WO2004054951A1 - Process for the preparation of 3-[2-(3,4-dimethoxy-benzoyl)-4,5-dimethoxy-phenyl]-pentan-2-one - Google Patents

Process for the preparation of 3-[2-(3,4-dimethoxy-benzoyl)-4,5-dimethoxy-phenyl]-pentan-2-one Download PDF

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Publication number
WO2004054951A1
WO2004054951A1 PCT/HU2002/000178 HU0200178W WO2004054951A1 WO 2004054951 A1 WO2004054951 A1 WO 2004054951A1 HU 0200178 W HU0200178 W HU 0200178W WO 2004054951 A1 WO2004054951 A1 WO 2004054951A1
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WO
WIPO (PCT)
Prior art keywords
compound
general formula
process according
dimethoxy
alkali
Prior art date
Application number
PCT/HU2002/000178
Other languages
English (en)
French (fr)
Inventor
Erika MOLNÁRNÉ SAMU
Gyula Simig
Original Assignee
Egis Gyogyszergyar Rt.
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 Egis Gyogyszergyar Rt. filed Critical Egis Gyogyszergyar Rt.
Priority to UAA200507059A priority Critical patent/UA78634C2/uk
Priority to EP02791921A priority patent/EP1575890A1/en
Priority to AU2002361068A priority patent/AU2002361068A1/en
Priority to JP2004559931A priority patent/JP4437093B2/ja
Priority to SK70-2005A priority patent/SK702005A3/sk
Priority to EA200500966A priority patent/EA007788B1/ru
Publication of WO2004054951A1 publication Critical patent/WO2004054951A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
    • C07C45/455—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation with carboxylic acids or their derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
    • C07C45/511—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups
    • C07C45/515—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups the singly bound functional group being an acetalised, ketalised hemi-acetalised, or hemi-ketalised hydroxyl group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/29—Saturated compounds containing keto groups bound to rings
    • C07C49/35—Saturated compounds containing keto groups bound to rings containing ether groups, groups, groups, or groups

