WO2003050092A2 - Process for the preparation of tofisopam and new intermediates - Google Patents

Process for the preparation of tofisopam and new intermediates Download PDF

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Publication number
WO2003050092A2
WO2003050092A2 PCT/HU2002/000141 HU0200141W WO03050092A2 WO 2003050092 A2 WO2003050092 A2 WO 2003050092A2 HU 0200141 W HU0200141 W HU 0200141W WO 03050092 A2 WO03050092 A2 WO 03050092A2
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compound
general formula
dimethoxy
process according
phenyl
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PCT/HU2002/000141
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French (fr)
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WO2003050092A3 (en
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Erika MOLNÁRNÉ SAMU
Gyula Simig
Pál VÁGÓ
Zoltán Greff
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EGIS Gyógyszergyár Rt.
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Priority claimed from HU0105327A external-priority patent/HUP0105327A3/en
Priority claimed from HU0105326A external-priority patent/HU225411B1/en
Application filed by EGIS Gyógyszergyár Rt. filed Critical EGIS Gyógyszergyár Rt.
Priority to SK279-2004A priority Critical patent/SK2792004A3/en
Priority to EP02781451A priority patent/EP1465879A2/en
Priority to AU2002348942A priority patent/AU2002348942A1/en
Publication of WO2003050092A2 publication Critical patent/WO2003050092A2/en
Publication of WO2003050092A3 publication Critical patent/WO2003050092A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/26—Radicals substituted by doubly bound oxygen or sulfur atoms or by two such atoms singly bound to the same carbon atom
    • 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
    • C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
    • C07C45/57—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom
    • C07C45/59—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom in five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/02—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
    • C07D317/22—Radicals substituted by singly bound oxygen or sulfur atoms etherified

