the present invention.
  • the method for preparing Fimasartan in accordance with the present invention includes the first preparation method of the present invention and a method for preparing Fimasartan using 2-(2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl)-N,N-dimethylacetamide as a starting material, as described in Korean Patent No. 10-0521980.
  • the present invention provides a method for preparing 2-(2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl)-N,N-dimethylacetamide of the following formula 1, comprising the steps of: a) reacting 2-(2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl)-acetic acid of the following formula 5 with the compound of the following formula 6 in the presence of a base, and b) reacting the product of Step a) with dimethylamine (hereinafter, referred to as “second preparation method”).
  • R represents C 1-6 alkyl;C 3-6 cycloalkyl;phenyl or benzyl,and
  • Y represents Cl, Br or I.
  • the compound of formula 5 is commercially available or may be prepared by a known method, for example, the method described in Korean Patent No. 10-0521980.
  • the compound of formula 6 is commercially available or may be prepared by a known method (Justus Liebigs Annalen der Chemie, 1880, vol. 205, p. 231, or Gazzetta Chimica Italiana, 1920, vol. 50 II, p. 10).
  • the compound of formula 6 is preferably ethyl chloroformate, methyl chloroformate, isopropyl chloroformate, phenyl chloroformate, benzyl chloroformate, ethyl bromoformate, methyl bromoformate, isopropyl bromoformate or the like, and more preferably ethyl chloroformate.
  • the molar ratio of the compound of formula 5:the compound of formula 6 in Step a) is preferably in the range of 1:1 to 5, more preferably 1:2 to 3, and still more preferably 1:2.5.
  • the compound of formula 6 and the base in Step a) may be used in various molar ratios, but they are preferably used in an equimolar ratio for minimizing the occurrence of impurities.
  • Step a) of the second preparation method of the present invention when a base and the compound of formula 6 are added to a solution in which the compound of formula 5 is contained, the base is added and then the compound of formula 6 is added, followed by reaction.
  • An interval may be given between the addition of a base and the addition of the compound of formula 6.
  • a base is added to the solution in which the compound of formula 5 is contained, followed by stirring for 30 minutes, and the compound of formula 6 is added thereto, followed by reaction.
  • the present invention is not limited to such an addition order.
  • the base of Step a) is preferably triethylamine, trimethylamine, triisopropylamine or diisopropylethylamine.
  • the reaction temperature of Step a) is preferably in the range of -10°C to 35°C and may be changed during the reaction.
  • the reaction time is preferably in the range of 10 minutes to 3 hours and may vary depending on the reaction temperature or the like. For example, after the reaction at a temperature of -10°C to 5°C for 30 minutes, the reaction temperature may be increased to 25°C, followed by reaction.
  • Step b) the product of Step a) is a separately isolated compound or otherwise may be one used in a state where it is not isolated ( in-situ state).
  • dimethylamine of Step b) may be one prepared by reacting dimethylamine hydrochloride with triethylamine.
  • dimethylamine hydrochloride and triethylamine are preferably used in an equimolar ratio, and they are preferably used in a 1 to 5-fold amount relative to moles of the compound of formula 5, and more preferably a 2 to 3.5-fold amount.
  • the reaction temperature of Step b) is preferably in the range of 20°C to the boiling point of a reaction solvent (reflux temperature).
  • the reaction temperature may be changed during the reaction and may vary depending on the reaction solvent.
  • the reaction time is preferably in the range of 1 to 24 hours and may vary depending on the reaction temperature, the reaction solvent, or the like.
  • the reaction solvent is dichloromethane
  • the reaction may be carried out at a temperature of 50 to 60°C for about 12 hours.
  • the reaction solvent of Step a) and Step b) may be a conventional organic solvent and examples thereof include dichloromethane, chloroform, and tetrahydrofuran.
  • the amount of the reaction solvent is within the range which is used in a common reaction by ordinary organic manufacturers, and it is preferable to use about a 5 to 40-fold volume (g/mL) of the reaction solvent per weight of the compound of formula 5, preferably a 15 to 30-fold volume, and more preferably about a 20-fold volume.
  • the present invention provides a method for preparing Fimasartan, comprising the second preparation method of the present invention.
  • the method for preparing Fimasartan in accordance with the present invention includes the second preparation method of the present invention and a method for preparing Fimasartan using 2-(2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl)-N,N-dimethylacetamide as a starting material, as described in Korean Patent No. 10-0521980.
