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.

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

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• 2012
  • 2012-09-03 WO PCT/JP2012/072307 patent/WO2013038931A1/ja not_active Ceased
  • 2012-09-03 KR KR1020147009562A patent/KR20140063792A/ko not_active Withdrawn
  • 2012-09-03 IN IN2611CHN2014 patent/IN2014CN02611A/en unknown
  • 2012-09-03 CN CN201280042641.2A patent/CN103781773A/zh active Pending
  • 2012-09-03 JP JP2013533610A patent/JPWO2013038931A1/ja active Pending

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