Definitions

  • This invention relates to a new and improved process for the preparation of tofisopam, new intermediates useful in the synthesis and a process for the preparation of said intermediates.
  • Tofisopam is the International Non-Proprietory Name (INN) of 1 -(3 ,4-dimethoxy-phenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H- 2,3-benzodiazepine, a known anxiolytic agent. Tofisopam and the preparation thereof was first described in HU 155,572.
  • the 2,3-benzodiazepine ring is formed starting from 3-[2-(3,4-dimethoxy-benzoyl)-4,5- dimethoxy-phenyl]-pentan-2-one of the Formula
  • the object of the present invention is to avoid the above discussed drawbacks of the known processes and to provide a process for the preparation of tofisopam of high purity which process eliminates the use of chromium salts, applies readily available starting materials, can be simply carried out and gives high yields.
  • R and R independently each stands for C ⁇ -4 -alkyl or together form C 2-6 -alkylene
  • C ⁇ _ 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.).
  • the present invention is based on the recognition that ring closure which leads to tofisopam of the Formula I can be carried out with good yields by using the readily available compounds of the general Formula II.
  • hydrazine salts formed with inorganic or organic acids can be used.
  • Hydrazine, hydrazine hydrate or the hydrazine salt, respectively, can be used in an amount of 1-8 molar equivalent(s), related to the compound of the general Formula II.
  • the reaction can be carried out in the presence or absence of a solvent.
  • Lower aliphatic alcohols e.g. methanol, ethanol or isopropanol
  • glacial acetic acid can be used as solvent.
  • the reaction can be carried out at a temperature between 10°C and 100°C.
  • an inorganic acid preferably hydrochloric acid, sulfuric acid or acetic acid can be used.
  • the compound of the general Formula II is reacted with a buffer system consisting of an inorganic acid, an organic acid, a salt formed with an inorganic acid and/or a salt formed with an organic acid.
  • the compound of the general Formula II can be converted into tofisopam of the general Formula I by adding the total amount of hydrazine or a hydrate or salt thereof to the reaction mixture at the beginning of the reaction. It has been found that by carrying out the reaction in this manner the desired compound can be obtained in high purity with good yields.
  • R and R each stands for ethyl or R and R together form an ethylene group, is reacted with 1-8 molar equivalent(s) of hydrazine, hydrazine hydrate, hydrazine hydrochloride or hydrazine sulfate in the absence of a solvent or in methanol, ethanol and/or glacial acetic acid as medium at a temperature between 10°C and 100°C, optionally in the presence of hydrochloric acid.
  • the compound of the general Formula II is first treated with in an alcohol and/or organic acid in the presence of a mineral acid, whereupon the total amount of hydrazine or a hydrate or salt thereof is added to the reaction mixture.
  • Hydrazine hydrochloride or hydrazine sulfate can be also in situ formed in the reaction mixture.
  • an inorganic or organic acid or a salt formed with.an inorganic or organic acid (preferably acetic acid, hydrochloric acid or sulfuric acid) is added to the mixture of a compound of the general Formula II and hydrazine, hydrazine hydrate or a hydrazine salt, in the presence or absence of an alcohol.
  • the compound of the Formula I can be isolated by making the reaction mixture alkaline with an alkali hydroxide (e.g. sodium hydroxide or potassium hydroxide) or ammonium hydroxide, extracting the desired compound with a water non-miscible solvent (e.g. ethyl acetate), evaporating the extract and crystallizing the evaporation residue.
  • an alkali hydroxide e.g. sodium hydroxide or potassium hydroxide
  • ammonium hydroxide e.g. sodium hydroxide or potassium hydroxide
  • a water non-miscible solvent e.g. ethyl acetate
  • One may also proceed by isolating the crystalline product precipitated from the reaction mixture by filtration or centrifuging.
  • the compounds of the general Formula II are new. These starting materials can be prepared by brominating the compound of the Formula V
  • the compound of the Formula V can be preferably converted into the compound of the Formula VI by brominating with N- bromo-succinimide.
  • the compound of the Formula VI thus obtained is reacted with a C ⁇ -4 -aliphatic alcohol (preferably methanol or ethanol) or a C 2-6 -aliphatic diol (preferably ethylene glycol), used preferably in a 1.5-2.0-fold excess.
  • a C ⁇ -4 -aliphatic alcohol preferably methanol or ethanol
  • a C 2-6 -aliphatic diol preferably ethylene glycol
  • the compound of the general Formula VII thus obtained is converted into a compound of the general Formula II.
  • the reaction can be carried out in two ways. According to one alternative the bromine atom in the compound of the general Formula VII is replaced by an alkali or magnesium atom, whereupon the alkali or a magnesium compound thus obtained is reacted with an approximately equimolar amount of 3,4-dimethoxy-benzaldehyde.
  • the compound of the general Formula VIII thus formed can be isolated from the reaction mixture.
  • the compound of the general Formula VIII is first deprotonated with a strong base, whereupon an excess of 3,4-dimethoxy- benzaldehyde - acting as oxidizing agent - is added.
  • the 3,4- dimethoxy-benzaldehyde is preferably added in a 2.0-2.5 molar amount.
  • the bromine atom in the compound of the general Formula VII is replaced by an alkali or magnesium ion, whereupon the alkali metal or magnesium compound thus obtained is reacted with an excess - preferably a 2.0-2.5 molar excess - of 3,4-dimethoxy-benzaldehyde.
  • the compound of the general Formula VIII is formed as intermediate product and is then oxidized into a compound of the general Formula II. It has been surprisingly found that the excess of the 3,4-dimethoxy- benzaldehyde used as reactant acts as oxidizing agent. During the oxidation reaction the temperature of the reaction mixture is raised to 60-90°C.
  • the advantages of the process of the present invention is that it enables the preparation of tofisopam from readily available starting materials, with good yields in high purity.
  • the present invention is also directed to a process for the preparation of 3-[2-(3,4-dimethoxy-benzoyl)-4,5-dimethoxy- phenyl]-pentan-2-one of the Formula IV.
  • the compound of the Formula IV 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 IV is prepared with the aid of a chromium-free process by reacting 3-(3,4-dimethoxy-phenyl)-pentan-2-one with 3,4-dimethoxy-benzoyl chloride in the presence of aluminium(III)chloride and decomposing the benzopyrilium salt formed in alkaline medium.
  • a process for the preparation of 3-[2-(3,4-dimethoxy-benzoyl)-4,5- dimethoxy-phenyl]-pentan-2-one of the Formula IV from 3- (3,4-dimethoxyphenyl)-pentan-2-one of the Formula V which comprises ai) brominating the compound of the Formula V; reacting the compound of the Formula VI thus obtained with a C 1-4 -aliphatic alcohol or a C 2 . 6 -aliphatic diol; converting the compound of the general Formula VII thus obtained
  • R and R each stands for C ⁇ -alkyl or R and R together form a C 2 .. 6 -alkylene group
  • R and R each stands for C ⁇ -alkyl or R and R together form a C 2 .. 6 -alkylene 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 IV can be prepared via the new 3- [2-( ⁇ -hydroxy-3,4-dimethoxy-benzyl)-4,5-dimethoxy-phenyl]- pentan-2-one ketals of the Formula VIII and the 3-[2-(3,4- dimethoxy-benzoyl)-4,5-dimethoxy-phenyl]-pentan-2-one ketals of the general Formula II as intermediates in a manner which meets the above requirements and solves the object of the invention.
  • 3-(3,4-dimethoxy- phenyl)-pentan-2-one of the Formula V is brominated into 3-(2- bromo-4,5-dimethoxy-phenyl)-pentan-2-one of the Formula VI.
  • Bromination is preferably carried out with N-bromo- succinimide.
  • the brominating agent is used in an equimolar amount or in a small excess.
  • As reaction medium a lower aliphatic alcohol (preferably methanol or ethanol) or a mixture thereof can be used.
  • Bromination may be carried out at 0-30°C, preferably at 20-30°C.