  • the first preparation method and second preparation method of the present invention suppress the generation of a by-product urea which is produced in a conventional preparation method and is not readily removed in a purification process, and simultaneously improve a yield of the product.
  • the preparation method of the present invention is very economic and is easier to be industrially applicable, as compared to the conventional preparation method.
  • reagents and solvents referred hereinafter are purchased from Aldrich, Acros, Daejung Co., Ltd., or Samjeon Co., Ltd., and 1 H-NMR data are values measured by a JNM-LA400(manufactured by JEOL Ltd.) or GEMINI200(manufactured by VERIAN Inc.).
  • Methyl acetoacetate (11.61 g, 0.1 mol) was dissolved in methanol (60 mL) in an ice bath, 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 separation of the organic layer.
  • Ethyl acetoacetate (16.92 g, 0.130 mol) was dissolved in dry ethanol (90 mL) in an ice bath, 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 separation of the organic layer.
  • Example 1 Preparation of 2-(2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl)-N,N-dimethylacetamide using methyl 2-(N,N-dimethylaminocarbonylmethyl)-acetoacetate
  • Pentanamidine hydrochloride (5.96 g, 43.6 mmol) was dissolved in 60 mL of ethanol, and methyl 2-(N,N-dimethylaminocarbonylmethyl)-acetoacetate (8.77 g, 43.6 mmol) obtained in Preparation Example 1 and potassium hydroxide (2.88 g, 43.6 mmol) were added thereto, followed by stirring at 25°C for 15 hours. Concentration was carried out 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.
  • Pentanamidine hydrochloride (6.83 g, 50.0 mmol) was dissolved in 70 mL of ethanol, and ethyl 2-(N,N-dimethylaminocarbonylmethyl)-acetoacetate (10.76 g, 50.0 mmol) obtained in Preparation Example 2 and potassium hydroxide (3.30 g, 50.0 mmol) were added thereto, followed by stirring at 25°C for 4 hours. Concentration was carried out 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 70 mL of hexane was added thereto, followed by reflux, cooling and solid filtration. The solid was washed with 10 mL of hexane and then dried to afford 6.56 g (23.5 mmol, yield: 47.0%) of the title compound as a white powder.
  • the preparation method of the present invention improves a production yield as compared to the conventional preparation method, and therefore is very economic and is easier to be industrially applicable.

Abstract

The present invention provides a method for preparing 2-(2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl)-N,N-dimethylacetamide, comprising reacting a compound of the following formula 2 with pentanamidine or a salt thereof in the presence of a base. [Formula 2] wherein R1 represents C1-C6 linear or branched alkyl or C3-C6 cycloalkyl. Further, the present invention provides a method for preparing 2-(2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl)-N,N-dimethylacetamide, comprising the steps of: a) reacting 2-(2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl)-acetic acid with a haloformate compound in the presence of a base, and b) reacting the product of Step a) with dimethylamine.

Description

NOVEL PREPARATION METHOD OF 2-(2-N-BUTYL-4-HYDROXY-6-METHYL-PYRIMIDIN-5-YL)-N,N-DIMETHYLACETAMIDE
The present invention relates to a method for preparing 2-(2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl)-N,N-dimethylacetamide.
Fimasartan, chemically defined as 2-n-butyl-5-dimethylaminothiocarbonylmethyl-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]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.
[Fimasartan]
Figure PCTKR2011000401-appb-I000001
The method for preparing Fimasartan is described in Korean Patent No. 10-521980, wherein the compound of formula 1 prepared as an intermediate of Fimasartan is reacted with 4-[2'-(N-triphenylmethyltetrazol-5-ylphenyl]benzyl bromide in the presence of a base, the resulting product is subjected to thioamidation using a Lawesson's reagent, and the protective group is removed under acidic conditions to prepare Fimasartan (Reaction Scheme 1).
[Reaction Scheme 1]
Figure PCTKR2011000401-appb-I000002
Further, Korean patent No. 10-521980 describes a method for preparing the compound of formula 1 which is a useful intermediate of Fimasartan, as shown in the following Reaction Scheme 2.
[Reaction Scheme 2]
Figure PCTKR2011000401-appb-I000003
However, as shown in Reaction Scheme 2, when pentanamidine hydrochloride and dimethyl acetyl succinate are reacted in the presence of a base such as potassium hydroxide, the terminal functional group in the form of methyl ester of dimethyl acetyl succinate is inevitably hydrolyzed during the reaction by a base, and consequently the terminal functional group of formula b which is a product has a form of carboxylic acid. Therefore, when the terminal functional group, that is, a carboxyl group is converted into an imide group using N-hydroxybenzotriazole, N-methylmorpholine or dicyclohexylcarboimide, there is a disadvantage associated with the production of by-product urea which is not readily filtered by general centrifugation because of its high moisture-absorbing property.
