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WO2013038931A1 - Procédé de production d'un analogue de 2-oxo-2h-cyclohepta[b]furane - Google Patents

Procédé de production d'un analogue de 2-oxo-2h-cyclohepta[b]furane Download PDF

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Publication number
WO2013038931A1
WO2013038931A1 PCT/JP2012/072307 JP2012072307W WO2013038931A1 WO 2013038931 A1 WO2013038931 A1 WO 2013038931A1 JP 2012072307 W JP2012072307 W JP 2012072307W WO 2013038931 A1 WO2013038931 A1 WO 2013038931A1
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WO
WIPO (PCT)
Prior art keywords
cyclohepta
oxo
furan
producing
analog
Prior art date
Application number
PCT/JP2012/072307
Other languages
English (en)
Japanese (ja)
Inventor
剛 冨山
冨山　泰
昌幸 横田
将博 本間
正文 安並
Original Assignee
壽製薬株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 壽製薬株式会社 filed Critical 壽製薬株式会社
Priority to CN201280042641.2A priority Critical patent/CN103781773A/zh
Priority to IN2611CHN2014 priority patent/IN2014CN02611A/en
Priority to KR1020147009562A priority patent/KR20140063792A/ko
Publication of WO2013038931A1 publication Critical patent/WO2013038931A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered

Definitions

  • the present invention relates to a method for producing a 2-oxo-2H-cyclohepta [b] furan analog useful as an intermediate for pharmaceutical synthesis.
  • 2-oxo-2H-cyclohepta [b] furan analogs have been used as intermediates for pharmaceutical synthesis.
  • methyl 5-isopropyl-2-oxo-2H-cyclohepta [b] furan-3-carboxylate represented by the following formula (III) is an intermediate for the production of anti-ulcer agent eguarene sodium (registered trade name Azuroxa) Useful as.
  • the present invention reacts 2-chlorotropone analog and malonic acid dimethyl ester to produce 2-oxo-2H-cyclohepta [b] furan analog, which is an inexpensive alternative to the above-mentioned t-butylamine and sodium alkoxide.
  • An object of the present invention is to provide a compound that is easy to handle and can be produced with high yield and high purity.
  • the present inventor conducted a reaction between 2-chlorotropone analog and malonic acid dimethyl ester in an alcohol solvent, particularly an alkali metal hydroxide, particularly sodium hydroxide or hydroxide. It has been found that by carrying out in the presence of potassium, the reaction proceeds smoothly under mild conditions and 2-oxo-2H-cyclohepta [b] furan analog (II) can be produced in high yield and high purity.
  • an alcohol solvent particularly an alkali metal hydroxide, particularly sodium hydroxide or hydroxide.
  • R represents a hydrogen atom or a lower alkyl group which may be branched (1-5 carbon atoms)
  • the alkali metal hydroxide is preferably sodium hydroxide or potassium hydroxide.
  • the alcohol solvent is preferably methanol. In the above reaction, it is preferable to use 0.5 to 3.0 moles of malonic acid dimethyl ester and alkali metal hydroxide with respect to 1 mole of 2-chlorotropone analog (I).
  • R is a hydrogen atom or a lower alkyl group (1-5 carbon atoms) which may be branched.
  • the lower alkyl group which may be branched is, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a butyl group, an isobutyl group, a pentyl group or a cyclopentyl group.
  • the 2-chlorotropone analog represented by the general formula (I) of the starting material can be produced by a known method (for example, Journal of American Chemical society, 74, 5683, 1952, Journal2of Organic Chemistry, 43, 3621, 1978, Patent Document 1).
  • Scheme 3 shows a method for producing 2-oxo-2H-cyclohepta [b] furan represented by the general formula (II) from the 2-chlorotropone analog represented by the general formula (I) in the present invention.
  • dimethyl malonate and alkali metal hydroxide in an amount of 0.5 to 3.0 mol, more preferably 1 mol, per mol of 2-chlorotropone analog (I).
  • the range is from 8 to 2.2 mol.
  • the alkali metal hydroxide include lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, and cesium hydroxide, with sodium hydroxide and potassium hydroxide being preferred.
  • the reaction solvent alcohols such as methanol, ethanol, 1-propanol and isopropanol are used, preferably methanol.
  • the reaction is carried out at ⁇ 78 ° C. to solvent reflux temperature, and the preferred reaction temperature is in the range of ⁇ 30 ° C. to 10 ° C.
  • the present invention will be described with reference to examples.
  • the example shows the reaction of 2-chloro-5-isopropyltropone (IV) with malonic acid diester ester to give methyl 5-isopropyl-2-oxo-2H-cyclohepta [b] furan-3-carboxylate (III ).
  • Example 1 To a solution of 2-chloro-5-isopropyltropone (1.494 g) and dimethyl malonate (1.9 mL) in methanol (5.0 mL), add a solution of sodium hydroxide (0.656 g) in methanol (7.0 mL) to -19 to -6. After dropwise addition at ° C, the mixture was stirred for 1 hour. The reaction solution was poured into water and stirred at room temperature. The solid was collected by filtration, washed with water, and dried to give methyl 5-isopropyl-2-oxo-2H-cyclohepta [b] furan-3-carboxylate (1.726 g) as a yellow solid.
  • Example 2 After dropwise addition of a solution of potassium hydroxide (0.184 g) in methanol (2.0 mL) to a solution of 2-chloro-5-isopropyltropone (0.300 g) and dimethyl malonate (0.37 mL) in methanol (1.6 mL) with ice cooling And stirred for 2 hours. The reaction solution was poured into water and stirred at room temperature. The solid was collected by filtration, washed with water, and dried to give methyl 5-isopropyl-2-oxo-2H-cyclohepta [b] furan-3-carboxylate (0.353 g) as a yellow solid.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Furan Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Procédé de production économique et facile d'un analogue de 2-oxo- 2H-cyclohepta[b]furane à titre d'intermédiaire pharmaceutique à une pureté élevée et des rendements élevés. Dans ce procédé, l'analogue de 2-oxo- 2H-cyclohepta[b]furane représenté par la formule générale (II) (R étant un atome d'hydrogène ou un groupe alkyle inférieur éventuellement ramifié, (1 à 5 atomes de carbone) est obtenu par réaction, dans un milieu de type alcool en présence d''un hydroxyde de métal alcalin, d'esters diméthyliques d'acide malonique avec un analogue de 2-chlorotropone représenté par la formule générale (1) (R comme ci-dessus).
PCT/JP2012/072307 2011-09-12 2012-09-03 Procédé de production d'un analogue de 2-oxo-2h-cyclohepta[b]furane WO2013038931A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CN201280042641.2A CN103781773A (zh) 2011-09-12 2012-09-03 2-氧代-2H-环庚并[b]呋喃类似物的制造方法
IN2611CHN2014 IN2014CN02611A (fr) 2011-09-12 2012-09-03
KR1020147009562A KR20140063792A (ko) 2011-09-12 2012-09-03 ２-옥소-２Ｈ-사이클로헵타［ｂ］푸란 유사체의 제조 방법