  • the bromo compound of the Formula VI is isolated after removing the succinimide formed as byproduct.
  • the 3-(2-bromo-4,5-dimethoxy-phenyl)-pentan- 2-one of the Formula VI is reacted with an aliphatic alcohol or aliphatic diol to yield a 3-(2-bromo-4,5-dimethoxy-phenyl)- pentan-2-one-ketal of the general Formula VII.
  • the compound of the Formula VI is reacted with a C 1 . 4 -aliphatic alcohol (preferably methanol or ethanol) or a C 2 . 6 -aliphatic diol (preferably ethylene glycol).
  • the aliphatic alcohol or diol is preferably used in an excess, particularly in a 1.5-2.0-fold excess.
  • the reaction is carried out under acidic catalysis and the water formed is separated.
  • catalyst weak organic acids preferably aromatic sulfuric acids, particularly benzenesulfonic acid or p-toluenesulfonic acid can be used.
  • the separation of water is performed in a large excess of a water non-miscible solvent, at the boiling point of the solvent.
  • aromatic hydrocarbons - particularly benzene or toluene - can be used.
  • the reaction can be carried out in two ways.
  • the bromine atom in a compound of the general Formula VII is replaced by an alkali or magnesium atom, the alkali or magnesium compound thus obtained is reacted with a approximately equimolar amount of 3,4-dimethoxy-benzaldehyde and the compound of the general Formula VIII thus formed is oxidized into a compound of the general Formula II.
  • the bromine atom in the compound of the general Formula VII is replaced by an alkali (e.g. sodium, potassium or lithium) atom or by a magnesium atom with the aid of a Grignard-reaction.
  • One may proceed preferably by carrying out a bromine -» lithium exchange reaction.
  • This may be performed by reacting the compound of the general Formula VII with an alkyl lithium (preferably n-butyl lithium or n-hexyl lithium).
  • 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 reacted with an approximately equimolar amount (preferably 1.0-1.2 molar amount) of 3,4-dimethoxy-benzaldehyde.
  • One may proceed preferably by reacting the lithium compound with 3,4-dimethoxy-benzaldehyde 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 -10°C.
  • the compound of the general Formula VIII thus formed can be isolated from the reaction mixture.
  • the isolated alcohol of the general Formula VIII is oxidized into the ketone of the general Formula II by the excess of 3,4-dimethoxy-benzaldehyde used as reactant.
  • the alcohol of the general Formula VIII is first deprotonated with a strong base.
  • alkali hydrides preferably sodium hydride
  • alkyl alkali compounds preferably n-butyl lithium or n-hexyl lithium
  • alkali or alkaline earth metal alcoholates preferably potassium tertiary butylate
  • aluminium tertiary butylate or lithium diisopropyl amide can be used.
  • the reaction is carried out in an inert solvent.
  • reaction medium preferably tetrahydrofurane, benzene, toluene or xylene can be used.
  • the 3,4-dimethoxy- benzaldehyde acting also as oxidizing agent is used in an excess, advantageously in a 2.0-2.5 molar excess.
  • the compound of the general Formula VIII can be converted into the compound of the general Formula II with other oxidizing agents too.
  • oxidizing agents known from prior art for the conversion of secondary alcohols into ketones can be used (e.g. potassium permanganate, manganese oxide, chromium(VI)reactants etc.).
  • the suitable oxidizing agents and oxidation methods are known from prior art [Y. March, Advanced Organic Chemistry, 4 th edition, 1167-1169, Wiley, New York].
  • the bromine atom in a compound of the general Formula VII is replaced by an alkali or magnesium atom, whereupon the alkali or magnesium compound thus obtained is converted into a compound of the general Formula II by reacting with an excess of 3,4-dimethoxy- benzaldehyde.
  • a 3-[2-( ⁇ -hydroxy- 3,4-dimethoxy-benzyl)-4,5-dimethoxy-phenyl]-pentan-2-one- ketal of the general Formula VIII is formed as intermediate which is then oxidized into a compound of the general Formula II. Oxidation is performed by raising the reaction temperature, preferably to 60-90°C. One may particularly preferably work at about 80°C.
  • the compound of the general Formula II is hydrolysed into the desired 3-[2-(3,4-dimethoxy-benzoyl)-4,5- dimethoxy-phenyl]-pentan-2-one of the Formula IV.
  • Hydrolysis is preferably carried out by using a mineral acid, particularly diluted sulfuric acid or diluted hydrochloric acid, particularly advantageously diluted sulfuric acid.
  • the reaction may be carried out in a two-phase reaction mixture, preferably at 20- 40°C.
  • One phase consists of a water non-miscible organic solvent (preferably aromatic hydrocarbons, e.g. benzene, toluene or xylene; or aliphatic halogenated hydrocarbons, e.g.
  • The. compound of the general Formula IV thus obtained can be purified by recrystallization from a suitable solvent, if desired.
  • a suitable solvent preferably straight or branched chain aliphatic alcohols containing 1-4 carbon atoms can be used.
  • the compound of the general Formula IV thus obtained has.a purity higher than 98 % and is excellently suitable for conversion into the tofisopam end-product of the general Formula I.
  • the invention relates to the diastereomers and optical antipodes of the new intermediates of the general Formula VIII and to mixtures thereof..
  • the compounds of the general Formula VIII can be prepared by replacing in a compound of the general Formula VII the bromine atom by a lithium atom and reacting the lithium , compound thus obtained with a 1.0-1.2 molar amount of 3,4- dimethoxy-benzaldehyde.
  • the compounds of the general Formula II can be prepared by a) . replacing in a compound of the general Formula VII the bromine atom by a lithium atom and reacting the lithium compound thus obtained with an excess - preferably 2.0- 2.5 molar equivalents - of 3,4-dimethoxy-benzaldehyde; or b) oxidizing a compound of the general Formula VIII.
  • the advantage of the process of the present invention is that 3- [2-(3,4-dimethoxy-benzoyl)-4,5-dimethoxy-phenyl]-pentan-2- one of the Formula IV is prepared by using environment friendly materials, with good yields and in high purity.
  • reaction mixture is cooled to room temperature, whereupon a further 0.46 g (9 millimoles) of 98 % hydrazine monohydrate is added, the reaction mixture is subjected to post-reaction at 20°C for a further hour.
  • the product is isolated and purified as described in Example 1. Thus 0.92 g of the title compound is obtained. Yield 80 %, m.p.: 157-158°C.
  • reaction mixture is subjected to post-reaction at this temperature for 30 minutes, made alkaline, cooled and the precipitated product is filtered and dried. Thus 10.9 g of the title compound is obtained. After recrystallization 9.7 g of the title compound is obtained. Yield 84 %. Mp.: 157-158°C.
  • Example 7 One proceeds as described in Example 7 except that a 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.
  • 18,5 g of the title compound is obtained. Yield 86 %.
  • Example 13 One proceeds as described in Example 7 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 -5°C. Thus 16.5 g of the title compound is obtained. Yield 79 %.
  • Example 13 One proceeds as described in Example 7 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 -5°C. Thus 16.5 g of the title compound is obtained. Yield 79 %.
  • Example 13 Example 13
  • Example 8 One proceeds ais described in Example 8 except that the reaction is carried out at -10°C. Thus 12.7 g of the title compound is obtained. Yield 59 %. Mp.: 164-166°C.
  • Example 7 One proceeds as described in Example 7 except that a 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 -78°C. Thus 14,4 g of the title compound is obtained. Yield 67 %.
  • Example 7 One proceeds as described in Example 7 except that a 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 -5°C. Thus 11.8 g of the title compound is obtained. Yield 55 %.
  • the reaction mixture is heated to boiling for 2 hours, cooled to room temperature and 15 ml of a saturated ammonium chloride solution is added. The mixture is stirred for 10 minutes and extracted with ethyl acetate. The ethyl acetate layer is washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. Thus 3.2 g of a crude product is obtained. After purification 1.38 g of the title compound is obtained. Yield 64 %. Mp.: 165-166°C.