Definitions

  • the invention relates to a new process for the preparation of 3- [2-(3,4-dimethoxy-benzoyl)-4,5-dimethoxy-phenyl]-pentan-2- one of the Formula
  • one of the Formula I is an intermediate useful in the preparation of the anxiolytic active ingredient l-(3,4-dimethoxy- ⁇ henyl)-4- methyl-5-ethyl-7, ⁇ -dimethoxy-5H-2,3-benzodiazepine having the International Non-Proprietory Name (INN) tofisopam.
  • INN International Non-Proprietory Name
  • the compound of the Formula I is prepared from diisohomoeugenol ' by oxidation with chrome(VI)oxide; only low yields are obtained.
  • HU 187,161 aims the elimination of the above drawbacks, of the known procedures.
  • the compound of the Formula I is prepared with the aid of a chromium-free process by reacting 3-(3,4-dimethoxy-phenyl)- ⁇ entan-2-one with 3,4-dimethoxy-benzoyl chloride in the presence of aluminium(III)chloride and decomposing the benzopyrilium salt formed in alkaline medium.
  • the disadvantage of the above process is that 3,4-dimethoxy- benzoyl chloride used as starting material is very susceptible to decomposition and the Friedel-Crafts product formed in the reaction is strongly contaminated, difficult to handle and the purification thereof encounters serious problems.
  • C 2-6 -alkylene which comprises a) replacing the bromine atom in a compound of the general Formula II by an alkali or magnesium atom; reacting the alkali or magnesium compound thus obtained with an approximately equimolar amount of an acid amide of the general Formula (wherein R 3 and R 4 are C ⁇ _ 4 -alkyl) and hydrolysing the compound of the general Formula
  • C 1-4 -alkyl relates to straight or branched chain alkyl groups containing 1-4 carbon atoms (e.g. methyl, ethyl, n- propyl, isopropyl, n-butyl etc.).
  • C 2 _ 6 -alkylene relates to straight or branched chain alkylene groups containing 2-6 carbon atoms (e.g. ethylene, trimethylene etc.).
  • diaryl ketones are prepared from aryl metal compounds by reacting said aryl metal compound with an aromatic nitrile and hydrolysing the imine formed.
  • said general process is not applicable for the preparation of 3 ⁇ [2-(3,4-dimethoxy-benzoyl)-4,5-dimethoxy- phenyl]-pentan-2-one because on the basis of prior art in the place of 3-[2-(3,4-dimethoxy-benzoyl)-4,5-dimethoxy-phenyl]- pentan-2-one of the Formula I rather the formation of an isoquinoline derivative could be expected [Khim. Geterosikl. Soedin, (1988), (1), 134-5].
  • the compounds of the general Formula IV can be readily prepared with the aid of amides of the general Formula Ilia and esters of the general Formula Illb, whereby said compounds of the general Formulae Ilia and Mb have not been hitherto generally used in metal organic chemistry for the formation of the ketone group.
  • the present invention is based on the recognition that the desired 3-[2-(3,4-dimethoxy-benzoyl)-4,5-dimethoxy-phenyl]- pentan-2-one of the Formula I can be readily prepared by reacting an alkali or magnesium compound, formed from a 3-(2- bromo-4,5-dimethoxy-phenyl)-pentan-2-one ketal of the general Formula II, with a compound of the general Formula Ilia or Illb and thereafter subjecting the 3-[2-(3,4-dimethoxy-benzoyl)-4,5- dimethoxy-phenyl]-pentan-2-one ketal of the general Formula IV thus obtained to hydrolysis.
  • the bromine atom in a compound of the general Formula II is replaced by an alkali or magnesium atom, whereupon the alkali or magnesium compound thus obtained is reacted with a 3,4- dimethoxy-benzoic acid-N,N-dial yl-amide of the general Formula Ilia; said compound can be prepared from 3,4- dimethoxy-benzoic acid in a known manner.
  • the bromine atom in the compound of the general Formula Ills replaced by an alkali (e.g. sodium, potassium or lithium) atom or by a magnesium atom with the aid of a Grignard-reaction.
  • an alkali e.g. sodium, potassium or lithium
  • a magnesium atom with the aid of a Grignard-reaction.
  • the alkyl lithium compound is preferably used in a solution formed with an alkane, preferably n-hexane.
  • the replacement of the bromine atom by lithium can be carried out at a temperature between -78°C and -10°C - preferably at about -10°C - in anhydrous tetrahydrofurane.
  • the alkali or magnesium compound formed - advantageously the lithium compound - is then reacted with an approximately equimolar amount (preferably 1.0-1.2 molar amount) of an amide of the general Formula Ilia.
  • One may proceed preferably by reacting the lithium compound with the compound of the general Formula Ilia without isolation in the reaction mixture obtained during the preparation of said lithium compound.
  • the reaction can be carried out at a temperature below 0°C, preferably at about -20°C.
  • the compound of the general Formula IV thus formed can be isolated from the reaction mixture.
