EP1575890A1 - 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-oneInfo
- Publication number
- EP1575890A1 EP1575890A1 EP02791921A EP02791921A EP1575890A1 EP 1575890 A1 EP1575890 A1 EP 1575890A1 EP 02791921 A EP02791921 A EP 02791921A EP 02791921 A EP02791921 A EP 02791921A EP 1575890 A1 EP1575890 A1 EP 1575890A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- general formula
- process according
- dimethoxy
- alkali
- Prior art date
- Legal status (The legal status 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 status listed.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims abstract description 35
- 230000008569 process Effects 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 55
- ZWUMDFWFKWDFBI-UHFFFAOYSA-N 3-[2-(3,4-dimethoxybenzoyl)-4,5-dimethoxyphenyl]pentan-2-one Chemical compound CCC(C(C)=O)C1=CC(OC)=C(OC)C=C1C(=O)C1=CC=C(OC)C(OC)=C1 ZWUMDFWFKWDFBI-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 4
- 239000003513 alkali Substances 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 16
- -1 alkyl lithium compound Chemical class 0.000 claims description 12
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 10
- 150000002681 magnesium compounds Chemical class 0.000 claims description 10
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical group [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- 230000003301 hydrolyzing effect Effects 0.000 claims description 7
- 229910052749 magnesium Inorganic materials 0.000 claims description 7
- 239000011541 reaction mixture Substances 0.000 claims description 6
- 150000001408 amides Chemical class 0.000 claims description 5
- 229910052744 lithium Inorganic materials 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 3
- 238000002955 isolation Methods 0.000 claims description 3
- CETVQRFGPOGIQJ-UHFFFAOYSA-N lithium;hexane Chemical compound [Li+].CCCCC[CH2-] CETVQRFGPOGIQJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000011707 mineral Substances 0.000 claims description 3
- 239000007858 starting material Substances 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 238000011065 in-situ storage Methods 0.000 claims description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims 1
- 239000005977 Ethylene Substances 0.000 claims 1
- 150000002641 lithium Chemical group 0.000 claims 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 17
- 239000000243 solution Substances 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 5
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical group [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 4
- WSSLDBVWUSSAGE-UHFFFAOYSA-N Veratrumsaeure-dimethylamid Natural products COC1=CC=C(C(=O)N(C)C)C=C1OC WSSLDBVWUSSAGE-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 150000002642 lithium compounds Chemical class 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- BLWGLUGFLOPVHX-UHFFFAOYSA-N 3-(2-bromo-4,5-dimethoxyphenyl)pentan-2-one Chemical compound CCC(C(C)=O)C1=CC(OC)=C(OC)C=C1Br BLWGLUGFLOPVHX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- RUJBDQSFYCKFAA-UHFFFAOYSA-N Tofisopam Chemical compound N=1N=C(C)C(CC)C2=CC(OC)=C(OC)C=C2C=1C1=CC=C(OC)C(OC)=C1 RUJBDQSFYCKFAA-UHFFFAOYSA-N 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 229960002501 tofisopam Drugs 0.000 description 3
- BIGQPYZPEWAPBG-UHFFFAOYSA-N veratric acid methyl ester Natural products COC(=O)C1=CC=C(OC)C(OC)=C1 BIGQPYZPEWAPBG-UHFFFAOYSA-N 0.000 description 3
- VIOBGCWEHLRBEP-UHFFFAOYSA-N 3,4-dimethoxybenzoyl chloride Chemical compound COC1=CC=C(C(Cl)=O)C=C1OC VIOBGCWEHLRBEP-UHFFFAOYSA-N 0.000 description 2
- LNWAOJCHFJZVPU-UHFFFAOYSA-N 3-[2-(3,4-dimethoxybenzoyl)-4,5-dimethoxyphenyl]pentan-2-one;ethene Chemical group C=C.CCC(C(C)=O)C1=CC(OC)=C(OC)C=C1C(=O)C1=CC=C(OC)C(OC)=C1 LNWAOJCHFJZVPU-UHFFFAOYSA-N 0.000 description 2
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 150000001805 chlorine compounds Chemical class 0.000 description 2
- 150000001844 chromium Chemical class 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- DAUAQNGYDSHRET-UHFFFAOYSA-N 3,4-dimethoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1OC DAUAQNGYDSHRET-UHFFFAOYSA-N 0.000 description 1