Abstract

The invention relates to a new process for the preparation of 1-(3,4-dimethoxy-phenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodizepine of Formula (I) which comprises reacting a compound of general Formula (II) (wherein R1 and R2 independently each stands for C1-4-alkyl or together form C2-6-alkylene) with hydrazine or a hydrate or salt thereof formed with an inorganic or organic acid. 1-(3,4-dimethoxy-phenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine of the Formula I is a known anxiolytic agent. The invention also relates to new intermediates and a process for the preparation thereof.

Description

Process for the preparation of tofisopam and new intermediates
FIELD OF THE INVENTION
This invention relates to a new and improved process for the preparation of tofisopam, new intermediates useful in the synthesis and a process for the preparation of said intermediates.
TECHNICAL BACKGROUND OF THE INVENTION
Tofisopam is the International Non-Proprietory Name (INN) of 1 -(3 ,4-dimethoxy-phenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H- 2,3-benzodiazepine, a known anxiolytic agent. Tofisopam and the preparation thereof was first described in HU 155,572.
Known procedures directed to the preparation of tofisopam can be divided into two groups, depending on the reaction used in the final step of the synthesis.
According to an alternative a l-(3,4-dimethoxy-phenyl)-3- methyl-4-ethyl-6,7-dimethoxy-2-benzopyrilium salt of the general Formula
Figure imgf000004_0001
OCH,
(wherein X' is an anion) is reacted with hydrazine or hydrazine hydrate [HU 155,572 or Chem. Berichte 107 (12) 3883-93 (1974)].
According to the other reaction route the 2,3-benzodiazepine ring is formed starting from 3-[2-(3,4-dimethoxy-benzoyl)-4,5- dimethoxy-phenyl]-pentan-2-one of the Formula
Figure imgf000004_0002
which is reacted with hydrazine or hydrazine hydrate [HU 155,572: Chem. Berichte 107 (12) 3883-93 (1974); Farmaco Ed. Sci. 40/12/942-55 (1985)].
According to the above known processes tofisopam of the Formula
Figure imgf000005_0001
can be prepared by from medium to good yields. The drawback of the above procedures resides in the fact that the l-phenyl-2- benzopyrilium salts of the general Formula III and the benzoyl- phenyl-acetone derivative of the Formula IV can be prepared only with low yields in numerous reaction steps. A further disadvantage of the known procedures is that during the synthesis chromium salts being extremely detrimental to the environment are formed and the storing, neutralization and recycling of said by-products encounters serious problems of the protection of the environment.
SUMMARY OF THE INVENTION
The object of the present invention is to avoid the above discussed drawbacks of the known processes and to provide a process for the preparation of tofisopam of high purity which process eliminates the use of chromium salts, applies readily available starting materials, can be simply carried out and gives high yields.
The above object is solved with the aid of the present invention.
According to the present invention there is provided a process for the preparation of l-(3,4-dimethoxy-phenyl)-4-methyl-5- ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine of the Formula I which comprises reacting a compound of the general Formula
Figure imgf000007_0001
1 9
(wherein R and R independently each stands for Cι-4-alkyl or together form C2-6-alkylene) with hydrazine or a hydrate or salt thereof formed with an inorganic or organic acid.
DETAILED DESCRIPTION OF THE INVENTION
The terms used in the present patent specification are to be interpreted as follows:
The term "Cι_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.).
The term "C2-6-alkylene" relates to straight or branched chain alkylene groups containing 2-6 carbon atoms (e.g. ethylene, trimethylene etc.). The present invention is based on the recognition that ring closure which leads to tofisopam of the Formula I can be carried out with good yields by using the readily available compounds of the general Formula II.
As starting material preferably compounds of the general Formula II can be used wherein R and R each stands for
1 methyl or ethyl, or R and R together form an ethylene group.
According to the process of the present invention hydrazine salts formed with inorganic or organic acids can be used. One may proceed particularly preferably by using hydrazine hydrochloride or hydrazine sulfate.
Hydrazine, hydrazine hydrate or the hydrazine salt, respectively, can be used in an amount of 1-8 molar equivalent(s), related to the compound of the general Formula II.
The reaction can be carried out in the presence or absence of a solvent. Lower aliphatic alcohols (e.g. methanol, ethanol or isopropanol) and/or glacial acetic acid can be used as solvent.
The reaction can be carried out at a temperature between 10°C and 100°C. One may also proceed by carrying out the reaction in the presence of an inorganic acid, an organic acid, a salt formed with an inorganic acid and/or a salt formed with an organic acid. For this purpose preferably hydrochloric acid, sulfuric acid or acetic acid can be used.
According to a form of realization of the invention process the compound of the general Formula II is reacted with a buffer system consisting of an inorganic acid, an organic acid, a salt formed with an inorganic acid and/or a salt formed with an organic acid. The compound of the general Formula II can be converted into tofisopam of the general Formula I by adding the total amount of hydrazine or a hydrate or salt thereof to the reaction mixture at the beginning of the reaction. It has been found that by carrying out the reaction in this manner the desired compound can be obtained in high purity with good yields.
According to a very advantageous form of realization of the invention process a compound of the general Formula II,
1 1 9 wherein R and R each stands for ethyl or R and R together form an ethylene group, is reacted with 1-8 molar equivalent(s) of hydrazine, hydrazine hydrate, hydrazine hydrochloride or hydrazine sulfate in the absence of a solvent or in methanol, ethanol and/or glacial acetic acid as medium at a temperature between 10°C and 100°C, optionally in the presence of hydrochloric acid.
According to a very advantageous form of realization of the invention process the compound of the general Formula II is first treated with in an alcohol and/or organic acid in the presence of a mineral acid, whereupon the total amount of hydrazine or a hydrate or salt thereof is added to the reaction mixture.
One may also proceed by adding hydrazine or a hydrate or salt thereof in two or more portions to the reaction mixture. It is particularly preferred to react the compound of the general Formula II with 1-4 molar equivalent(s) of hydrazine, hydrazine hydrate or a hydrazine salt and adding a further 1-4 molar equivalent(s) of hydrazine or a hydrate or salt thereof in the course of the reaction.
Hydrazine hydrochloride or hydrazine sulfate can be also in situ formed in the reaction mixture.
According to an advantageous form of realization of the invention process an inorganic or organic acid or a salt formed with.an inorganic or organic acid (preferably acetic acid, hydrochloric acid or sulfuric acid) is added to the mixture of a compound of the general Formula II and hydrazine, hydrazine hydrate or a hydrazine salt, in the presence or absence of an alcohol.
One may proceed advantageously by carrying out the reaction in the presence of a mixture of hydrochloric acid and acetic acid or sulfuric acid and acetic acid, in methanol or ethanol as medium, at 60-80°C. It is preferred to subject the reaction mixture to a post-reaction at 10-30°C.
The compound of the Formula I can be isolated by making the reaction mixture alkaline with an alkali hydroxide (e.g. sodium hydroxide or potassium hydroxide) or ammonium hydroxide, extracting the desired compound with a water non-miscible solvent (e.g. ethyl acetate), evaporating the extract and crystallizing the evaporation residue. One may also proceed by isolating the crystalline product precipitated from the reaction mixture by filtration or centrifuging.
The compounds of the general Formula II are new. These starting materials can be prepared by brominating the compound of the Formula V
0
H3CO
reacting the compound of the Formula
Figure imgf000012_0001
thus obtained with a C1. -aliphatic alcohol or a C2-6-aliphatic diol; and converting the compound of the general Formula
Figure imgf000012_0002
1 9 thus obtained (wherein R and R each stands for Cι- -alkyl or R1 and R2 together form C2-6-alkylene) into a compound of the general Formula II directly or via a compound of the general Formula
Figure imgf000013_0001
OCH,
(wherein R ,ι and R are as stated above).
The compound of the Formula V can be preferably converted into the compound of the Formula VI by brominating with N- bromo-succinimide.
The compound of the Formula VI thus obtained is reacted with a Cι-4-aliphatic alcohol (preferably methanol or ethanol) or a C2-6-aliphatic diol (preferably ethylene glycol), used preferably in a 1.5-2.0-fold excess. The reaction is carried out under acidic catalysis, whereby the water formed is separated.
