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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Publication number
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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English (en)
French (fr)
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WO2011090323A3 (en
Inventor
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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Publication date
Priority claimed from KR20100005945A external-priority patent/KR101058284B1/ko
Application filed by Boryung Pharmaceutical Co., Ltd filed Critical Boryung Pharmaceutical Co., Ltd
Priority to IN2695DEN2012 priority Critical patent/IN2012DN02695A/en
Priority to CN201180004629.8A priority patent/CN102666496B/zh
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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
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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IN2695DEN2012 IN2012DN02695A (enrdf_load_stackoverflow) 2010-01-21 2011-01-20
CN201180004629.8A CN102666496B (zh) 2010-01-21 2011-01-20 2-(2-正丁基-4-羟基-6-甲基-嘧啶-5-基)-n,n-二甲基乙酰胺的制备方法

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Application Number Priority Date Filing Date Title
KR20100005725 2010-01-21
KR10-2010-0005725 2010-01-21
KR10-2010-0005945 2010-01-22
KR20100005945A KR101058284B1 (ko) 2010-01-22 2010-01-22 2-(2-ｎ-부틸-4-히드록시-6-메틸-피리미딘-5-일)-Ｎ,Ｎ-디메틸아세트아미드의 신규한 제조방법

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014115977A1 (ko) * 2013-01-28 2014-07-31 보령제약 주식회사 암 예방 또는 치료용 조성물
US9592233B2 (en) 2013-03-14 2017-03-14 Boryung Pharmaceutical Co., Ltd. Pharmaceutical combination drug
EP4089090A4 (en) * 2019-12-31 2024-04-10 Fosun Orinove Pharmatech, Inc. PROCESS FOR PREPARING COUMARIN COMPOUND, POSITION 3 OF WHICH IS SUBSTITUTED BY AN AMIDOALKYL, AND ASSOCIATED PRODUCTS AND INTERMEDIATES THEREOF

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104478811B (zh) * 2014-11-14 2017-01-25 浙江浙邦制药有限公司 一种非马沙坦中间体的制备方法
CN107973784B (zh) * 2017-11-16 2021-08-24 珠海市海瑞德生物科技有限公司 一种非马沙坦的合成方法
CN113336709B (zh) * 2021-06-25 2022-06-03 上海立科化学科技有限公司 一种n,n-二甲基乙酰胺的制备方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR19990081093A (ko) * 1998-04-25 1999-11-15 조생현 피리미디논 화합물, 이를 함유하는 약제학적 조성물 및 이의제조방법
EP1436283B1 (en) * 2001-09-21 2008-01-23 Boryung Pharmaceutical Co., Ltd. Method for preparing pyrimidinone compound and pharmaceutically acceptable salts thereof
KR100521980B1 (ko) * 2002-10-10 2005-10-17 보령제약 주식회사 피리미디논 화합물 및 이의 염의 삼수화물의 제조 방법

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014115977A1 (ko) * 2013-01-28 2014-07-31 보령제약 주식회사 암 예방 또는 치료용 조성물
US9592233B2 (en) 2013-03-14 2017-03-14 Boryung Pharmaceutical Co., Ltd. Pharmaceutical combination drug
EP4089090A4 (en) * 2019-12-31 2024-04-10 Fosun Orinove Pharmatech, Inc. PROCESS FOR PREPARING COUMARIN COMPOUND, POSITION 3 OF WHICH IS SUBSTITUTED BY AN AMIDOALKYL, AND ASSOCIATED PRODUCTS AND INTERMEDIATES THEREOF

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IN2012DN02695A (enrdf_load_stackoverflow) 2015-09-04
CN102666496B (zh) 2015-05-20
WO2011090323A3 (en) 2011-11-10
CN104610164A (zh) 2015-05-13
CN102666496A (zh) 2012-09-12
CN104610164B (zh) 2018-03-16

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