WO2004054952A1 - Process for the preparation of 3-[2-(3,4-dimethoxybenzoyl)-4,5- dimethoxyphenyl] -pentan-2-one - Google Patents
Process for the preparation of 3-[2-(3,4-dimethoxybenzoyl)-4,5- dimethoxyphenyl] -pentan-2-one Download PDFInfo
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- WO2004054952A1 WO2004054952A1 PCT/HU2003/000104 HU0300104W WO2004054952A1 WO 2004054952 A1 WO2004054952 A1 WO 2004054952A1 HU 0300104 W HU0300104 W HU 0300104W WO 2004054952 A1 WO2004054952 A1 WO 2004054952A1
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- Prior art keywords
- general formula
- compound
- alkali
- atom
- magnesium
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 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 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 62
- 230000007062 hydrolysis Effects 0.000 claims abstract description 12
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 12
- 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 claims abstract description 4
- 229960002501 tofisopam Drugs 0.000 claims abstract description 4
- 230000000949 anxiolytic effect Effects 0.000 claims abstract description 3
- 239000002249 anxiolytic agent Substances 0.000 claims abstract 2
- 239000012450 pharmaceutical intermediate Substances 0.000 claims abstract 2
- 239000003513 alkali Substances 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 13
- -1 alkyl lithium Chemical compound 0.000 claims description 12
- 150000002681 magnesium compounds Chemical class 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 125000001246 bromo group Chemical group Br* 0.000 claims description 10
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical group [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 8
- 150000001408 amides Chemical class 0.000 claims description 8
- 229910052749 magnesium Inorganic materials 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 229910052744 lithium Inorganic materials 0.000 claims description 6
- 239000011541 reaction mixture Substances 0.000 claims description 6
- 125000002947 alkylene group Chemical group 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 4
- CETVQRFGPOGIQJ-UHFFFAOYSA-N lithium;hexane Chemical compound [Li+].CCCCC[CH2-] CETVQRFGPOGIQJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 3
- 238000002955 isolation Methods 0.000 claims description 3
- 150000002641 lithium Chemical group 0.000 claims description 3
- 239000011707 mineral Substances 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 2
- 238000011065 in-situ storage Methods 0.000 claims description 2
- 239000001117 sulphuric acid Substances 0.000 claims description 2
- 235000011149 sulphuric acid Nutrition 0.000 claims description 2
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 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
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 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
- 230000015572 biosynthetic process Effects 0.000 description 6
- GPVDHNVGGIAOQT-UHFFFAOYSA-N Veratric acid Natural products COC1=CC=C(C(O)=O)C(OC)=C1 GPVDHNVGGIAOQT-UHFFFAOYSA-N 0.000 description 5
- DAUAQNGYDSHRET-UHFFFAOYSA-N 3,4-dimethoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1OC DAUAQNGYDSHRET-UHFFFAOYSA-N 0.000 description 4
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 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 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 3
- 239000005977 Ethylene Substances 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
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- WSSLDBVWUSSAGE-UHFFFAOYSA-N 3,4-dimethoxy-n,n-dimethylbenzamide Chemical compound COC1=CC=C(C(=O)N(C)C)C=C1OC WSSLDBVWUSSAGE-UHFFFAOYSA-N 0.000 description 2
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 2
- 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 2
- 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 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-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
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229910052799 carbon 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
- 238000000354 decomposition reaction Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 150000002642 lithium compounds Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 230000003647 oxidation Effects 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
- 235000002639 sodium chloride Nutrition 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
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- VIOBGCWEHLRBEP-UHFFFAOYSA-N 3,4-dimethoxybenzoyl chloride Chemical compound COC1=CC=C(C(Cl)=O)C=C1OC VIOBGCWEHLRBEP-UHFFFAOYSA-N 0.000 description 1
- SOJNQJRJHNNHHG-UHFFFAOYSA-N 3-(3,4-dimethoxyphenyl)pentan-2-one Chemical compound CCC(C(C)=O)C1=CC=C(OC)C(OC)=C1 SOJNQJRJHNNHHG-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
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-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
- KYOIPUDHYRWSFO-UHFFFAOYSA-N [Br].[Li] Chemical group [Br].[Li] KYOIPUDHYRWSFO-UHFFFAOYSA-N 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- ANUZKYYBDVLEEI-UHFFFAOYSA-N butane;hexane;lithium Chemical compound [Li]CCCC.CCCCCC ANUZKYYBDVLEEI-UHFFFAOYSA-N 0.000 description 1
- 229960004424 carbon dioxide Drugs 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- ZCDOYSPFYFSLEW-UHFFFAOYSA-N chromate(2-) Chemical compound [O-][Cr]([O-])(=O)=O ZCDOYSPFYFSLEW-UHFFFAOYSA-N 0.000 description 1
- 150000001844 chromium Chemical class 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 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
- 125000000468 ketone group Chemical group 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- BIGQPYZPEWAPBG-UHFFFAOYSA-N methyl 3,4-dimethoxybenzoate Chemical compound COC(=O)C1=CC=C(OC)C(OC)=C1 BIGQPYZPEWAPBG-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 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
- 125000004123 n-propyl group Chemical group [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
- 125000002524 organometallic group Chemical group 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 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
- 238000003860 storage Methods 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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-di ethoxy-phen ⁇ l] -pentan-2-one of the formula (I) .