The compound of the general Formula VII thus obtained is converted into a compound of the general Formula II. The reaction can be carried out in two ways. According to one alternative the bromine atom in the compound of the general Formula VII is replaced by an alkali or magnesium atom, whereupon the alkali or a magnesium compound thus obtained is reacted with an approximately equimolar amount of 3,4-dimethoxy-benzaldehyde. The compound of the general Formula VIII thus formed can be isolated from the reaction mixture.
The compound of the general Formula VIII is first deprotonated with a strong base, whereupon an excess of 3,4-dimethoxy- benzaldehyde - acting as oxidizing agent - is added. The 3,4- dimethoxy-benzaldehyde is preferably added in a 2.0-2.5 molar amount.
According to the other alternative the bromine atom in the compound of the general Formula VII is replaced by an alkali or magnesium ion, whereupon the alkali metal or magnesium compound thus obtained is reacted with an excess - preferably a 2.0-2.5 molar excess - of 3,4-dimethoxy-benzaldehyde. Also under such reaction conditions the compound of the general Formula VIII is formed as intermediate product and is then oxidized into a compound of the general Formula II. It has been surprisingly found that the excess of the 3,4-dimethoxy- benzaldehyde used as reactant acts as oxidizing agent. During the oxidation reaction the temperature of the reaction mixture is raised to 60-90°C.
The advantages of the process of the present invention is that it enables the preparation of tofisopam from readily available starting materials, with good yields in high purity.
According to a further aspect of the present invention there are provided new intermediates and a process for the preparation thereof.
The present invention is also directed to a process for the preparation of 3-[2-(3,4-dimethoxy-benzoyl)-4,5-dimethoxy- phenyl]-pentan-2-one of the Formula IV.
3-[2-(3,4-dimethoxy-benzoyl)-4,5-dimethoxy-phenyl]-pentan-2- one of the Formula IV is a useful intermediate in the synthesis of tofisopam of the Formula I.
According to HU 158,091 the compound of the Formula IV is prepared from diisohomoeugenol by oxidation with chrome(VI)oxide; only low yields are obtained.
According to HU 194,529 l-(3,4-dimethoxy-ρhenyl)-3-methyl- 4-ethyl-6,7-dimethoxy-isochromane is oxidized with chrome(VI)oxide into the corresponding benzopyrilium salt which is then converted into the desired compound of the Formula IV by alkaline-aqueous decomposition.
Both known procedures have the common disadvantage that in the oxidation reaction highly toxical chromium salts detrimental to the environment are formed. The storing, neutralization and recycling of said chromium salts represent a serious problem for the protection of the environment.
HU 187,161 aims the elimination of the above drawbacks of the known procedures. According to HU 187,161 the compound of the Formula IV is prepared with the aid of a chromium-free process by reacting 3-(3,4-dimethoxy-phenyl)-pentan-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- benzyol 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. It is the object of this aspect of the invention to provide a chromium-free process for the preparation of 3-[2-(3,4- dimethoxy-benzoyl)-4,5-dimethoxy-phenyl]-pentan-2-one ofthe Formula IV which eliminates the above drawbacks of the known procedures, is friendly to the environment and gives the desired compound of the Formula IV with better yields and higher purity than the known methods.
The above object is solved by the process of the present invention.
According to the present invention there is provided a process for the preparation of 3-[2-(3,4-dimethoxy-benzoyl)-4,5- dimethoxy-phenyl]-pentan-2-one of the Formula IV from 3- (3,4-dimethoxyphenyl)-pentan-2-one of the Formula V which comprises ai) brominating the compound of the Formula V; reacting the compound of the Formula VI thus obtained with a C1-4-aliphatic alcohol or a C2.6-aliphatic diol; converting the compound of the general Formula VII thus obtained
1 1
(wherein R and R each stands for C^-alkyl or R and R together form a C2..6-alkylene group) into a compound of the general Formula II directly or via a compound of the general Formula VIII; and hydrolysing the compound of the general Formula II; or a2) reacting the compound of the general Formula VI with a Cι-4-aliphatic alcohol or a C2-6-aliphatic diol; converting the compound of the general Formula VII thus obtained into a compound of the general Formula II directly or via a compound of the general Formula VIII; and hydrolysing the compound of the general Formula II thus obtained; or a3) converting a compound of the general Formula VII into a compound of the general Formula II directly or via a compound of the general Formula VIII; and hydrolysing the compound of the general Formula II thus obtained; or a4) hydrolysing a compound of the general Formula II.
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 IV can be prepared via the new 3- [2-(α-hydroxy-3,4-dimethoxy-benzyl)-4,5-dimethoxy-phenyl]- pentan-2-one ketals of the Formula VIII and the 3-[2-(3,4- dimethoxy-benzoyl)-4,5-dimethoxy-phenyl]-pentan-2-one ketals of the general Formula II as intermediates in a manner which meets the above requirements and solves the object of the invention.
According to the first step of the process 3-(3,4-dimethoxy- phenyl)-pentan-2-one of the Formula V is brominated into 3-(2- bromo-4,5-dimethoxy-phenyl)-pentan-2-one of the Formula VI. Bromination is preferably carried out with N-bromo- succinimide. The brominating agent is used in an equimolar amount or in a small excess. As reaction medium a lower aliphatic alcohol (preferably methanol or ethanol) or a mixture thereof can be used. Bromination may be carried out at 0-30°C, preferably at 20-30°C. The bromo compound of the Formula VI is isolated after removing the succinimide formed as byproduct.
In the next step the 3-(2-bromo-4,5-dimethoxy-phenyl)-pentan- 2-one of the Formula VI is reacted with an aliphatic alcohol or aliphatic diol to yield a 3-(2-bromo-4,5-dimethoxy-phenyl)- pentan-2-one-ketal of the general Formula VII. The compound of the Formula VI is reacted with a C1.4-aliphatic alcohol (preferably methanol or ethanol) or a C2.6-aliphatic diol (preferably ethylene glycol). The aliphatic alcohol or diol is preferably used in an excess, particularly in a 1.5-2.0-fold excess. The reaction is carried out under acidic catalysis and the water formed is separated. As catalyst weak organic acids, preferably aromatic sulfuric acids, particularly benzenesulfonic acid or p-toluenesulfonic acid can be used. The separation of water is performed in a large excess of a water non-miscible solvent, at the boiling point of the solvent. For this purpose preferably aromatic hydrocarbons - particularly benzene or toluene - can be used.
In the next step the 3-(2-bromo-4,5-dimethoxy-phenyl)-pentan- 2-one-ketal of the general Formula VII is converted into a 3-[2- (3,4-dimethoxy-benzoyl)-4,5-dimethoxy-phenyl]-pentan-2-one- ketal of the general Formula II.
The reaction can be carried out in two ways.
According to a variant of the process the bromine atom in a compound of the general Formula VII is replaced by an alkali or magnesium atom, the alkali or magnesium compound thus obtained is reacted with a approximately equimolar amount of 3,4-dimethoxy-benzaldehyde and the compound of the general Formula VIII thus formed is oxidized into a compound of the general Formula II. The bromine atom in the compound of the general Formula VII is replaced by an alkali (e.g. sodium, potassium or lithium) atom or by a magnesium atom with the aid of a Grignard-reaction. One may proceed preferably by carrying out a bromine -» lithium exchange reaction. This may be performed by reacting the compound of the general Formula VII with an alkyl lithium (preferably n-butyl lithium or n-hexyl lithium). 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 reacted with an approximately equimolar amount (preferably 1.0-1.2 molar amount) of 3,4-dimethoxy-benzaldehyde. One may proceed preferably by reacting the lithium compound with 3,4-dimethoxy-benzaldehyde 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 -10°C. The compound of the general Formula VIII thus formed can be isolated from the reaction mixture.
It has been surprisingly found that the isolated alcohol of the general Formula VIII is oxidized into the ketone of the general Formula II by the excess of 3,4-dimethoxy-benzaldehyde used as reactant. In this reaction the alcohol of the general Formula VIII is first deprotonated with a strong base. For this purpose alkali hydrides (preferably sodium hydride), alkyl alkali compounds (preferably n-butyl lithium or n-hexyl lithium), alkali or alkaline earth metal alcoholates (preferably potassium tertiary butylate), aluminium tertiary butylate or lithium diisopropyl amide can be used. The reaction is carried out in an inert solvent. As reaction medium preferably tetrahydrofurane, benzene, toluene or xylene can be used. The 3,4-dimethoxy- benzaldehyde acting also as oxidizing agent is used in an excess, advantageously in a 2.0-2.5 molar excess.
The compound of the general Formula VIII can be converted into the compound of the general Formula II with other oxidizing agents too. For this purpose oxidizing agents known from prior art for the conversion of secondary alcohols into ketones can be used (e.g. potassium permanganate, manganese oxide, chromium(VI)reactants etc.). The suitable oxidizing agents and oxidation methods are known from prior art [Y. March, Advanced Organic Chemistry, 4th edition, 1167-1169, Wiley, New York].