  • the bromine atom in the compound of the general Formula II is replaced by an alkali or magnesium atom, whereupon the alkali or magnesium compound thus obtained is reacted with an alkyl- 3,4-dimethoxy-benzoate of the general Formula Illb to yield a compound of the general Formula IV.
  • the compound of the general Formula IV obtained in reaction variant a) or b) can be optionally isolated and purified by recrystallization.
  • the isolated ketal of the general Formula IV is hydrolysed into the corresponding ketone of the Formula I with a mineral acid in a manner known per se.
  • Hydrolysis of the ketal of the general Formula IV can be preferably carried out by using a mineral acid, particularly diluted sulfuric acid or diluted hydrochloric acid, most advantageously diluted sulfuric acid.
  • the reaction can be performed in a two-phase reaction mixture, preferably at 20-40 °C.
  • One phase of said two-phase system consists of a water non-miscible organic solvent (preferably an aromatic hydrocarbon, e.g. benzene, toluene or xylene; or an aliphatic halogenated hydrocarbon, e.g. dichloro methane) and the other phase consists of the aqueous acidic solution.
  • the reaction can be promoted by adding kieselgel, used in a 2-5-fold amount related to the compound of the general Formula IV.
  • the compound of the Formula I can also be prepared directly, i.e. without isolating the intermediate of the general Formula IV.
  • the compound of the Formula I thus obtained can be purified, if desired, by recrystallization from a suitable solvent.
  • a suitable solvent preferably C 1 . 4 straight or branched chain aliphatic alcohols can be used.
  • the compound of the Formula I thus obtained has a purity above 98 % and is excellently suitable for the preparation of the pharmaceutically active tofisopam end-product.
  • the advantage of the process of the present invention is that it enables the preparation of the intermediate 3-[2-(3,4- dimethoxy-benzoyl)-4,5-dimethoxy-phenyl]-pentan-2-one ofthe Formula I useful in the manufacture of tofisopam with high yields and by using environment-friendly compounds.
  • Example 2 One proceeds as described in Example 1 except that the reaction is carried out at -20°C. Thus 6.9 g of the title compound is obtained. Yield 32 %. M.p.: 164-166°C.
  • Example 4 One proceeds as described in Example 1 except that the 2.5 molar hexane solution of butyl lithium is replaced by a 2.5 molar hexane solution of hexyl lithium; the reaction is carried out at -78°C. Thus 8.6 g of the title compound is obtained. Yield 40 %.
  • Example 4 One proceeds as described in Example 1 except that the 2.5 molar hexane solution of butyl lithium is replaced by a 2.5 molar hexane solution of hexyl lithium; the reaction is carried out at -78°C. Thus 8.6 g of the title compound is obtained. Yield 40 %.
  • Example 4 One proceeds as described in Example 1 except that the 2.5 molar hexane solution of butyl lithium is replaced by a 2.5 molar hexane solution of hexyl lithium; the reaction is carried out at -78°C. Thus 8.6 g of the title compound is obtained. Yield 40 %.
  • Example 4 One proceeds as described in Example
  • Example 2 One proceeds as described in Example 1 except that the 2.5 molar hexane solution of butyl lithium is replaced by a 2.5 molar hexane solution of hexyl lithium and the reaction is carried out at -20°C. Thus 6.2 g of the title compound is obtained. Yield 29 %.
  • Example 6 One proceeds as described in Example 6 except that the compound of the general Formula IV is not purified, but for the acidic hydrolysis the crude product obtained by the process according to any of Examples 1-5 is used. It is only the compound of the Formula I which is purified by recrystallization. Thus 6.2-9.6 g of the title compound is obtained. Yield 32-50 % (related to the compound of the general Formula II).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
PCT/HU2002/000178 2002-12-16 2002-12-31 Process for the preparation of 3-[2-(3,4-dimethoxy-benzoyl)-4,5-dimethoxy-phenyl]-pentan-2-one WO2004054951A1 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
UAA200507059A UA78634C2 (en) 2002-12-16 2002-12-31 A process for the preparation of 3-[2-(3,4-dimethoxy-benzoyl)-4,5-dimethoxy-pheny]]-pentan-2-one
EP02791921A EP1575890A1 (en) 2002-12-16 2002-12-31 Process for the preparation of 3- 2-(3,4-dimethoxy-benzoyl)- 4,5-dimethoxy-phenyl -pentan-2-one
AU2002361068A AU2002361068A1 (en) 2002-12-16 2002-12-31 Process for the preparation of 3-(2-(3,4-dimethoxy-benzoyl)-4,5-dimethoxy-phenyl)-pentan-2-one
JP2004559931A JP4437093B2 (ja) 2002-12-16 2002-12-31 ３−［２−（３，４−ジメトキシ−ベンゾイル）−４，５−ジメトキシ−フェニル］−ペンタン−２−オンの製法
SK70-2005A SK702005A3 (sk) 2002-12-16 2002-12-31 Spôsob prípravy 3-[2-(3,4-dimetoxybenzoyl)-4,5-dimetoxyfenyl]- pentán-2-ónu
EA200500966A EA007788B1 (ru) 2002-12-16 2002-12-31 Способ получения 3-[2-(3,4-диметоксибензоил)-4,5-диметоксифенил]пентан-2-она