- the compound of the formula (I) can be prepared from diisohomoeugenol by oxidation carried out with chromium(VI) oxide. The yield of this process is rather poor.
- the process provided in Hungarian patent specification No. 187 161 aims at eliminating the above drawbacks .
- the compound of the formula (I) is produced by a technique devoid of chromate by reacting 3- (3 , 4-dimethoxy- phenyl) -pentan-2-one with 3 , 4-dimethoxy- benzoic chloride in the presence of aluminum(III) chloride and decomposing the thus-obtained benzopyrilium salt in an alkaline medium.
- the drawback of the above process resides in the fact that the 3 , 4-dimethox ⁇ - benzoic chloride used as starting substance is liable to decomposition, and the Friedel-Crafts product formed in the reaction is strongly contaminated, difficult to handle and can be purified only at a heavy loss .
- R 1 and R 2 each represents a C 1 _ alkyl group, or R 1 and R 2 together form a
- C 2 - 6 alkylene group which comprises a) exchanging the bromo atom in a compound of the general formula (II) for an alkali or magnesium atom; reacting the thus-obtained alkali or magnesium compound with an approximately equimolar amount of an acid amide of the general formula (Ilia)
- FIG. 1 _ 4 alkyl used in the present specification relates to straight or branched chain saturated aliphatic hydrocarbon groups having 1-4 carbon atom(s) (e.g. methyl , ethyl , n-propyl , isopropyl, n-butyl, etc.) .
- Thus,C 2 _ 6 alkylene group covers straight or branched chain alkylene groups having 2-6 carbon atoms (e.g. ethylene, trimethylene, tetramethylene group, etc.) .
- the compound of the general formula (IV) can be created with the amides of the general formula (Ilia) and esters of the general formula (Illb) generally not applied for the formation of a keto group in the organometallic chemistry.
- the present invention is based on the recognition that the desired 3-[2- (3 , 4-di- methoxybenzoyl) -4 , 5-dimethoxyphenyl]- pentan-2-on of the general formula (I) can be prepared by reacting an alkali or magnesium compound formed from a 3- (2- bromo-4 , 5-dimethoxyphenyl) -pentan-2-one ketal of the general formula (II) with a compound of the general formula (Ilia) or (Illb) , and subjecting the thus-obtained 3- [2- (3 , 4-dimethoxybenzoyl) -4 , 5-dimethoxy- phenyl]-pentan-2-one ketals of the general formula (IV) to hydrolysis .
- the bromo atom in the compound of the general formula (II) is exchanged for an alkali or magnesium atom, and the thus-obtained alkali or magnesium compound is reacted with a 3,4- dimethoxybenzoic acid N,N-dialkyl amide of the formula (Ilia) .
- the latter compounds are prepared from 3 , 4-dimethoxybenzoic acid by known methods .
- the bromo atom in the compound of the general formula (II) is exchanged for an alkali atom (e.g. sodium, potassium or lithium atom) or for a magnesium atom in a Grignard reaction.
- an alkali atom e.g. sodium, potassium or lithium atom
- a magnesium atom in a Grignard reaction.
- a bromine - lithium exchange is carried out.
- a compound of the general formula (II) is reacted with an alkyl lithium (preferably with n-butyl lithium or n-hexyl lithium) .
- the alkyl lithium is preferably applied in an alkane solution. As alkane preferably n-hexane is used.
- the bromo atom is exchanged for a lithium atom at a temperature between -78 °C and -10 °C, preferably at -10 °C, in anhydrous tetrahydrofurane .
- the thus-formed alkali or magnesium compound - preferably lithium compound - is then reacted with an approximately equimolar amount (preferably 1,0 - 1,2 mole) of the 3 , 4-dimethoxybenzoic acid N,N-dialkyl amide of the formula (Ilia) .
- the lithium compound is expediently reacted without isolation, in the reaction mixture where it has been formed, with the 3,4- dimethoxybenzoic acid N,N-dialkyl amide of the general formula (Ilia) .
- the reaction is carried out at a temperature below 0 ° C , preferably at about -20 °C.
- the thus- obtained compound of the general formula (IV) can be isolated from the reaction mixture .
- the bromo atom in the compound of the general formula (II) is exchanged for an alkali or magnesium atom, then the thus-obtained alkali or magnesium compound is transformed with a 3 , 4-dimethoxybenzoic acid alkyl ester of the general formula (Illb) into a compound of the general formula (IV) .