An object of the present invention is intended to provide a method for preparing 2-(2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl)-N,N-dimethylacetamide, which is capable of suppressing the formation of a by-product urea and achieving an improved production yield.
In order to achieve the object, the present invention provides a method for preparing 2-(2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl)-N,N-dimethylacetamide which is a compound of the following formula 1, comprising reacting a compound of the following formula 2 with pentanamidine or a salt thereof in the presence of a base (hereinafter, referred to as “first preparation method”).
[Formula 1]
Figure PCTKR2011000401-appb-I000004
[Formula 2]
Figure PCTKR2011000401-appb-I000005
wherein R1 represents C1-C6 linear or branched alkyl or C3-C6 cycloalkyl.
In the present invention, pentanamidine or a salt thereof is commercially available or may be prepared by a known method. Here, the salt includes hydrochloride, bromate, or the like, and hydrochloride is preferable.
In the first preparation method of the present invention, the compound of formula 2 is a commercially available compound or may be prepared by a known method. And the compound of formula 2 is prepared by reacting the compound of the following formula 3 with the compound of the following formula 4 in the presence of a base. The present invention includes this method for preparing the compound of formula 2.
[Formula 3]
Figure PCTKR2011000401-appb-I000006
[Formula 4]
Figure PCTKR2011000401-appb-I000007
wherein R1 represents C1-C6 linear or branched alkyl or C3-C6 cycloalkyl, and
X represents F, Cl, Br or I.
In the method for preparing the compound of formula 2, the compound of formula 3 is preferably a compound wherein R1 represents methyl or ethyl,and the compound of formula 4 is preferably a compound wherein X represents Cl(chloro). Further, the base in the above reaction is preferably sodium ethoxide or sodium methoxide.
In the first preparation method of the present invention, the molar ratio of the compound of formula 2:pentanamidine or a salt thereof may vary, but is preferably in the range of 1:0.9 to 2, and more preferably 1:1 to 1.5.
In the first preparation method 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 or potassium hydroxide. The amount of the base used relative to pentanamidine or a salt thereof is preferably in the molar range of 1:1 to 2.
In the first preparation method of the present invention, the compound of formula 2 is a compound wherein R1 preferably represents methyl or ethyl,and more preferably methyl.
In the first preparation method of the present invention, the reaction temperature is preferably in the range of about 5℃ to 45℃, more preferably about 20℃ to 30℃. The reaction time is in the range of 1 hour to 48 hours and may vary depending on the reaction temperature, the reaction solvent or whether or not a catalyst is used.
In the first preparation method of the present invention, the reaction solvent is preferably a polar solvent, and examples of the solvent that can be used in the present invention include ethanol, methanol, acetonitrile and a mixed solvent thereof. Ethanol is more preferable. Although the amount of the reaction solvent is within the range which is used in a common reaction by ordinary organic manufacturers, it is preferable to use about a 5 to 40-fold volume (g/mL) of the reaction solvent per weight of pentanamidine or a salt thereof, preferably a 9 to 20-fold volume, and more preferably a 9 to 12-fold volume.
Further, the present invention provides a method for preparing Fimasartan, comprising the first preparation method of the present invention. For example, the method for preparing Fimasartan in accordance with the present invention includes the first preparation method of the present invention and a method for preparing Fimasartan using 2-(2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl)-N,N-dimethylacetamide as a starting material, as described in Korean Patent No. 10-0521980.
Further, the present invention provides a method for preparing 2-(2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl)-N,N-dimethylacetamide of the following formula 1, comprising the steps of: a) reacting 2-(2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl)-acetic acid of the following formula 5 with the compound of the following formula 6 in the presence of a base, and b) reacting the product of Step a) with dimethylamine (hereinafter, referred to as “second preparation method”).
[Formula 1]
Figure PCTKR2011000401-appb-I000008
[Formula 5]
Figure PCTKR2011000401-appb-I000009
[Formula 6]
Figure PCTKR2011000401-appb-I000010
wherein R represents C1-6 alkyl;C3-6 cycloalkyl;phenyl or benzyl,and
Y represents Cl, Br or I.
In the second preparation method of the present invention, the compound of formula 5 is commercially available or may be prepared by a known method, for example, the method described in Korean Patent No. 10-0521980.