According to another variant of the process the bromine atom in a compound of the general Formula VII is replaced by an alkali or magnesium atom, whereupon the alkali or magnesium compound thus obtained is converted into a compound of the general Formula II by reacting with an excess of 3,4-dimethoxy- benzaldehyde. Also in said reaction variant a 3-[2-(α-hydroxy- 3,4-dimethoxy-benzyl)-4,5-dimethoxy-phenyl]-pentan-2-one- ketal of the general Formula VIII is formed as intermediate which is then oxidized into a compound of the general Formula II. Oxidation is performed by raising the reaction temperature, preferably to 60-90°C. One may particularly preferably work at about 80°C.
In the next step the compound of the general Formula II is hydrolysed into the desired 3-[2-(3,4-dimethoxy-benzoyl)-4,5- dimethoxy-phenyl]-pentan-2-one of the Formula IV. Hydrolysis is preferably carried out by using a mineral acid, particularly diluted sulfuric acid or diluted hydrochloric acid, particularly advantageously diluted sulfuric acid. The reaction may be carried out in a two-phase reaction mixture, preferably at 20- 40°C. One phase consists of a water non-miscible organic solvent (preferably aromatic hydrocarbons, e.g. benzene, toluene or xylene; or aliphatic halogenated hydrocarbons, e.g. dichloro methane or chloroform, preferably dichloro methane) and the other phase consists of an aqueous acidic solution, In order to. romote the reaction optionally Kieselgel can be added, preferably in a 2-5-fold amount, related to the compound of the general Formula II.
The. compound of the general Formula IV thus obtained can be purified by recrystallization from a suitable solvent, if desired. As recrystallization solvent preferably straight or branched chain aliphatic alcohols containing 1-4 carbon atoms can be used. The compound of the general Formula IV thus obtained ,has.a purity higher than 98 % and is excellently suitable for conversion into the tofisopam end-product of the general Formula I.
According to a further aspect of the present invention there are provided new 3-[2-(α-hydroxy-3,4-dimethoxy-benzyl)-4,5- dimethoxy-phenyl]-pentan-2-one-ketal intermediates of the general Formula VIII.
The invention relates to the diastereomers and optical antipodes of the new intermediates of the general Formula VIII and to mixtures thereof..
The compounds of the general Formula VIII can be prepared by replacing in a compound of the general Formula VII the bromine atom by a lithium atom and reacting the lithium , compound thus obtained with a 1.0-1.2 molar amount of 3,4- dimethoxy-benzaldehyde.
According to a further aspect of the present invention there are provided new 3-[2-(3,4-dimethoxy-benzoyl)-4,5-dimethoxy- phenyl]-ρentan-2-one ketals of the general Formula II.
The compounds of the general Formula II can be prepared by a) . replacing in a compound of the general Formula VII the bromine atom by a lithium atom and reacting the lithium compound thus obtained with an excess - preferably 2.0- 2.5 molar equivalents - of 3,4-dimethoxy-benzaldehyde; or b) oxidizing a compound of the general Formula VIII.
The advantage of the process of the present invention is that 3- [2-(3,4-dimethoxy-benzoyl)-4,5-dimethoxy-phenyl]-pentan-2- one of the Formula IV is prepared by using environment friendly materials, with good yields and in high purity.
Further details of the present invention are to be found in the following Examples without limiting the scope of protection to said Examples.
Example 1 l-(3,4-dimethoxy-phenyl)-4-methyl-5-ethyl-7,8-dimethoxy- 5H-2,3-benzodiazepine (I)
A mixture of 1.30 g (3 millimoles) of 3-[2-(3,4-dimethoxy- benzoyl)-4,5-dimethoxy-phenyl]-pentan-2-one-ethylene ketal (II), 0.82 g (12 millimoles) of hydrazine monohydrochloride and 30 ml of methanol is stirred under heating to boiling for 3 hours. The reaction mixture is cooled to 20°C and made alkaline by adding an aqueous ammonium hydroxide solution. The solvent is evaporated, the residue taken up in ethyl acetate, washed successively with water and a saturated sodium chloride solution, dried over magnesium sulfate, filtered and the filtrate is evaporated. The crude product thus obtained (1.01 g) is recrystallized and treated with water. Thus 0.79 g of the title compound is obtained, yield 69 %. Mp.: 157-158°C.
Example 2 l-(3,4-dimethoxy-phenyl)-4-metlιyl-5-ethyI-7,8-dimethoxy- 5H-2,3-benzodiazepine (I)
A mixture of 1.30 g (3 millimoles) of 3-[2-(3,4-dimethoxy- benzoyl)-4,5-dimethoxy-phenyl]-pentan-2-one-ethylene ketal (II), 0.46 g (9 millimoles) of 98 % hydrazine monohydrate, 1.18 g (12 millimoles) of 37 % aqueous hydrochloric acid, 1.45 g (24 millimoles) of 99 % acetic acid and 13 ml of methanol is stirred under heating to boiling for 3 hours. The reaction mixture is cooled to room temperature, whereupon a further 0.46 g (9 millimoles) of 98 % hydrazine monohydrate is added, the reaction mixture is subjected to post-reaction at 20°C for a further hour. The product is isolated and purified as described in Example 1. Thus 0.92 g of the title compound is obtained. Yield 80 %, m.p.: 157-158°C.
Example 3 l-(3,4-dimetlιoxy-phenyl)-4-methyl-5-ethyl-7,8-dimethoxy- 5H-2,3-benzodiazepine (I)
A mixture of 1.30 g (3 millimoles) of 3-[2-(3,4-dimethoxy- benzoyl)-4,5-dimethoxy-phenyl]-pentan-2-one-ethylene ketal (II), 0.62 g (9 millimoles) of hydrazine monohydrochloride, 0.9 g (9 millimoles) of 37 % aqueous hydrochloric acid and 6.0 g (100 millimoles) of 99 % acetic acid is stirred at 20°C for 2 hours, whereupon 13 ml of methanol and 0.60 g (12 millimoles) of hydrazine monohydrate is added and the reaction mixture is subjected to post-reaction at 20°C for 2 hours. The product is isolated and purified as described in Example 1. Thus 0.84 g of the title compound is obtained, yield 73 %. Mp.: 157- 158°C. Example 4 l-(3,4-dimethoxy-phenyl)-4-methyl-5-ethyl-7,8-dimethoxy- 5H-2,3-foenzodiazepine (I)
To a mixture of 9.10 g (150 millimoles) of 99 % acetic acid and 8.87 g (90 millimoles) of 37 % aqueous hydrochloric acid 12.9 g (30 millimoles) of 3-[2-(3,4-dimethoxy-benzoyl)-4,5- dimethoxy-phenyl]-pentan-2-one-ethylene ketal (II) and 20 ml of methanol is added. The mixture is stirred under boiling for 20 minutes, whereupon 6.1 g (120 millimoles) of 98 % hydrazine monohydrate is added in several portions. The reaction mixture is subjected to post-reaction at this temperature for 30 minutes, made alkaline, cooled and the precipitated product is filtered and dried. Thus 10.9 g of the title compound is obtained. After recrystallization 9.7 g of the title compound is obtained. Yield 84 %. Mp.: 157-158°C.
Preparation of the starting materials
Example 5
3,-(2-bromo-4,5-dimethoxy-phenyl)-pentan-2-one (VI)
111 g (0.50 mole) of 3-(3,4-dimethoxy-phenyl)-pentan-2-one (V) is dissolved in 500 ml of ethanol. To the solution at 5-10°C 94 g (0,52 mole) of N-bromo-succinimide is added in small portions. The addition having been completed the reaction mixture is evaporated and the residue is distilled off at 144- -147°C/20 Pa. Thus 128 g of the chromatographically uniform title compound is obtained. Yield 85 %.
IR (film): 2963 (CH30), 1715 (G=0), 594 (C-Br) cm"1. HNMR (CDC13, TMS, g200): 7.06 (s, IH), 6.60 (s, IH), 4.11 (dd, J=6.6, 8.1 Hz, IH), 2.11-1.96 (m, IH), 2.08 (s, 3H), 1.73- 1.57 (m, IH), 0.84 (t, J=7.5 Hz, 3H) ppm. CNMR (CDC13, TMS, g200): 208.1, 149.0, 148.6, 130.3, 121.4, 115.5, 110.5, 58.6, 56.1, 56.0, 29.6, 24.8, 11.6 ppm.
Example 6 3-(2-bromo-4,5-dimethoxy-phenyl)-pentan-2-one-ethylene ketal (VII)
34.3 g (0.11 mole) of 3-(2-bromo-4,5-dimethoxy-phenyl)- pentan-2-one (VI) is dissolved in 250 ml of toluene. To the solution 11.2 ml (0.20 mole) of ethylene glycol and 1.5 g of p- toluenesulfonic acid is added. The apparatus is equipped with a water separator and the reaction mixture is stirred under hearing to boiling until the theoretical amount of water is separated. The water is removed, the toluene solution is washed acid free with a sodium carbonate solution, dried over magnesium sulfate, filtered and evaporated in vacuo. Thus 38 g of a crude product is obtained which is distilled off at 149-152°C/12 Pa. Thus 36.2 g of the chromatographically uniform title product is obtained. Yield 92 %. Mp.: 44-45°C.
IR (film): 2962 (CH30), 591 (C-Br) cm-1.
HNMR (DMSO-d6, TMS, i400): 7.09 (s, IH), 7.01 (s, IH),
3.94-3.77 (m, 4H), 3.72 (s, 3H), 3.71 (s, 3H), 3.27 (dd, J=3.4,
11.5 Hz, IH), 1.92-1.85 (m, IH), 1.64-1.56 (m, IH), 1.07 (s,
3H), 0.63 (t, J=7.4 Hz, 3H) ppm.
CNMR (DMSO-d6, TMS, i400): 148.3, 148.1, 132.1, 116.6,
115.1, 111.9, 110.8, 65.2, 64.4, 55.8, 55.7, 53.3, 23.3, 22.8,
11.9 ppm.
Elemental analysis: calc: C 52.19%, H 6.13%, Br 23.14% found: C 52.36%, H 6.12%, Br 23.23%
Example 7
3-[2-(α-hydroxy-3,4-dimethoxy-benzyI)-4,5-dimethoxy- phenyl]-pentan-2-one-ethylene ketal (VIII)
17.26 g (0.05 mole) of 3-(2-bromo-4,5-dimethoxy-ρhenyl)- pentan-2-one-ethylene ketal (VII) is dissolved in 173 ml of anhydrous tetrahydrofurane whereupon the mixture is cooled to -78°C by using external dry ice cooling. A 2.5 molar solution of butyl lithium (0.06 mole) in 24 ml of hexane is added under stirring within 45 minutes. The addition having been completed the mixture is stirred at -78°C for a further period of 2 hours. To the solution 8.3 g (0.05 mole) of 3,4-dimethoxy-benzaldehyde is added, the reaction mixture is allowed to react for 20 minutes, then cooled to 0°C and at this temperature 150 ml of a saturated ammonium chloride solution is added. The mixture is stirred for