- RUEQJZPDBYLHPF-UHFFFAOYSA-N 3-(2-bromo-4,5-dimethoxyphenyl)pentan-2-one;ethene Chemical group C=C.CCC(C(C)=O)C1=CC(OC)=C(OC)C=C1Br RUEQJZPDBYLHPF-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 125000006416 CBr Chemical group BrC* 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- GPVDHNVGGIAOQT-UHFFFAOYSA-N Veratric acid Natural products COC1=CC=C(C(O)=O)C(OC)=C1 GPVDHNVGGIAOQT-UHFFFAOYSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000008570 general process Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical class C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- XNLICIUVMPYHGG-UHFFFAOYSA-N methyl n-propyl ketone Natural products CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- KRKPYFLIYNGWTE-UHFFFAOYSA-N n,o-dimethylhydroxylamine Chemical compound CNOC KRKPYFLIYNGWTE-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
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)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU0204342 | 2002-12-16 | ||
| HU0204342A HU227044B1 (en) | 2002-12-16 | 2002-12-16 | Process for producing 3-[2-(3,4-dimethoxybenzoyl)-4,5-dimethoxyphenyl]-pentan-2-one |
| 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 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1575890A1 true EP1575890A1 (en) | 2005-09-21 |
Family
ID=89981000
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP02791921A Withdrawn 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 |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP1575890A1 (cs) |
| JP (1) | JP4437093B2 (cs) |
| KR (1) | KR100936306B1 (cs) |
| AU (2) | AU2002361068A1 (cs) |
| BG (1) | BG109230A (cs) |
| CZ (1) | CZ2005388A3 (cs) |
| EA (1) | EA007788B1 (cs) |
| HU (1) | HU227044B1 (cs) |
| PL (1) | PL376530A1 (cs) |
| SK (1) | SK702005A3 (cs) |
| UA (1) | UA78634C2 (cs) |
| WO (2) | WO2004054951A1 (cs) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Family Cites Families (2)
| 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 |
| AU2002348942A1 (en) * | 2001-12-13 | 2003-06-23 | Egis Gyogyszergyar Rt. | Process for the preparation of tofisopam and new intermediates |
-
2002
- 2002-12-16 HU HU0204342A patent/HU227044B1/hu not_active IP Right Cessation
- 2002-12-31 EP EP02791921A patent/EP1575890A1/en not_active Withdrawn
- 2002-12-31 SK SK70-2005A patent/SK702005A3/sk unknown
- 2002-12-31 AU AU2002361068A patent/AU2002361068A1/en not_active Abandoned
- 2002-12-31 PL PL376530A patent/PL376530A1/pl not_active IP Right Cessation
- 2002-12-31 EA EA200500966A patent/EA007788B1/ru not_active IP Right Cessation
- 2002-12-31 WO PCT/HU2002/000178 patent/WO2004054951A1/en active Application Filing
- 2002-12-31 CZ CZ2005388A patent/CZ2005388A3/cs unknown
- 2002-12-31 JP JP2004559931A patent/JP4437093B2/ja not_active Expired - Fee Related
- 2002-12-31 UA UAA200507059A patent/UA78634C2/uk unknown
- 2002-12-31 KR KR1020057011012A patent/KR100936306B1/ko not_active Expired - Fee Related
-
2003
- 2003-12-16 WO PCT/HU2003/000104 patent/WO2004054952A1/en not_active Application Discontinuation
- 2003-12-16 AU AU2003292449A patent/AU2003292449A1/en not_active Abandoned
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2005
- 2005-07-14 BG BG109230A patent/BG109230A/bg unknown
Non-Patent Citations (1)
| Title |
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| See references of WO2004054951A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| HUP0204342A3 (en) | 2004-11-29 |
| HU227044B1 (en) | 2010-05-28 |
| KR100936306B1 (ko) | 2010-01-12 |
| AU2002361068A1 (en) | 2004-07-09 |
| AU2003292449A1 (en) | 2004-07-09 |
| CZ2005388A3 (cs) | 2005-09-14 |
| WO2004054951A1 (en) | 2004-07-01 |
| EA200500966A1 (ru) | 2005-12-29 |
| PL376530A1 (pl) | 2006-01-09 |
| SK702005A3 (sk) | 2005-09-08 |
| BG109230A (bg) | 2006-04-28 |
| HU0204342D0 (en) | 2003-02-28 |
| JP4437093B2 (ja) | 2010-03-24 |
| EA007788B1 (ru) | 2007-02-27 |
| HUP0204342A2 (hu) | 2004-07-28 |
| UA78634C2 (en) | 2007-04-10 |
| WO2004054952A1 (en) | 2004-07-01 |
| KR20050085686A (ko) | 2005-08-29 |
| JP2006509814A (ja) | 2006-03-23 |
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