SK702005A3 - Process for the preparation of 3-[2-(3,4-dimethoxy-benzoyl)-4,5- dimethoxy-phenyl]-pentan-2-one - Google Patents
Process for the preparation of 3-[2-(3,4-dimethoxy-benzoyl)-4,5- dimethoxy-phenyl]-pentan-2-one Download PDFInfo
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- SK702005A3 SK702005A3 SK70-2005A SK702005A SK702005A3 SK 702005 A3 SK702005 A3 SK 702005A3 SK 702005 A SK702005 A SK 702005A SK 702005 A3 SK702005 A3 SK 702005A3
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- alkali metal
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- 238000000034 method Methods 0.000 title claims abstract description 37
- 230000008569 process Effects 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 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 claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 57
- 230000007062 hydrolysis Effects 0.000 claims abstract description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 229910052783 alkali metal Inorganic materials 0.000 claims description 16
- 150000001340 alkali metals Chemical class 0.000 claims description 16
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 10
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 10
- 150000002681 magnesium compounds Chemical class 0.000 claims description 9
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 9
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical group [Mg] FYYHWMGAXLPEAU-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
- 229910052749 magnesium Inorganic materials 0.000 claims description 8
- 229910052744 lithium Inorganic materials 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 150000001408 amides Chemical class 0.000 claims description 6
- 239000011541 reaction mixture Substances 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 230000003301 hydrolyzing effect Effects 0.000 claims description 4
- 238000002955 isolation Methods 0.000 claims description 4
- 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
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 3
- 239000011707 mineral Substances 0.000 claims description 3
- 239000007858 starting material Substances 0.000 claims description 3
- 239000005977 Ethylene Substances 0.000 claims description 2
- 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
- 150000002641 lithium Chemical group 0.000 claims 1
- 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 abstract description 5
- 229960002501 tofisopam Drugs 0.000 abstract description 4
- 239000002249 anxiolytic agent Substances 0.000 abstract 1
- 230000000949 anxiolytic effect Effects 0.000 abstract 1
- 239000012450 pharmaceutical intermediate Substances 0.000 abstract 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 17
- -1 3,4-dimethoxybenzoyl Chemical group 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 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
- 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
- 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 5
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- DAUAQNGYDSHRET-UHFFFAOYSA-N 3,4-dimethoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1OC DAUAQNGYDSHRET-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
- GPVDHNVGGIAOQT-UHFFFAOYSA-N Veratric acid Natural products COC1=CC=C(C(O)=O)C(OC)=C1 GPVDHNVGGIAOQT-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- CETVQRFGPOGIQJ-UHFFFAOYSA-N lithium;hexane Chemical compound [Li+].CCCCC[CH2-] CETVQRFGPOGIQJ-UHFFFAOYSA-N 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-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
- 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
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000002051 biphasic effect Effects 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 150000001805 chlorine compounds Chemical class 0.000 description 2
- 150000001844 chromium Chemical class 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 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
- VYRHYSCIJYOTJB-UHFFFAOYSA-N 1-(3,4-dimethoxyphenyl)-4-ethyl-6,7-dimethoxy-3-methyl-3,4-dihydro-1h-isochromene Chemical compound C12=CC(OC)=C(OC)C=C2C(CC)C(C)OC1C1=CC=C(OC)C(OC)=C1 VYRHYSCIJYOTJB-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
- 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
- 239000005711 Benzoic acid Substances 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
- 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
- 150000001339 alkali metal compounds Chemical class 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- 229910000423 chromium oxide Inorganic materials 0.000 description 1
- 229940117975 chromium trioxide Drugs 0.000 description 1
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 230000007613 environmental effect Effects 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
- 150000002642 lithium compounds Chemical class 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 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
- 230000003647 oxidation Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000047 product Substances 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
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 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
- 125000001424 substituent group Chemical group 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Oblasť technikyTechnical field
Predložený vynález sa týka nového spôsobu prípravy 3-(2-(3,4-dimetoxybenzoyl)-4,5The present invention relates to a novel process for the preparation of 3- (2- (3,4-dimethoxybenzoyl) -4,5)
-dimetoxyfenyl]-pentán-2-ónu vzorca-dimethoxyphenyl] -pentan-2-one of formula
Doterajší stav technikyBACKGROUND OF THE INVENTION
3-(2-(3,4-dimetoxybenzoyl)-4,5-dimetoxyfenyl]-pentán-2-ón vzorca I je medziprodukt použiteľný pri príprave anxiolyticky účinnej zložky l-(3,4-dimetoxyfenyl)-4-metyl-5-etyl-7,8-dimetoxy-5//-2,3-benzodiazepínu, ktorý má medzinárodný generický názov (INN) tofísopam.3- (2- (3,4-dimethoxybenzoyl) -4,5-dimethoxyphenyl) -pentan-2-one of formula I is an intermediate useful in the preparation of the anxiolytically active ingredient 1- (3,4-dimethoxyphenyl) -4-methyl-5 -ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine having the international generic name (INN) tofisopam.