10 minutes and extracted with ethyl acetate. The organic phase is washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered and the filtrate is evaporated. 26 g of a crude product is obtained which is purified. Thus 19,4 g of the oily title compound is obtained which consists of a mixture of the two diastereomers. Yield 90 %.
„A" diastereomer:
VRK: R/= 0,60 (Si02, ethyl acetate - hexane 2:1)
IR (film): 3427, 2835 (CH30), 1257 (CH30) cm"1'.
HNMR (CDC13, TMS, i400): 7.00 (s, IH), 6.95 (s, IH), 6.88-
6.85 (m, 2H), 6.52 (s, IH), 6.13 (s, IH), 3.90-3.70 (m, 4H), 3.89
(s, 3H),3.87 (s, 6H), 3.65 (s, 3H), 3.38 (dd, J=3.7, 11.6 Hz, l.H),.2.10-2.00 (m, IH), 1.95-1.85 (m, IH), 1.45 (s, 3H), 0.76 (t,
J=7.3 Hz, 3H) ppm.
CNMR (CDCI3, TMS, 1400): 148.6, 148.0, 147.6, 146.9, 137.7,
136.2, 130.6, 118.1, 113.0, 112.4, 111.8, 110.7, 104.4, 75.3,
64.8, 64.7, 55.9, 55.8, 55.7, 48.8, 23.6, 23.5, 11.6 ppm.
„B" diastereomer:
VRK: Rj= 0,50 (Si02, ethyl acetate -hexane :1)
IR (film): 3446, 2835 (CH3O), 1261 (CH3O) cm"1. HNMR (CDC13, TMS, i400): 6.90 (s, IH), 6.98 (s, IH), 6.95 (d, J=1.6 Hz, IH), 6.87 (dd, J=1.6, 8.3 Hz, IH), 6.80 (d, J=8.3 Hz, IH), 5.80 (s, IH), 4.00-3.80 (m, 4H), 3.90 (s, 3H), 3.87 (s, 3H), 3.86 (s, 3H), 3.81 (s, 3H), 3.17 (dd, J=5.0, 10.2 Hz, IH), 1.65- 1.70 (m, 2H), 1.26 (s, 3H), 0.26 (t, J=7.4 Hz, 3H) ppm. CNMR (CDC13, TMS, 1400): 148.7, 147.8, 147.8, 147.3, 137.2, 135.7, 130.0, 119.0, 111.8, 110.9, 110.8, 110.6, 109.9, 70.5, 65.0, 64.6, 55.9, 55.8, 55.8, 55.4, 49.4, 23.4, 23.1, 12.3 ppm. Elemental analysis: calc: C 66.65%, H 7.46% found: C 66.37%, H 7.44%
Example 8
3-[2-(3,4-dimethoxy-benzoyl)-4,5-dimethoxy-phenyl]~ pentan-2-one-ethylene ketal (II)
17.26 g (0.05 mole) of 3-(2-bromo-4,5-dimethoxy-phenyl)- pentan-2-one-ethylene ketal (VII) is dissolved in 173 ml of anhydrous tetrahydrofurane, whereupon the solution is cooled to -78°C by using external dry ice cooling. A 2.5 molar solution of butyl lithium (0.06 mole) in 24 ml of hexane is added. The addition having been completed the mixture is stirred at -78°C for a further period of 2 hours. To the solution 20.75 g (0.125 mole) of 3,4-dimethoxy-benzaldehyde is added, the reaction mixture is subjected to post-reaction for 20 minutes, and the temperature is slowly raised to the boiling point. The reaction mixture is heated to boiling for 2 hours, whereupon 150 ml of a saturated ammonium chloride solution is added, the mixture is stirred for 10 minutes and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and the filtrate is evaporated. Thus 38 g of a crude product is obtained which is stirred with a five-fold volume of isopropyl ether for 3 hours. The precipitated crude product is purified. Thus 14.0 g of the desired compound is obtained. Yield 65 %. Mp.: 165-166°C. IR CKBi i lβSδ cm"1.
HNMR (DMSO-d6, TMS, i400): 7.35 (d, J=1.9 Hz, IH), 7.20 (dd, J=1.9, 8.4 FIz, IH), 7.08 (s, IH), 7.00 (d, J=8.5 Hz, IH), 6.75 (s, IH), 3.80 (s, 3H), 3.76 (s, 3H), 3.74 (s, 3H), 3.65 (s, 3H), 3.80-3.50 (m, 4H), 3.02 (dd, J=3.7, 11.2 Hz, IH), 1.76 (m, IH), 1.62 (m, IH), 1.00 (s, 3H), 0.56 (t, J=7.4 Hz, 3H) ppm. CNMR (DMSO-d6, TMS, i400): 197.1, 154.6, 151.1, 149.9, 147.4, 134.8, 134.2, 132.1, 127.2, 113.1, 112.9, 112.7, 112.4, 112.0, 66.3, 65.5, 57.3, 57.0, 56.9, 50.8, 24.6, 24.0, 13.8 ppm. Elemental analysis: calc: C 66.96%, H 7.02% found: C 67.07%, H 7.01% Example 9
3~[2-(3,4-dimethoxy-benzoyl)-4,5-dimethoxy-phenyl]- pentan-2-one-ethylene ketal (II)
2.16 g (0.005 mole) of 3-[2-(α-hydroxy-3,4-dimethoxy~benzyl)- 4,5-dimethoxy-phenyl]-pentan-2-one-ethylene ketal (VIII) is dissolved in 24 ml of anhydrous tetrahydrofurane. The solution is cooled to -10°C under stirring. A 2.5 molar solution of butyl lithium (0.006 mole) in 2.4 ml of hexane is added, whereupon 1.32 g (0.008 mole) of 3,4-dimethoxy-benzaldehyde is added at -10°C. The reaction mixture is subjected to post-reaction for 20 minutes, whereupon the temperature is slowly raised to the boiling point. The reaction mixture is heated to boiling for 2 hours, 15 ml of a saturated ammonium chloride solution is added, the mixture is stirred for 10 minutes and extracted with ethyl acetate. The organic phase is washed with a saturated sodium, chloride solution, dried over magnesium sulfate, filtered and the filtrate is evaporated. 3.2 g of a crude product is obtained which is purified. Thus 1.47 of the title compound is obtained, yield 6.8 %. Mp. : 165- 166°C.
Example 10
3- 2-(α-hydroxy-3,4-dimethoxy-benzyϊ)-4,5-dimethoxy- phenyϊ]~pentan-2-one-ethyIene ketal (VIII) One proceeds as described in Example 7 except that the reaction is carried out at - 0°C. Thus 17.7 g of the title compound is obtained. Yield 82 %.
Example 11
3-[2-(α-hydroxy-3,4~dimethoxy-benzyl)-4,5-dimethoxy- phenyl]-pentan-2-one-ethylene ketal (VIII)
One proceeds as described in Example 7 except that a 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 18,5 g of the title compound is obtained. Yield 86 %.
Example 12
3-[2-(α-hydroxy-3,4-dimethoxy-benz3d)-4,5-dimethoxy- phenyl]-pentan-2-one-ethylene ketal (VIII)
One proceeds as described in Example 7 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 -5°C. Thus 16.5 g of the title compound is obtained. Yield 79 %. Example 13
3-[2-(3,4-dimethoxy-benzoyI)-4,5-dimethoxy-phenyl]- pentan-2-one-ethylene ketal (II)
One proceeds ais described in Example 8 except that the reaction is carried out at -10°C. Thus 12.7 g of the title compound is obtained. Yield 59 %. Mp.: 164-166°C.
Example 14
3-[2-(3,4-dimethoxy-benzoyl)~4,5-dimethoxy-phenyl]- pentan-2-one-ethylene ketal (II)
One proceeds as described in Example 7 except that a 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 -78°C. Thus 14,4 g of the title compound is obtained. Yield 67 %.
Example 15
3-[2-(3,4-dimethoxy-benzoyl)-4,5-dimethoxy-phenyl]- pentan-2-one-ethylene ketal (II)
One proceeds as described in Example 7 except that a 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 -5°C. Thus 11.8 g of the title compound is obtained. Yield 55 %.
Example 16
3-[2-(3,4-dimethoxy-benzoyl)-4,5-dimethoxy-phenyϊ]- pentan-2-one (IV)
To a mixture of 25.0 g of Kieselgel 100 ml of dichloro methane and 2.5 ml of a 15 % sulfuric acid solution at room temperature 6.46 g (0.015 mole) of 3-[2~(3,4-dimethoxy-benzoyι)-4,5- dimethoxy-phenyl]-pentan-2-one-ethylene ketal (II) is added. The reaction mixture is stirred at room temperature for 2 hours, the Kieselgel is filtered off and washed with dichloro methane. The dichloro methane solution is dried over magnesium sulfate and evaporated. The crude product is recrystallized. Thus 5.0 g of the chromatographically uniform title compound is obtained. Yield 87 %. Mp.: 158-159°C.
Example 17
3-[2-(3,4-dimethoxy-benzoyl)-4,5-dimethoxy-phenyl]- pentan-2-one-ethylene ketal (II)
2.16 g (0.005 mole) of 3-[2-(α-hydroxy-3,4-dimethoxy-benzyl)- 4,5-dimethoxy-phenyl]-pentan-2-one ethylene ketal (VIII) is dissolved in 24 ml of anhydrous tetrahydrofurane. The solution is cooled to -10°C whereupon successively 2.4 ml (0.006 mole) of a 2.5 molar butyl lithium solution and 1.32 g (0.008 mole) of 3,4-dimethoxy-benzaldehyde is added under stirring at -10°C. The reaction mixture is subjected to 20 minutes of post- reaction, whereupon the temperature is slowly- raised to the boiling point. The reaction mixture is heated to boiling for 2 hours, cooled to room temperature and 15 ml of a saturated ammonium chloride solution is added. The mixture is stirred for 10 minutes and extracted with ethyl acetate. The ethyl acetate layer is washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. Thus 3.2 g of a crude product is obtained. After purification 1.38 g of the title compound is obtained. Yield 64 %. Mp.: 165-166°C.
Example 18
3-[2-(3,4-diιnethoxy-benzoyI)-4,5-diιnethoxy-phenyl]- pentan-2-one-ethylene ketal (II)
2,16 g (0.005 mole) of 3-[2-(α-hydroxy-3,4-dimethoxy-benzyl)- 4,5-dimethoxy-phenyl]-pentan-2-one ethylene ketal (VIII) is dissolved in 24 ml of tetrahydrofurane, whereupon 0.24 g (0.006 mole) of a 60 % sodium hydride dispersion is added. At room temperature 1.32 g (0.008 mole) of 3,4-dimethoxy- benzaldehyde is added. The reaction mixture is heated to boiling for aii hour, cooled to room temperature, the solvent is evaporated, the residue is taken up in icecold water and extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried over magnesium sulfate, filtered and evaporated. The crude product is purified. Thus 1.62 g of the title compound is obtained. Mp.: 165-166°C. Yield 75 %.
Example 19
3-[2-(3,4-dimethoxy-benzoyl)-4,5-dimethoxy-phenyI]~ pentan-2-one-ethyϊene ketal (II)
1.73 g (0.004 mole) of 3-[2-( -hydroxy-3,4-dimethoxy-benzyl)- 4,5-dimethoxy-phenyl]-pentan-2-one ethylene ketal (VIII) is dissolved in 24 ml of xylene, whereupon 1.2 ml (0.012 mole) of cyclohexanone and 1.2 g (0.005 mole) of aluminium tertiary butylate is added. The reaction mixture is heated to boiling for 24 hours. The solid product is filtered off and washed with toluene. The united toluene phases are washed with water, dried over magnesium sulfate, filtered and evaporated. The crude product is purified. Thus 0.-56 g of the title compound is obtained. Yield 3.2 %. Mp. : 165- 166°C.