- the compound of the general formula (IV) is preferably isolated and purified by re ⁇ rystallization.
- the isolated ketal of the general formula (IV) is hydrolized with a mineral acid by methods known per se into the corresponding ketone of the general formula (I) .
- the hydrolysis is preferably carried out with a mineral acid, particularly with diluted sulfuric acid or with diluted hydrogen chloride.
- the most preferable is the application of diluted sulfuric acid.
- the reaction is performed in a two-phase reaction mixture, preferably at a temperature between 20 °C and 40 °C.
- One of the phases is composed of a water- immiscible organic solvent (preferably an aromatic hydrocarbon, such as benzene, toluene or xylene; or an aliphatic halogenated hydrocarbon, e.g. dichloro- ethane)
- the other is composed of an aqueous acidic solution.
- silica gel may be applied in a 2-5-fold amount related to the weight of the compound of the general formula (IV) .
- the compound of the general formula (I) can also be produced directly, without isolating the intermediate compound of the general formula (IV) .
- the compound of the general formula (IV) prepared as specified above is treated in situ with an acid, and only the ketone of the general formula (I) is isolated and purified.
- the thus-obtained compound of the formula (I) may optionally be purified by recrystallization from a suitable solvent.
- a suitable solvent for the recrystallization preferably a straight or branched chain aliphatic alcohol may be applied.
- the purity of the thus-obtained compound of the formula (I) exceeds 98%, and it is highly suitable for transformation into tofisopam.
- the advantages of the process according to the invention reside in the application of environment-friendly substances and the high yield of the obtained 3-[2- (3 ,4-dimethox ⁇ benzoyl) -4,5- dimethoxyphenyl]propan-2-one intermediate of the formula (I) necessary for the production of tofisopam.
- Example 2 One proceeds as specified in Example 1, with the difference that the reaction is carried out at a temperature of -20 °C. Thus 6.9 g (32%) of the title compound melting at 164-166 °C are obtained.
- Example 2 One proceeds as specified in Example 1 , with the difference that instead of 2.5M butyl lithium solution in hexane 2 , 5M hexyl lithium solution in hexane is used, and the reaction is carried out at a temperature of 20 °C. Thus 6.2 g (29%) of the title compound are obtained.
- Example 6 One proceeds as specified in Example 6, with the difference that the compound of the general formula (IV) is not purified, but the crude product obtained according to the process specified in Examples 1 to 5 is subjected to acidic treatment, and only the thus-obtained compound of the formula (I) is purified by recrystallization. Thus 6.2 - 9.6 g of the title compound (32 - 50% calculated for the compound of the general formula (II) ) are obtained.
Abstract
The invention relates to a new process for the preparation of 3-[2-(3,4-dimethoxybenzoyl)-4,5- dimethoxyphenyl]-pentan-2-one of the formula (I), starting from a compound of the general formula (II) and subjecting the thus-obtained compound of the general formula (IV) to hydrolysis. The compound of the formula (I) is a pharmaceutical intermediate, which can be used for the preparation of an anxiolytic, namely tofisopam (INN).
Description
PROCESS FOR THE PREPARATION OF 3-
[2- (3 , 4-DIMETHOXYBENZOYL) -4 , 5-DI-
METHOXYPHENYL] -PENTAN-2-ONE
Technical field of the invention
The invention relates to a new process for the preparation of 3- [2- (3 , 4-dimethoxy- benzoyl) -4 ,5-di ethoxy-phenγl] -pentan-2-one of the formula (I) .
Said 3- [2- (3 , 4-dimethoxybenzoyl) -4 , 5- dimethoxyphenyl] -pentan-2-one is a valuable intermediate, which can be used for the preparation of 1- (3 ,4-dimethoxyphenyl) -4- methyl-5-ethγl-7 , 8-dimethoxy-5H-2 , 3-benzo- diazepine known under the international non-proprietory name tofisopa . The compound exerts an anxiolytic activity.
Background of the invention
According to a process known from Hungarian patent specification No. 158 091 the compound of the formula (I) can be prepared from diisohomoeugenol by oxidation carried out with chromium(VI) oxide. The yield of this process is rather poor.
According to the method provided in Hungarian patent specification No. 194 529 1- (3 , 4-dimethoxyphenyl) -3-methyl-4-ethyl- 6 , 7-dimethoxy-isocroman is oxidized with chromium(VI) oxide into the corresponding benzopyrilium salt. This compound is then decomposed in an alkaline aqueous solution to obtain the desired compound of the formula (I) .
Both methods are accompanied by the same drawback: the chromium salts applied as oxidizing agents or formed during the oxidation process are strongly toxic compounds damaging the environment. The storage, neutralization and re-utilization of these substances cause serious environmental problems .