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2011198541 2011-09-12
JP2011-198541 2011-09-12

Publications (1)

Publication Number Publication Date
WO2013038931A1 true WO2013038931A1 (fr) 2013-03-21

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PCT/JP2012/072307 WO2013038931A1 (fr) 2011-09-12 2012-09-03 Procédé de production d'un analogue de 2-oxo-2h-cyclohepta[b]furane

Country Status (5)

Country Link
JP (1) JPWO2013038931A1 (fr)
KR (1) KR20140063792A (fr)
CN (1) CN103781773A (fr)
IN (1) IN2014CN02611A (fr)
WO (1) WO2013038931A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115991697A (zh) * 2023-03-22 2023-04-21 中国中医科学院中药研究所 一种制备环庚三烯并ε-己内酯类化合物的方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH01199938A (ja) * 1986-11-07 1989-08-11 Ajinomoto Co Inc 抗脂血剤

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63239248A (ja) * 1986-11-07 1988-10-05 Ajinomoto Co Inc 抗脂血剤
JPH0753681B2 (ja) * 1989-12-25 1995-06-07 高砂香料工業株式会社 トロポン誘導体の製造法
JPWO2002053523A1 (ja) * 2000-12-26 2004-04-30 財団法人乙卯研究所 トロポロン誘導体

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH01199938A (ja) * 1986-11-07 1989-08-11 Ajinomoto Co Inc 抗脂血剤

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
TERUKO SATO: "2-Methoxy-3-Methyltropone to Malonic Acid Dimethyl tono Shukugobutsu ni Tsuite", JOURNAL OF THE CHEMICAL SOCIETY OF JAPAN, vol. 80, no. 11, 1959, pages 1345 - 1347 *
TERUKO SATO: "4-methyltropone-rui to Malonic Acid Dimethyl Oyobi Acetoacetic Acid Ethyl tono Shukugobutsu no Kozo ni Tsuite", JOURNAL OF THE CHEMICAL SOCIETY OF JAPAN, vol. 80, no. 11, 1959, pages 1347 - 1349 *
TERUKO SATO: "5-methyltropone-rui to Malonic Acid Dimethyl Oyobi Acetoacetic Acid Ethyl Ester tono Shukugobutsu no Kozo ni Tsuite", JOURNAL OF THE CHEMICAL SOCIETY OF JAPAN, vol. 80, no. 11, 1959, pages 1342 - 1345 *
TERUKO SATO: "6-methyltropone-rui to Malonic Acid Dimethyl Oyobi Acetoacetic Acid Ethyl tono Shukugobutsu no Kozo ni Tsuite", JOURNAL OF THE CHEMICAL SOCIETY OF JAPAN, vol. 80, no. 11, 1959, pages 1349 - 1352 *

Also Published As

Publication number Publication date
KR20140063792A (ko) 2014-05-27
CN103781773A (zh) 2014-05-07
IN2014CN02611A (fr) 2015-08-07
JPWO2013038931A1 (ja) 2015-03-26

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