Podľa patentu HU 158,091 sa zlúčenina vzorca I pripraví z diizohomoeugenolu oxidáciou oxidom chrómovým iba v nízkym výťažkoch.According to patent HU 158,091, the compound of formula I is prepared from diisohomoeugenol by oxidation with chromium oxide only in low yields.
Podľa patentu HU 194,529 sa l-(3,4-dimetoxyfenyl)-3-metyl-4-etyl-6,7-dimetoxyizochróman oxiduje oxidom chrómovým na zodpovedajúcu benzopyríliovú soľ, ktorá sa potom konvertuje na požadovanú zlúčeninu vzorca I vodno-alkalickým rozkladom.According to patent HU 194,529, 1- (3,4-dimethoxyphenyl) -3-methyl-4-ethyl-6,7-dimethoxyisochroman is oxidized with chromium trioxide to the corresponding benzopyrrile salt, which is then converted to the desired compound of formula I by aqueous-alkaline decomposition.
Oba známe postupy majú všeobecné nevýhody spočívajúce v tom, že pri oxidačnej reakcii vznikajú vysoko toxické chrómové soli, ktoré sú škodlivé. Skladovanie, neutralizácia a recyklácia uvedených chrómových solí predstavuje vážny problém pre ochranu prostredia.Both known processes have the general disadvantage that the oxidation reaction produces highly toxic chromium salts which are harmful. The storage, neutralization and recycling of these chromium salts is a serious environmental problem.
Zámerom patentu HU 187,161 je eliminovať hore uvedené nevýhody známych spôsobov. Podľa patentu 187.161 sa pripraví zlúčenina vzorca I postupom nevyužívajúcim chróm, a to reakciou 3-(3.4-dimetoxyfenyl)-pentán-2-ónu s 3,4-dimetoxybenzovlchloridom v prítomnosti chloridu hlinitého a rozkladom vzniknutej benzopyríliovej soli v alkalickom prostredí.The purpose of patent HU 187,161 is to eliminate the above disadvantages of the known methods. According to patent 187.161, a compound of formula I is prepared by a chromium-free process by reacting 3- (3,4-dimethoxyphenyl) -pentan-2-one with 3,4-dimethoxybenzovl chloride in the presence of aluminum chloride and decomposing the benzopyrilium salt formed in an alkaline medium.
Nevýhoda hore uvedeného procesu spočíva v tom, že 3,4-dimetoxybenzoylchlorid používaný ako východisková látka je veľmi citlivý voči rozkladu a Friedel-Craftsov produkt vznikajúci pri reakcii je veľmi kontaminovaný, manipulácia s ním je veľmi ťažká a jeho purifikácia predstavuje závažné problémy.A disadvantage of the above process is that the 3,4-dimethoxybenzoyl chloride used as the starting material is very sensitive to decomposition and the Friedel-Crafts reaction product is very contaminated, difficult to handle and difficult to purify.
Zámerom predloženého vynálezu je poskytnúť spôsob prípravy 3-[2-(3,4-dimetoxybenzoyl)-4,5-dimetoxyfenyl]-pentán-2-ónu vzorca I, v ktorom sa nepoužíva chróm, eliminujú sa hore uvedené nevýhody známych postupov, a ktorý poskytuje požadovanú zlúčeninu vzorca I s lepšími výťažkami a vyššou čistotou než známe spôsoby.It is an object of the present invention to provide a process for the preparation of 3- [2- (3,4-dimethoxybenzoyl) -4,5-dimethoxyphenyl] -pentan-2-one of formula I in which chromium is not used, eliminates the above disadvantages of known processes, and which yields the desired compound of formula I with better yields and higher purity than known methods.