The process provided in Hungarian patent specification No. 187 161 aims at
eliminating the above drawbacks . According to this method the compound of the formula (I) is produced by a technique devoid of chromate by reacting 3- (3 , 4-dimethoxy- phenyl) -pentan-2-one with 3 , 4-dimethoxy- benzoic chloride in the presence of aluminum(III) chloride and decomposing the thus-obtained benzopyrilium salt in an alkaline medium.
The drawback of the above process resides in the fact that the 3 , 4-dimethoxγ- benzoic chloride used as starting substance is liable to decomposition, and the Friedel-Crafts product formed in the reaction is strongly contaminated, difficult to handle and can be purified only at a heavy loss .
It is the aim of the present invention to eliminate the drawbacks of the hitherto known processes and to provide a feasible method for the preparation of 3- [2- (3,4- dimethoxybenzoyl) -4,5-dimethoxy-phenyl] - pentan-2-one of the formula (I) , said method involving a technique devoid of chromium and utilising environmental- friendly substances, so that the desired
compound may be obtained in higher yield and purity than according to the hitherto known processes. Summary of the invention
It has been found that the above aim is achieved by the process according to the present invention.
According to the present invention there is provided a process for the preparation of 3- [2- (3 ,4-dimethoxybenzoyl) - 4 , 5-dimethoxyphenyl] -pentan-2-one starting from a compound of the general formula (ID .
(wherein R1 and R2 each represents a C1_ alkyl group, or R1 and R2 together form a
C2-6 alkylene group) , which comprises a) exchanging the bromo atom in a compound of the general formula (II) for an alkali or magnesium atom; reacting the thus-obtained alkali or
magnesium compound with an approximately equimolar amount of an acid amide of the general formula (Ilia)
(wherein R3 and R4 each denotes a Cι_4 alkyl group) , and subjecting the thus-obtained compound of the general formula (IV)
(wherein R1 and R2 are as stated above) to hydrolysis; or
b) exchanging the bromo atom in a compound of the general formula (II) for an alkali or magnesium atom; reacting the thus-obtained alkali or magnesium compound with an approximately equimolar amount of an ester of the general formula (Ilib)
(wherein R5 represents a Cι_ alkyl group) , and subjecting the thus- obtained compound of the general formula (IV) to hydrolysis. Description of the preferred embodiments
The term „C1_4 alkyl" used in the present specification relates to straight or branched chain saturated aliphatic hydrocarbon groups having 1-4 carbon atom(s) (e.g. methyl , ethyl , n-propyl , isopropyl, n-butyl, etc.) .
The term „C2_6 alkylene group" covers straight or branched chain alkylene groups
having 2-6 carbon atoms (e.g. ethylene, trimethylene, tetramethylene group, etc.) .
The synthesis and characterization of the 3- (2-bromo-4 , 5-di-methoxyphenyl) - ρentan-2-on ketals of the general formula
(II) used as starting substances is provided in the pending Hungarian patent applications Nos. 5326/01 and 5327/01
(filing date: 13. 12. 2001).
According to the method generally applied for the preparation of diary1 ketons from aryl-metal compounds the aryl- metal compound is reacted with an aromatic nitrile, and the thus-obtained imine is subjected to hydrolysis. In the present case this method cannot be applied, because according to the technical literature instead of the formation of the compound of general formula (I) the production of an izokinoline derivative can be expected
(Khim. Geterosikl. Soedin, 1988 , (1) , 134-5) .
In the reaction of the aryl-metal compounds with the generally applied einreb -amides (N-methyl-N-rrtethoxy amide) the formation of a compound of the general formula (IV) would be expected, but the
application of this reagents renders the synthesis very expensive (Bioorganic and Medicinal Chemistry Letters 1993, 1991-2) .
The synthesis of the compounds of the general formula (IV) with aryl-metal compounds and acid chlorides is not expedient, as acid chlorides are highly liable to decomposition, and generally they are contaminated with inorganic acids. Thus said compounds considerably decrease the yield and increase the extent of side- reactions.
Surprisingly it has been found that the compound of the general formula (IV) can be created with the amides of the general formula (Ilia) and esters of the general formula (Illb) generally not applied for the formation of a keto group in the organometallic chemistry.
The present invention is based on the recognition that the desired 3-[2- (3 , 4-di- methoxybenzoyl) -4 , 5-dimethoxyphenyl]- pentan-2-on of the general formula (I) can be prepared by reacting an alkali or magnesium compound formed from a 3- (2- bromo-4 , 5-dimethoxyphenyl) -pentan-2-one
ketal of the general formula (II) with a compound of the general formula (Ilia) or (Illb) , and subjecting the thus-obtained 3- [2- (3 , 4-dimethoxybenzoyl) -4 , 5-dimethoxy- phenyl]-pentan-2-one ketals of the general formula (IV) to hydrolysis .