In the second preparation method of the present invention, the compound of formula 6 is commercially available or may be prepared by a known method (Justus Liebigs Annalen der Chemie, 1880, vol. 205, p. 231, or Gazzetta Chimica Italiana, 1920, vol. 50 II, p. 10). The compound of formula 6 is preferably ethyl chloroformate, methyl chloroformate, isopropyl chloroformate, phenyl chloroformate, benzyl chloroformate, ethyl bromoformate, methyl bromoformate, isopropyl bromoformate or the like, and more preferably ethyl chloroformate.
In the second preparation method of the present invention, the molar ratio of the compound of formula 5:the compound of formula 6 in Step a) is preferably in the range of 1:1 to 5, more preferably 1:2 to 3, and still more preferably 1:2.5.
In the second preparation method of the present invention, the compound of formula 6 and the base in Step a) may be used in various molar ratios, but they are preferably used in an equimolar ratio for minimizing the occurrence of impurities.
In Step a) of the second preparation method of the present invention, when a base and the compound of formula 6 are added to a solution in which the compound of formula 5 is contained, the base is added and then the compound of formula 6 is added, followed by reaction. An interval may be given between the addition of a base and the addition of the compound of formula 6. For example, a base is added to the solution in which the compound of formula 5 is contained, followed by stirring for 30 minutes, and the compound of formula 6 is added thereto, followed by reaction. However, the present invention is not limited to such an addition order.
In the second preparation method of the present invention, the base of Step a) is preferably triethylamine, trimethylamine, triisopropylamine or diisopropylethylamine.
In the second preparation method of the present invention, the reaction temperature of Step a) is preferably in the range of -10℃ to 35℃ and may be changed during the reaction. The reaction time is preferably in the range of 10 minutes to 3 hours and may vary depending on the reaction temperature or the like. For example, after the reaction at a temperature of -10℃ to 5℃ for 30 minutes, the reaction temperature may be increased to 25℃, followed by reaction.
In the second preparation method of the present invention, in Step b), the product of Step a) is a separately isolated compound or otherwise may be one used in a state where it is not isolated (in-situ state).
In the second preparation method of the present invention, dimethylamine of Step b) may be one prepared by reacting dimethylamine hydrochloride with triethylamine. Here, dimethylamine hydrochloride and triethylamine are preferably used in an equimolar ratio, and they are preferably used in a 1 to 5-fold amount relative to moles of the compound of formula 5, and more preferably a 2 to 3.5-fold amount.
In the second preparation method of the present invention, the reaction temperature of Step b) is preferably in the range of 20℃ to the boiling point of a reaction solvent (reflux temperature). The reaction temperature may be changed during the reaction and may vary depending on the reaction solvent. The reaction time is preferably in the range of 1 to 24 hours and may vary depending on the reaction temperature, the reaction solvent, or the like. For example, when the reaction solvent is dichloromethane, the reaction may be carried out at a temperature of 50 to 60℃ for about 12 hours.
In the second preparation method of the present invention, the reaction solvent of Step a) and Step b) may be a conventional organic solvent and examples thereof include dichloromethane, chloroform, and tetrahydrofuran. The amount of the reaction solvent is within the range which is used in a common reaction by ordinary organic manufacturers, and it is preferable to use about a 5 to 40-fold volume (g/mL) of the reaction solvent per weight of the compound of formula 5, preferably a 15 to 30-fold volume, and more preferably about a 20-fold volume.
Further, the present invention provides a method for preparing Fimasartan, comprising the second preparation method of the present invention. For example, the method for preparing Fimasartan in accordance with the present invention includes the second preparation method of the present invention and a method for preparing Fimasartan using 2-(2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl)-N,N-dimethylacetamide as a starting material, as described in Korean Patent No. 10-0521980.
The first preparation method and second preparation method of the present invention suppress the generation of a by-product urea which is produced in a conventional preparation method and is not readily removed in a purification process, and simultaneously improve a yield of the product.
Therefore, the preparation method of the present invention is very economic and is easier to be industrially applicable, as compared to the conventional preparation method.
Now, the present invention will be described in more detail with reference to the following Examples. These non-limiting examples are provided only for illustrating the present invention and exemplify the preparation method of the present invention, and should not be construed as limiting the scope and spirit of the present invention.
Unless otherwise specified, reagents and solvents referred hereinafter are purchased from Aldrich, Acros, Daejung Co., Ltd., or Samjeon Co., Ltd., and 1H-NMR data are values measured by a JNM-LA400(manufactured by JEOL Ltd.) or GEMINI200(manufactured by VERIAN Inc.).