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU0204342A HU227044B1 (en) 2002-12-16 2002-12-16 Process for producing 3-[2-(3,4-dimethoxybenzoyl)-4,5-dimethoxyphenyl]-pentan-2-one
HUP0204342 2002-12-16

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WO2004054951A1 true WO2004054951A1 (en) 2004-07-01

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PCT/HU2002/000178 WO2004054951A1 (en) 2002-12-16 2002-12-31 Process for the preparation of 3-[2-(3,4-dimethoxy-benzoyl)-4,5-dimethoxy-phenyl]-pentan-2-one
PCT/HU2003/000104 WO2004054952A1 (en) 2002-12-16 2003-12-16 Process for the preparation of 3-[2-(3,4-dimethoxybenzoyl)-4,5- dimethoxyphenyl] -pentan-2-one

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Country Status (12)

Country Link
EP (1) EP1575890A1 (ja)
JP (1) JP4437093B2 (ja)
KR (1) KR100936306B1 (ja)
AU (2) AU2002361068A1 (ja)
BG (1) BG109230A (ja)
CZ (1) CZ2005388A3 (ja)
EA (1) EA007788B1 (ja)
HU (1) HU227044B1 (ja)
PL (1) PL376530A1 (ja)
SK (1) SK702005A3 (ja)
UA (1) UA78634C2 (ja)
WO (2) WO2004054951A1 (ja)

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KR100714181B1 (ko) * 2005-07-04 2007-05-04 주식회사 자동기 제설재 살포기용 연료공급장치
CN104098482B (zh) * 2013-04-12 2016-04-20 江苏英力科技发展有限公司 一种3,4-二甲氧基-n,n-二甲基苯甲酰胺的制备方法
CN104262128B (zh) * 2014-09-04 2016-04-13 山东金城医药化工股份有限公司 托非索泮中间体的制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HU194529B (en) * 1984-07-20 1988-02-29 Gyogyszerkutato Intezet New process for producing 2-aroyl-phenylacetone-derivatives

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SK2792004A3 (en) * 2001-12-13 2004-11-03 Egyt Gyogyszervegyeszeti Gyar Process for the preparation of tofisopam and new intermediates

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HU194529B (en) * 1984-07-20 1988-02-29 Gyogyszerkutato Intezet New process for producing 2-aroyl-phenylacetone-derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; LANG, TIBOR ET AL: "2-Aroylphenylacetone derivatives", XP002242492, retrieved from STN Database accession no. 105:152712 CA *

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Publication number Publication date
EA200500966A1 (ru) 2005-12-29
WO2004054952A1 (en) 2004-07-01
HUP0204342A2 (hu) 2004-07-28
AU2003292449A1 (en) 2004-07-09
AU2002361068A1 (en) 2004-07-09
CZ2005388A3 (cs) 2005-09-14
EP1575890A1 (en) 2005-09-21
UA78634C2 (en) 2007-04-10
HU0204342D0 (en) 2003-02-28
HU227044B1 (en) 2010-05-28
JP4437093B2 (ja) 2010-03-24
PL376530A1 (pl) 2006-01-09
SK702005A3 (sk) 2005-09-08
HUP0204342A3 (en) 2004-11-29
EA007788B1 (ru) 2007-02-27
KR20050085686A (ko) 2005-08-29
BG109230A (bg) 2006-04-28
JP2006509814A (ja) 2006-03-23
KR100936306B1 (ko) 2010-01-12

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