According to variant a) of the process according to the invention the bromo atom in the compound of the general formula (II) is exchanged for an alkali or magnesium atom, and the thus-obtained alkali or magnesium compound is reacted with a 3,4- dimethoxybenzoic acid N,N-dialkyl amide of the formula (Ilia) . The latter compounds are prepared from 3 , 4-dimethoxybenzoic acid by known methods .
The bromo atom in the compound of the general formula (II) is exchanged for an alkali atom (e.g. sodium, potassium or lithium atom) or for a magnesium atom in a Grignard reaction. According to a preferred embodiment of the process a bromine - lithium exchange is carried out. For this purpose a compound of the general formula (II) is reacted with an alkyl lithium (preferably with n-butyl lithium or
n-hexyl lithium) . The alkyl lithium is preferably applied in an alkane solution. As alkane preferably n-hexane is used. The bromo atom is exchanged for a lithium atom at a temperature between -78 °C and -10 °C, preferably at -10 °C, in anhydrous tetrahydrofurane . The thus-formed alkali or magnesium compound - preferably lithium compound - is then reacted with an approximately equimolar amount (preferably 1,0 - 1,2 mole) of the 3 , 4-dimethoxybenzoic acid N,N-dialkyl amide of the formula (Ilia) . During the process the lithium compound is expediently reacted without isolation, in the reaction mixture where it has been formed, with the 3,4- dimethoxybenzoic acid N,N-dialkyl amide of the general formula (Ilia) . The reaction is carried out at a temperature below 0 ° C , preferably at about -20 °C. The thus- obtained compound of the general formula (IV) can be isolated from the reaction mixture .
According to another embodiment of the process according to the invention the bromo atom in the compound of the general
formula (II) is exchanged for an alkali or magnesium atom, then the thus-obtained alkali or magnesium compound is transformed with a 3 , 4-dimethoxybenzoic acid alkyl ester of the general formula (Illb) into a compound of the general formula (IV) .
When the above reaction has been completed, the compound of the general formula (IV) is preferably isolated and purified by reσrystallization. The isolated ketal of the general formula (IV) is hydrolized with a mineral acid by methods known per se into the corresponding ketone of the general formula (I) .
The hydrolysis is preferably carried out with a mineral acid, particularly with diluted sulfuric acid or with diluted hydrogen chloride. The most preferable is the application of diluted sulfuric acid. The reaction is performed in a two-phase reaction mixture, preferably at a temperature between 20 °C and 40 °C. One of the phases is composed of a water- immiscible organic solvent (preferably an aromatic hydrocarbon, such as benzene, toluene or xylene; or an aliphatic
halogenated hydrocarbon, e.g. dichloro- ethane) , the other is composed of an aqueous acidic solution. In order to expedite the reaction optionally silica gel may be applied in a 2-5-fold amount related to the weight of the compound of the general formula (IV) .
The compound of the general formula (I) can also be produced directly, without isolating the intermediate compound of the general formula (IV) . During this process the compound of the general formula (IV) prepared as specified above is treated in situ with an acid, and only the ketone of the general formula (I) is isolated and purified.
The thus-obtained compound of the formula (I) may optionally be purified by recrystallization from a suitable solvent. For the recrystallization preferably a straight or branched chain aliphatic alcohol may be applied. The purity of the thus-obtained compound of the formula (I) exceeds 98%, and it is highly suitable for transformation into tofisopam.
The advantages of the process according to the invention reside in the application of environment-friendly substances and the high yield of the obtained 3-[2- (3 ,4-dimethoxγbenzoyl) -4,5- dimethoxyphenyl]propan-2-one intermediate of the formula (I) necessary for the production of tofisopam.
Further details of the present invention are to be found in the Examples without limiting our invention to the said Examples-.
Example 1
3-[2- (3 ,4-dimethoxybenzoyl) -4,5-dimethoxy- phenyl]-pentan-2-one ethylene ketal (IV) 17.26 g (0,05 mole) of 3- (2-bromo-4 , 5- dimethoxyphenyl) -pentan-2-one ethylene ketal (II) are dissolved in 173 ml of anhydrous tetrahydrofurane , and the reaction mixture is cooled to -78 °C by the external application of dry-ice. Then 24 ml of a 2 , 5M hexane butyl lithium solution
(0,06 mole) are added within 45 minutes, under stirring. When the addition has been terminated the mixture is stirred for further 2 hours at a temperature of -78 °C . Then 10.46 g (0,05 mole) of 3, 4-dimethoxybenzoic acid N,N-dimethyl amide
(Ilia) are added to the solution, it is allowed to react for 20 minutes and the temperature is raised slowly to room temperature. After 2 hours the mixture is stirred with saturated ammonium chloride solution and extracted with ethyl acetate. The ethyl acetate phase is washed with saturated sodium-chloride solution and dried over magnesium sulfate . The latter substance is then filtered off and the
filtrate is evaporated until it is free of solvent. The thus-obtained crude product is purified by recrystallization. Thus 9.0 g (42%) of the title compound melting at a temperature of 165 to 166 °C are obtained. IR (KBr) : 1638 cm"1.