Claims

What we claim is,
1. Process for the preparation of 1 -(3 ,4-dimethoxy-phenyl)- 4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepineofthe Formula .
Figure imgf000040_0001
OCH,
which comp rises reacting a compound of the general Formula
Figure imgf000040_0002
1 9
(wherein R and R independently each stands for C1.4-alkyl or together form C2_6-alkylene) with hydrazine or a hydrate or salt thereof formed with an inorganic or organic acid.
2. Process according to Claim 1 which comprises using hydrazine hydrochloride or hydrazine sulfate as hydrazine salt.
3. Process according to any of Claims 1 and 2 which comprises using hydrazine or a hydrate or salt thereof in an amount of 1-8 molar equivalent(s), related to the compound of the general Formula II.
4. Process according to any of Claims 1-3 which comprises carrying out the reaction in the presence or absence of a solvent.
5. Process according to Claim 4 which comprises using a lower aliphatic alcohol and/or glacial acetic acid as solvent.
6. Process according to any of Claims 1-5 which comprises carrying out the reaction at a temperature between 10°C and 100°C.
7. Process according to Claim 1 or 2 which comprises reacting a compound of the general Formula II first with 1-4 molar equivalent(s) of hydrazine or a hydrate or salt thereof and adding a further 1-4 molar equivalent(s) of hydrazine or a hydrate or salt thereof in the course of the reaction.
8. Process according to any of Claims 1-7 which comprises forming hydrazine hydrochloride or hydrazine sulfate in situ in the reaction mixture.
>9. Process according to Claim 1 which comprises carrying out the reaction in the presence of an inorganic acid, an organic acid, or a salt formed with an inorganic acid and/or a salt formed with an organic acid.
10. Process according to Claim 9 which comprises using hydrochloric acid, sulfuric acid and/or acetic acid.
11. . Process according to any of Claims 1-10 which com rises using a compound of the general Formula II 1 9 1 wherein R and R each stands for methyl or ethyl or R and R together form an ethylene group.
12. Process' for the preparation of 3-[2-(3 ,4-dimethoxy- benzoyl)-4,5-dimethoxy-phenyl]-pentan-2-one of the Formula
Figure imgf000043_0001
from 3-(3,4-dimethoxypheny)-pentan-2-one of the Formula
Figure imgf000043_0002
which compris es brominating the compound of the Formula V; reacting the compound of the Formula
Figure imgf000044_0001
thus obtained with a C^-aliphatic alcohol or a C2-e- aliphatic diol; converting the compound of the general Formula
Figure imgf000044_0002
1 9 thus obtained (wherein R and R each stands for Cμ -
1 9 alkyl or R and R together form a C2.6-alkylene group) into a compound of the general Formula II directly or via a compound of the general Formula
Figure imgf000045_0001
OCH,
and hydrolysing the compound of the general Formula II; or a2) reacting the compound of the general Formula VI with a C1-4-aliphatic alcohol or a C2.6-alipb.atic diol; converting the compound of the general Formula VII thus obtained into a compound of the general Formula II directly or via a compound of the general Formula VIII; and hydrolysing the compound of the general Formula II thus obtained; or a3) converting a compound of the general Formula VII into a compound of the general Formula II directly or via a compound of the general Formula VIII; and hydrolysing the compound of the general Formula II thus obtained; or a4) hydrolysing a compound of the general Formula II.
13. Process according to Claim 12 which com rises carrying out bromination with N-bromo- succinimide.
14. Process according to Claim 12 which co prises using methanol, ethanol or ethylene glycol as Cι-4-aliphatic alcohol or C2-6-aliphatic diol.
15. Process according to Claim 14 which comprises carrying out the reaction in the presence of an acidic catalyst.
16. Process according to Claim 15 which comprises using an aromatic sulfonic acid, preferably p- toluenesulfonic acid as aromatic sulfonic acid.
17. Process according to Claim 12 which, comprises replacing the bromine atom in the compound of the general Formula VII by an alkali or magnesium atom and converting the alkali or magnesium compound thus obtained into a compound of the general Formula VIII by reacting with an approximately equimolar amount of 3,4-dimethoxy- benzaldehyde.
18. Process according to Claim 17 which comprises replacing the bromine atom in the compound of the general Formula VII by a lithium atom.
19. Process according to Claim 18 which com rises carrying out the reaction by using an alkyl lithium, preferably n-butyl-lithium.
20. Process according to Claim 17 which comprises caπying out the reaction at a temperature between -78°C and -10°C.
21. Process according to Claim 17 which comprises using 1.0- 1.2 molar equivalents of 3,4- dimethoxy-benzaldehyde.
22. Process according to any of Claims 17-19 which comprises reacting the alkali or magnesium compound without isolation with the 3,4-dimethoxy-benzaldehyde.
23. . Process according to Claim 12 which comprises replacing the bromine atom in the compound of the general Formula VII by an alkali or magnesium atom, and converting the alkali or magnesium compound thus obtained into a compound of the general Formula II by reacting with an excess of 3,4-dimethoxy-benzaldehyde.
24. Process according to Claim 23 which comprises using 2.0-2.5 molar equivalents of 3,4- dimethoxy-benzaldehyde.
25. Process according to Claim 23 or 24 which comprises reacting the reaction mixture without isolating the alkali or magnesium compound at a temperature between -78°C and -10°C with the 3,4-dimethoxy-benzaldehyde, and thereafter raising the temperature to 60-90°C.
26. Process according to Claim 12 which comprises oxidizing the compound of the general Formula VIII into a compound of the general Formula II.
27. Process according to Claim 26 which comprises carrying out oxidation with an excess of 3,4- dimethoxy-benzaldehyde.
28. Process according to Claim 12 which com rises hydrolysing the compound of the general Formula II with a mineral acid.
29. Process according to Claim 28 which comprises using sulfuric acid as mineral acid.
30. Process according to Claim 28 or 29 which comprises carrying out hydrolysis at 20-40°C.
31. 3-[2-(α-hydroxy-3,4-dimethoxy-benzyl)-4,5-dimethoxy- phenyl]-pentan-2-one-ketals of the general Formula VIII
1 9
(wherein R and R are as stated in Claim 12).
32. Process for the preparation of 3-[2-(α-hydroxy-3,4- dimethoxy-benzyl)-4,5-dimethoxy-phenyl]-pentan-2-one-ketals of the general Formula VIII which comprises replacing the bromine atom in a compound of the general Formula VII by a lithium atom and reacting the lithium compound thus obtained with 1.0-1.2 molar equivalent of 3,4- dimethoxy-benzaldehyde.
33. 3-[2-(3 ,4-dimethoxy-benzoyl)-4,5-dimethoxy-phenyl]- p ιeerntan-2-one-ketals of the general Formula II (wherein R1 and R2 are as stated in Claim 12).
34. Process for the preparation of 3-[2-(3,4-dimethoxy- benzoyl)-4,5-dimethoxy-phenyl]-pentan-2-one ketals of the general Formula II which comprises a) replacing in a compound of the general Formula VII the bromine atom by a lithium atom and reacting the lithium compound thus obtained with an excess - preferably 2.0- 2,5 molar equivalents - of 3,4-dimethoxy-benzaldehyde; or b) oxidizing a compound of the general Formula VIII.
35. Process according to Claim 34 which comprises carrying out oxidation with an excess of 3,4- dimethoxy-benzaldehyde.
PCT/HU2002/000141 2001-12-13 2002-12-12 Process for the preparation of tofisopam and new intermediates WO2003050092A2 (en)

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EP02781451A EP1465879A2 (en) 2001-12-13 2002-12-12 Process for the preparation of tofisopam and new intermediates
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HU0105326A HU225411B1 (en) 2001-12-13 2001-12-13 Process for producing tofisopam
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004054952A1 (en) * 2002-12-16 2004-07-01 Egis Gyogyszergyar Rt. Process for the preparation of 3-[2-(3,4-dimethoxybenzoyl)-4,5- dimethoxyphenyl] -pentan-2-one
JP2014080421A (en) * 2012-10-12 2014-05-08 Lab Servier Novel process for synthesis of 3-(2-bromo-4,5-dimethoxyphenyl)propanenitrile, and application in synthesis of ivabradine and addition salts thereof with pharmaceutically acceptable acid

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2122070A1 (en) * 1970-11-06 1972-06-08 E GY T Gyogyszervegyeszeti Gyar, Budapest 1 Veratryl 4 methyl 5 ethyl 7,8 dimethoxy 2,3 diazabicyclo square brackets to 5,4,0 square brackets to undeca pentaen (1,3,6,8,10) and its use

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2122070A1 (en) * 1970-11-06 1972-06-08 E GY T Gyogyszervegyeszeti Gyar, Budapest 1 Veratryl 4 methyl 5 ethyl 7,8 dimethoxy 2,3 diazabicyclo square brackets to 5,4,0 square brackets to undeca pentaen (1,3,6,8,10) and its use

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GATTA F ET AL: "Derivatives of 2,3-Benzodiazepine" FARMACO, EDIZIONE SCIENTIFICA, SOCIETA CHIMICA ITALIANA, PAVIA, IT, vol. 40, 1985, pages 942-955, XP009011786 ISSN: 0430-0920 cited in the application *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004054952A1 (en) * 2002-12-16 2004-07-01 Egis Gyogyszergyar Rt. Process for the preparation of 3-[2-(3,4-dimethoxybenzoyl)-4,5- dimethoxyphenyl] -pentan-2-one
JP2014080421A (en) * 2012-10-12 2014-05-08 Lab Servier Novel process for synthesis of 3-(2-bromo-4,5-dimethoxyphenyl)propanenitrile, and application in synthesis of ivabradine and addition salts thereof with pharmaceutically acceptable acid

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