A. First preparation method of present invention
Preparation Example 1: Preparation of methyl 2-(N,N-dimethylaminocarbonylmethyl)-acetoacetate
Methyl acetoacetate (11.61 g, 0.1 mol) was dissolved in methanol (60 mL) in an ice bath, 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℃, the solvent was removed under vacuum, and 100 mL of chloroform and 100 mL of purified water were added thereto, followed by stirring and separation of 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 afford 12.06 g (yield: 57.1%) of pale yellow transparent oil.
1H-NMR (200MHz, CDCl3)d 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)
Preparation Example 2: Preparation of ethyl 2-(N,N-dimethylaminocarbonylmethyl)-acetoacetate
Ethyl acetoacetate (16.92 g, 0.130 mol) was dissolved in dry ethanol (90 mL) in an ice bath, 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 separation of 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 afford 12.96 g (yield: 41.0%) of colorless transparent oil.
1H-NMR (200MHz, CDCl3)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), 4.17 (t,2H), 4.20 (m,1H)
Example 1: Preparation of 2-(2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl)-N,N-dimethylacetamide using methyl 2-(N,N-dimethylaminocarbonylmethyl)-acetoacetate
Pentanamidine hydrochloride (5.96 g, 43.6 mmol) was dissolved in 60 mL of ethanol, and methyl 2-(N,N-dimethylaminocarbonylmethyl)-acetoacetate (8.77 g, 43.6 mmol) obtained in Preparation Example 1 and potassium hydroxide (2.88 g, 43.6 mmol) were added thereto, followed by stirring at 25℃ for 15 hours. Concentration was carried out 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 resulting filtrate was washed with 10 mL of a 1:5 (v/v) mixed solvent of ethyl acetate:hexane and then dried to afford 7.7 g (30.6mmol, yield: 70%) of the title compound as a white powder.
1H-NMR (400MHz, CDCl3)d 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: Preparation of 2-(2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl)-N,N-dimethylacetamide using ethyl 2-(N,N-dimethylaminocarbonylmethyl)-acetoacetate
Pentanamidine hydrochloride (6.83 g, 50.0 mmol) was dissolved in 70 mL of ethanol, and ethyl 2-(N,N-dimethylaminocarbonylmethyl)-acetoacetate (10.76 g, 50.0 mmol) obtained in Preparation Example 2 and potassium hydroxide (3.30 g, 50.0 mmol) were added thereto, followed by stirring at 25℃ for 4 hours. Concentration was carried out 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 70 mL of hexane was added thereto, followed by reflux, cooling and solid filtration. The solid was washed with 10 mL of hexane and then dried to afford 6.56 g (23.5 mmol, yield: 47.0%) of the title compound as a white powder.
1H-NMR (400MHz, CDCl3)d 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)
B. Second preparation method of present invention
Preparation Example 3: Preparation of 2-(2-n-butyl-4-hydroxy-6-methylpyrimidin-5-yl)acetic acid
1.78 kg of pentanamidine hydrochloride and 1.89 kg of dimethyl acetyl succinate were dissolved in 5.5 L of methanol, and 1.31 kg of potassium hydroxide was added thereto, followed by stirring at room temperature for 15 hours. Then, 20 L of water was added thereto, and the reaction temperature was cooled to 0℃. The reaction solution was acidified to make a pH of 4 by adding a 4N aqueous hydrochloric acid solution. The resulting solid was filtered and dried to afford 1.57 kg (yield: 70%) of the title compound.
1H-NMR (400MHz, CDCl3)d 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 3: Preparation of 2-(2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl)-N,N-dimethylacetamide
5 g (22.3 mmol) of 2-(2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl)-acetic acid prepared in Preparation Example 3 and 7.8 mL (55.7 mmol) of triethylamine were dissolved in 100 mL of dichloromethane, followed by cooling to 0℃ and stirring for 30 minutes. To the resulting solution was added dropwise 5.5 mL (55.7 mmol) of ethyl chloroformate for 5 minutes, and the reaction temperature was adjusted to 25℃, followed by stirring for 30 minutes. To the solution were added 5.5 g (66.9 mmol) of dimethylamine hydrochloride and 9.5 mL (66.9 mmol) of triethylamine, followed by reflux at 55℃ for 12 hours. Then, the solution was cooled to 25℃, and 50 mL of purified water was added thereto. The solution was basified to make a pH of 9 by adding a 1N sodium hydroxide solution. The organic layer was separated, and the aqueous layer was extracted with 50 mL of dichloromethane. The combined organic layer was washed with 50 mL of brine and then dried over anhydrous sodium sulfate. After filtration, concentration was carried out under reduced pressure. The concentrate was crystallized using ethyl acetate and n-hexane to afford 5.2 g (yield: 93%) of a white title compound.