HNMR (DMSO-d6, TMS , i400) : 7.35 (d, J=l .9 Hz, 1H) , 7.20 (dd, J=1.9, 8.4 Hz, 1H) , 7.08 (s, 1H) , 7.00 (d, J=8.5 Hz, 1H) , 6.75 (s, 1H) , 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, 1H) , 1.76 (m, 1H) , 1.62 ( , 1H) , 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.
Example 2
3-[2- (3 ,4-dimethoxybenzoyl) -4 ,5-dimethoxy- phenyl]-pentan-2-one ethylene ketal (IV)
One proceeds as specified in Example 1, with the difference that the reaction is
carried out at a temperature of -20 °C. Thus 6.9 g (32%) of the title compound melting at 164-166 °C are obtained.
Example 3
3-[2- (3 ,4-dimethoxybenzoyl) -4 ,5-dimethoxy- phenγl]-ρentan-2-one ethylene ketal (IV)
One proceeds as specified in Example 1 , with the di ference that instead of 2.5M butyl lithium solution in hexane 2.5M hexyl lithium solution in hexane is used, and the reaction is carried out at a temperature of -78 °C. Thus 8.6 g (40%) of the title compound are obtained.
Example 4
3-[2- (3 ,4-dimethoxybenzoyl) -4 ,5-dimethoxy- phenyl]-pentan-2-one ethylene ketal (IV)
One proceeds as specified in Example 1 , with the difference that instead of 2.5M butyl lithium solution in hexane 2 , 5M hexyl lithium solution in hexane is used, and the reaction is carried out at a temperature of
20 °C. Thus 6.2 g (29%) of the title compound are obtained.
Example 5
3-[2- (3 , 4-dimethoxybenzoyl) -4 , 5-dimethoxγ- phenγl]-ρentan-2-one ethylene ketal (IV)
One proceeds as specified in Example 1 , with the difference that instead of 3,4- dimethoxybenzoic acid N,N-dimethyl amide (Ilia) 9.8 g (0.05 mole) of 3,4-di- methoxybenzoic acid methyl ester are applied. Thus 6.9 g (32%) of the title compound melting at 164-166 °C are obtained.
Example 6
3-[2- (3 ,4-dimethoxybenzoyl) -4 ,,5-dimethoxy- phenγl]-pentan-2-one (I)
To a mixture of 25.0 g of silica gel, 100 ml of diσhloromethane and 2.5 ml 15% (mass/volume) of sulphuric acid solution 6.46 g (0.015 mole) of 3-[2-(3,4- dimethoxybenzoyl) -4 ,5-dim thoxyρhenγl]-
ρentan-2-one ethylene ketal (IV) are added at room temperature. The mixture thus obtained is stirred for two hours at .room temperature. The silica gel is then filtered off and washed with dichloro- methane. The dichloromethane solution is dried over magnesium sulphate and evaporated. The thus-obtained crude product is recrystallized. Thus 5.4 g (93%) of the title compound are obtained, which melts at 158-159 °C.
Example 7
3-[2- (3 , 4-dimethoxγbenzoyl) -4 , 5-dimethoxy- phenγl]-pentan-2-one (I)
One proceeds as specified in Example 6, with the difference that the compound of the general formula (IV) is not purified, but the crude product obtained according to the process specified in Examples 1 to 5 is subjected to acidic treatment, and only the thus-obtained compound of the formula (I) is purified by recrystallization. Thus 6.2 - 9.6 g of the title compound (32 - 50%
calculated for the compound of the general formula (II) ) are obtained.
Preparation of the starting substances
Example 8
3- (2-bromo-4 , 5-dimethoxyphenyl) -pentan-2- one ethylene ketal (II)
34.3 g (0.11 mole) of 3- (2-bromo-4, 5-dimethoxyphenyl) -pentan-2-one are dissolved in 250 ml of toluene, and 11.2 ml (0,20 mole) of ethylene glycol and 1.5 g of p-toluenesulfonic acid are measured to the solution. The apparatus is then equipped with a condenser, and the reaction mixture is boiled and stirred until the theoretical amount of water has been condensed off. After condensation the toluene solution is washed acid-free with sodium carbonate solution and dried over magnesium sulfate. The solvent is evaporated in vacuo. Thus 38 g of crude product are obtained, which is distilled off at a temperature of 149-152 °C under a pressure of ,12 Pa. Thus 36.2 g (92%) of
chromatographically unified product melting at a temperature of 44 - 45 °C are obtained.
IR (film) : 2962 (CH30) , 591 (C-Br) cm"1.