Hore uvedený zámer je riešený spôsobom podľa predloženého vynálezu.The above object is solved by the method of the present invention.
Podstata vynálezuSUMMARY OF THE INVENTION
Predložený vynález poskytuje spôsob prípravy 3-[2-(3,4-dimetoxybenzoyl)-4,5-dimetoxyfenyl]-pentán-2-ónu vzorcaThe present invention provides a process for the preparation of 3- [2- (3,4-dimethoxybenzoyl) -4,5-dimethoxyphenyl] -pentan-2-one of the formula
zo zlúčeniny všeobecného vzorcafrom a compound of formula
II kde každý zo substituentov R1 a R2 znamená Ci-4-alkyl alebo spoločne vytvárajúWherein each of R 1 and R 2 represents C 1-4 -alkyl or together forms
C2-ó-alkylén. ktorý zahŕňaC 2-O-alkylene. which includes
JJ
a) nahradenie atómu brómu v zlúčenine všeobecného vzorca II atómom alkalického kovu alebo horčíka; reakciu týmto spôsobom pripravenej zlúčeniny obsahujúcej alkalický kov alebo horčík s približne ekvimolárnym množstvom amidu kyseliny všeobecného vzorca(a) replacing the bromine atom in the compound of formula II with an alkali metal or magnesium atom; reacting an alkali metal or magnesium compound prepared in this manner with an approximately equimolar amount of the acid amide of the formula
llla kde substituenty R3 a R4 sú Cj-4-alkyl, a hydrolýzu týmto spôsobom pripravenej zlúčeniny všeobecného vzorcaIIa wherein R 3 and R 4 are C 1-4 -alkyl, and hydrolysis of the compound of formula I thus prepared
kde substituenty R1 a R2 majú hore uvedený význam; alebowherein the substituents R 1 and R 2 are as defined above; or
b) nahradenie atómu brómu v zlúčenine všeobecného vzorca II atómom alkalického kovu alebo atómom horčíka; reakciu týmto spôsobom pripravenej zlúčeniny obsahujúcej alkalický kov alebo horčík s približne ekvimolárnym množstvom esteru všeobecného vzorcab) replacing the bromine atom in the compound of formula II with an alkali metal or magnesium atom; reacting an alkali metal or magnesium compound prepared in this manner with an approximately equimolar amount of an ester of formula
lllb kde substituent R' je Ciu-alkyl. a hydrolýzu týmto spôsobom pripravenej zlúčeniny všeobecného vzorca IV.IIIb wherein R 'is C 1-6 -alkyl. and hydrolyzing the compound of formula IV thus prepared.
Detailný opis vynálezuDETAILED DESCRIPTION OF THE INVENTION
Termíny používané v predloženom vynáleze majú nasledujúci význam:The terms used in the present invention have the following meanings:
Termín Ch^alkyl sa vzťahuje na alkylové skupiny s lineárnym alebo rozvetveným reťazcom s 1 - 4 atómami uhlíka (napr. metyl, etyl, rc-propyl, izopropyl. π-butyl. atď.).The term C 1-4 alkyl refers to straight or branched chain alkyl groups of 1-4 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, π-butyl, etc.).
Termín C2-6alkylén sa vzťahuje na alkylénové skupiny s lineárnym alebo rozvetveným reťazcom s 2 - 6 atómami uhlíka (napr. etylén, trimetylén, atď.).The term C 2-6 alkylene refers to straight or branched chain alkylene groups having 2 to 6 carbon atoms (e.g., ethylene, trimethylene, etc.).
Syntéza a charakterizácia 3-(2-bróm-4,5-dimetoxyfenyl)-pentán-2-ón-ketálov všeobecného vzorca II je publikovaná v súbežne prejednávaných maďarských patentových prihláškach č. 01/05326 a 01/05327 podaných 13. decembra 2001.The synthesis and characterization of 3- (2-bromo-4,5-dimethoxyphenyl) -pentan-2-one-ketals of formula II is disclosed in co-pending Hungarian patent applications no. 01/05326 and 01/05327, filed December 13, 2001.