1H-NMR (400MHz, CDCl3)d 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)
The preparation method of the present invention improves a production yield as compared to the conventional preparation method, and therefore is very economic and is easier to be industrially applicable.

Claims (16)

  1. A method for preparing 2-(2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl)-N,N-dimethylacetamide which is a compound of the following formula 1, comprising reacting a compound of the following formula 2 with pentanamidine or a salt thereof in the presence of a base.
    [Formula 1]
    Figure PCTKR2011000401-appb-I000011
    [Formula 2]
    Figure PCTKR2011000401-appb-I000012
    wherein R1 represents C1-C6 linear or branched alkyl or C3-C6 cycloalkyl.
  2. The method according to claim 1, wherein the pentanamidine salt is pentanamidine hydrochloride.
  3. The method according to claim 1, wherein the molar ratio of the compound of formula 2:pentanamidine or a salt thereof is in the range of 1:1 to 1.5.
  4. The method according to claim 1, wherein the base is potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide or sodium ethoxide.
  5. The method according to claim 1, wherein R1 in formula 2 represents methyl or ethyl.
  6. The method according to claim 1, wherein the compound of formula 2 is prepared by reacting the compound of the following formula 3 with the compound of the following formula 4 in the presence of a base.
    [Formula 3]
    Figure PCTKR2011000401-appb-I000013
    [Formula 4]
    Figure PCTKR2011000401-appb-I000014
    wherein R1 represents C1-C6 linear or branched alkyl or C3-C6 cycloalkyl, and
    X represents F, Cl, Br or I.
  7. The method according to claim 6, wherein R1 in formula 3 represents methyl or ethyl.
  8. The method according to claim 6, wherein the base is sodium methoxide or sodium ethoxide.
  9. A method for preparing Fimasartan, comprising the preparation method of any one of claims 1 to 8.
  10. A method for preparing 2-(2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl)-N,N-dimethylacetamide of the following formula 1, comprising the steps of:
    a) reacting 2-(2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl)-acetic acid of the following formula 5 with the compound of the following formula 6 in the presence of a base, and
    b) reacting the product of Step a) with dimethylamine.
    [Formula 1]
    Figure PCTKR2011000401-appb-I000015
    [Formula 5]
    Figure PCTKR2011000401-appb-I000016
    [Formula 6]
    Figure PCTKR2011000401-appb-I000017
    wherein R represents C1-6 alkyl;C3-6 cycloalkyl;phenyl or benzyl,and
    Y represents Cl, Br or I.
  11. The method according to claim 10, wherein the base of Step a) is triethylamine, trimethylamine, triisopropylamine or diisopropylethylamine.
  12. The method according to claim 10, wherein the compound of formula 6 in Step a) is ethyl chloroformate.
  13. The method according to claim 10, wherein the molar ratio of the compound of formula 5:the compound of formula 6 in Step a) is in the range of 1:2 to 3.
  14. The method according to claim 10, wherein the compound of formula 6 and the base in Step a) are used in an equimolar ratio.
  15. The method according to claim 10, wherein dimethylamine of Step b) is prepared by reacting dimethylamine hydrochloride with triethylamine.
  16. A method for preparing Fimasartan, comprising the preparation method of any one of claims 10 to 15.
PCT/KR2011/000401 2010-01-21 2011-01-20 Novel preparation method of 2-(2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl)-n,n-dimethylacetamide WO2011090323A2 (en)

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US9592233B2 (en) 2013-03-14 2017-03-14 Boryung Pharmaceutical Co., Ltd. Pharmaceutical combination drug
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CN107973784B (en) * 2017-11-16 2021-08-24 珠海市海瑞德生物科技有限公司 Synthesis method of fimasartan
CN113336709B (en) * 2021-06-25 2022-06-03 上海立科化学科技有限公司 Preparation method of N, N-dimethylacetamide

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EP4089090A4 (en) * 2019-12-31 2024-04-10 Fosun Orinove Pharmatech Inc Method for preparing coumarin compound, 3 position of which is substituted with amidoalkyl and products and related intermediates thereof

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