HNMR (DMSO-d6, TMS, 1400): 7.09 (s, 1H) ,
7.01 (s, 1H) , 3.94-3.77 (m, 4H) , 3.72 (s,
3H) , 3.71 (s, 3H) , 3.27 (dd, -7=3.4, 11.5
Hz, 1H) , 1.92-1.85 (m, 1H) , 1.64-1.56 (m,
1H) , 1.07 (s, 3H) , 0.63 (t, J=7.4 Hz, 3H) ppm.
CNMR (DMSO-d6, TMS, 1400): (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.
Elementary analysis : Calculated:
C 52.19%, H 6#13%, Br 23,14% Measured:
C 52,36%, H 6.12%, Br 23.23%
Claims
1 . A process for the preparation of 3- [2- (3 , 4-dimethoxγ-benzoyl) -4 , 5-dimethoxγ- phenyl] -pentan-2-one of the formula (I)
starting from a compound of the general formula (II)
(wherein R1 and R2 each stands for a C^ alkyl group, or Rα and R2 together form a C2_6 alkylene group) , which comprises a) exchanging the bromo atom in the compound of the general formula (II) for an alkali or magnesium atom; reacting the thus-obtained alkali or magnesium compound with an approximately equimolar amount of an acid amide of the general formula (Ilia)
Hg 
(wherein R3 and R4 each denotes a Cι_4 alkyl group) , and subjecting the thus- obtained compound of the general formula (IV)
(wherein R1 and R2 are as stated above) to hydrolysis; or b) exchanging the bromo atom in the compound of the general formula (II) for an alkali or magnesium atom; reacting the thus-obtained alkali or magnesium compound with an approximately equimolar amount of an ester of the general formula (Illb)
Illb
(wherein R5 represents a C^^ alkyl group) ; and subjecting the thus- obtained compound of the general formula (IV) to hydrolysis.
2. A process as claimed in claim 1, which comprises using as starting substance a compound of the general formula (II) , wherein R1 and R2 each stands for a methyl or ethyl group, or R1 and R2 together form an ethylene group .
3. A process as claimed in claim 1 or 2 , which comprises using a compound of the general formula (Ilia) , wherein R3 and R4 each represents a methyl group .
4. A process as claimed in claim 1 or 2 , which comprises using compounds of the general formula (Illb) , wherein Rs stands for a methyl group .
5. A process as claimed in any of claims 1 to 4, which comprises exchanging the bromo atom in the compounds of the general formula (II) for a lithium atom.
6. A process as claimed in claim 5, which comprises carrying out the reaction with an alkyl lithium, preferably n-butyl lithium or n-hexyl lithium.
7. A process as claimed in claim 5 or 6, which comprises carrying out the reaction at a temperature between -78 °C and -10 °C .
8. A process as claimed in claim 1, which comprises using the compound of the general formula (Ilia) in an amount of 1.0 to 1.2 molar equivalent.
9. A process as claimed in any of claims 1 and 5 to 8 , which comprises reacting the alkali or magnesium compound without isolation with the compound of the general formula (Ilia) .
10. A process as claimed in claim 9, which comprises carrying out the reaction at a temperature below 0 °C .
11. A process as claimed in claim 1, which comprises using the compound of the general formula (Illb) in an amount of 1.0 to 1.2 molar equivalent.
12. A process as claimed in claim 1 or 11, which comprises reacting the alkali or magnesium compound without isolation with the compound of the general formula (Illb) .
13. A process as claimed in claim 12, which comprises carrying out the reaction at a temperature below 0 °C .
14. A process as claimed in any of claims 1 to 13 , which comprises carrying out the hydrolysis of the compound of general formula (IV) with the aid of a mineral acid.
15. A process as claimed in claim 14, which comprises using hydrogen chloride or sulphuric acid.
16. A process as claimed in any of claims 1, 14 or 15, which comprises carrying out the hydrolysis at a temperature between 20 °C and 40 °C.
17. A process as claimed in any of claims 1 to 16, which comprises carrying out the hydrolysis of the compound of general formula (IV) in situ in the reaction mixture where it has been formed.
28
(wherein R1 and R2 each represents Cx_4 alkyl, or R1 and R2 together form a C2_s alkylene group) , which comprises exchanging the bromo atom in the compound of the general formula (II) for an alkali or magnesium atom; reacting the thus-obtained alkali or magnesium compound with an approximately equimolar amount of either an acid amide of the general formula (Ilia)
(wherein R3 and R4 each stands for a Cι_ alkyl group) , or with an ester of the general formula (Illb)
(wherein R5 represents a C1_4 alkyl) , 29
and subjecting the thus-obtained compound of the general formula (IV)
(wherein R1 and R2 are as stated above), to hydrolysis .
The compound of the formula (I) is a pharmaceutical intermediate, which can be used for the preparation of an anxiolytic, namely tofisopam (INN) .
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|---|---|---|---|
| AU2003292449A AU2003292449A1 (en) | 2002-12-16 | 2003-12-16 | Process for the preparation of 3-(2-(3,4-dimethoxybenzoyl)-4,5- dimethoxyphenyl) -pentan-2-one |
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|---|---|---|---|
| HUP0204342 | 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 |
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| PCT/HU2003/000104 WO2004054952A1 (en) | 2002-12-16 | 2003-12-16 | Process for the preparation of 3-[2-(3,4-dimethoxybenzoyl)-4,5- dimethoxyphenyl] -pentan-2-one |
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| AU (2) | AU2002361068A1 (en) |
| BG (1) | BG109230A (en) |
| CZ (1) | CZ2005388A3 (en) |
| EA (1) | EA007788B1 (en) |
| HU (1) | HU227044B1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104098482A (en) * | 2013-04-12 | 2014-10-15 | 江苏英力科技发展有限公司 | Preparation method of 3,4-dimethoxy-N,N-dimethylbenzamide |
| CN104262128A (en) * | 2014-09-04 | 2015-01-07 | 山东金城医药化工股份有限公司 | Preparation method of tofisopam intermediate |
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| KR100714181B1 (en) * | 2005-07-04 | 2007-05-04 | 주식회사 자동기 | Fuel supply system for snow removing apparatus |
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|---|---|---|---|---|
| HU194529B (en) * | 1984-07-20 | 1988-02-29 | Gyogyszerkutato Intezet | New process for producing 2-aroyl-phenylacetone-derivatives |
| WO2003050092A2 (en) * | 2001-12-13 | 2003-06-19 | EGIS Gyógyszergyár Rt. | Process for the preparation of tofisopam and new intermediates |
-
2002
- 2002-12-16 HU HU0204342A patent/HU227044B1/en not_active IP Right Cessation
- 2002-12-31 WO PCT/HU2002/000178 patent/WO2004054951A1/en active Application Filing
- 2002-12-31 AU AU2002361068A patent/AU2002361068A1/en not_active Abandoned
- 2002-12-31 UA UAA200507059A patent/UA78634C2/en unknown
- 2002-12-31 SK SK70-2005A patent/SK702005A3/en unknown
- 2002-12-31 JP JP2004559931A patent/JP4437093B2/en not_active Expired - Fee Related
- 2002-12-31 EP EP02791921A patent/EP1575890A1/en not_active Withdrawn
- 2002-12-31 CZ CZ2005388A patent/CZ2005388A3/en unknown
- 2002-12-31 KR KR1020057011012A patent/KR100936306B1/en not_active IP Right Cessation
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|---|---|---|---|---|
| HU194529B (en) * | 1984-07-20 | 1988-02-29 | Gyogyszerkutato Intezet | New process for producing 2-aroyl-phenylacetone-derivatives |
| WO2003050092A2 (en) * | 2001-12-13 | 2003-06-19 | EGIS Gyógyszergyár Rt. | Process for the preparation of tofisopam and new intermediates |
Non-Patent Citations (1)
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| DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; LANG, TIBOR ET AL: "2-Aroylphenylacetone derivatives", XP002242492, retrieved from STN Database accession no. 105:152712 CA * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104098482A (en) * | 2013-04-12 | 2014-10-15 | 江苏英力科技发展有限公司 | Preparation method of 3,4-dimethoxy-N,N-dimethylbenzamide |
| CN104098482B (en) * | 2013-04-12 | 2016-04-20 | 江苏英力科技发展有限公司 | A kind of 3,4-dimethoxy-N, the preparation method of N-dimethyl benzamide |
| CN104262128A (en) * | 2014-09-04 | 2015-01-07 | 山东金城医药化工股份有限公司 | Preparation method of tofisopam intermediate |
| CN104262128B (en) * | 2014-09-04 | 2016-04-13 | 山东金城医药化工股份有限公司 | The preparation method of Tofisopam intermediate |
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| BG109230A (en) | 2006-04-28 |
| PL376530A1 (en) | 2006-01-09 |
| SK702005A3 (en) | 2005-09-08 |
| UA78634C2 (en) | 2007-04-10 |
| EP1575890A1 (en) | 2005-09-21 |
| HUP0204342A2 (en) | 2004-07-28 |
| HU0204342D0 (en) | 2003-02-28 |
| CZ2005388A3 (en) | 2005-09-14 |
| EA200500966A1 (en) | 2005-12-29 |
| AU2002361068A1 (en) | 2004-07-09 |
| WO2004054951A1 (en) | 2004-07-01 |
| KR100936306B1 (en) | 2010-01-12 |
| AU2003292449A1 (en) | 2004-07-09 |
| HU227044B1 (en) | 2010-05-28 |
| JP2006509814A (en) | 2006-03-23 |
| HUP0204342A3 (en) | 2004-11-29 |
| KR20050085686A (en) | 2005-08-29 |
| JP4437093B2 (en) | 2010-03-24 |
| EA007788B1 (en) | 2007-02-27 |
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