Podľa všeobecne používaného spôsobu sú diarylketóny pripravené z aryl-kov (arylmetal) zlúčenín reakciou danej aryl-kov zlúčeniny s aromatickým nitrilom a hydrolýzou vzniknutého imínu. Avšak uvedený všeobecný spôsob nie je aplikovateľný na prípravu 3-[2-(3.4-dimetoxybenzoyl)-4,5-dimetoxyfenyl]-pentán-2-ónu, pretože na základe doterajšieho stavu techniky je možné očakávať, že miesto 3-[2-(3,4-dimetoxybenzoyl)-4,5-dimetoxyfenyl]-pentán-2-ónu všeobecného vzorca I bude skôr vznikať anizochinolínový derivát \Khim, Geterosikl. Soedin. (1988).(1), 134-5],According to the generally used method, diaryl ketones are prepared from aryl-metal (arylmetal) compounds by reacting the aryl-metal compound with an aromatic nitrile and hydrolyzing the resulting imine. However, the above general process is not applicable to the preparation of 3- [2- (3,4-dimethoxybenzoyl) -4,5-dimethoxyphenyl] -pentan-2-one, as it is expected from the prior art that instead of 3- [2- The (3,4-dimethoxybenzoyl) -4,5-dimethoxyphenyl] -pentan-2-one of formula (I) will produce an anisoquinoline derivative (Khim, Geterosikl). Soedin. (1988) (1), 134-5.
V reakcii aryl-kov zlúčenín so všeobecne používanými Weinrebovými amidmi (Nmetyl-A-metoxy-amid) je možné očakávať vznik zlúčeniny všeobecného vzorca IV. Avšak použitie uvedeného reaktantu robí syntézu veľmi drahou a neekonomickou [Bioorganic a Medicinal Chemistry Letters (1993), 1991-2],In the reaction of the aryl-metal compounds with the commonly used Weinreb amides (N-methyl-A-methoxy-amide), the formation of the compound of formula IV can be expected. However, the use of said reactant makes the synthesis very expensive and uneconomical [Bioorganic and Medicinal Chemistry Letters (1993), 1991-2],
Syntéza zlúčenín všeobecného vzorca IV reakciou aryl-kov zlúčenín s chloridmi kyselín nie je možná, pretože sa chloridy kyselín buď ľahko rozkladajú alebo sú všeobecne kontaminované anorganickými kyselinami, ktoré značne znižujú výťažok a zvyšujú mieru vedľajších reakcií.Synthesis of compounds of formula IV by reaction of aryl-metal compounds with acid chlorides is not possible because the acid chlorides are either readily decomposed or are generally contaminated with inorganic acids which greatly reduce yield and increase the rate of side reactions.
Prekvapujúco sa zistilo, že zlúčeniny všeobecného vzorca IV môžu byť ľahko pripravené pomocou amidov všeobecného vzorca Hla a esterov všeobecného vzorca Illb. pričom uvedené zlúčeniny všeobecných vzorcov Hla a Illb neboli v organickej chémii kovov na prípravu karbonylovej skupiny až dosiaľ všeobecne používané.It has surprisingly been found that compounds of formula IV can be readily prepared using amides of formula IIIa and esters of formula IIIb. wherein said compounds of formulas IIIa and IIIb have not been widely used in organic metal chemistry to prepare a carbonyl group to date.
Predložený vynález je založený na poznatku, že požadovaný 3-[2-(3.4-dimetoxybenzoyl)-4,5-dimetoxyfenyl]-pentán-2-ón všeobecného vzorca 1 môže byť ľahko pripravený reakciou zlúčeniny obsahujúcej horčík alebo alkalický kov, pripravenej z 3-(2-bróm-4.5-dimetoxyfenyl)-pentán-2-ón-ketálu všeobecného vzorca II, so zlúčeninou všeobecného vzorca Hla alebo Hĺb, a potom podrobením týmto spôsobom pripraveného 3-[2-(3,4-dimetoxybenzoyl)-4.5-dimetoxyfenyl]-pentán-2-ón-ketálu všeobecného vzorca IV hydrolýze.The present invention is based on the knowledge that the desired 3- [2- (3,4-dimethoxybenzoyl) -4,5-dimethoxyphenyl] -pentan-2-one of formula 1 can be readily prepared by reacting a magnesium or alkali metal compound prepared from 3 - (2-bromo-4,5-dimethoxyphenyl) -pentan-2-one ketal of formula II, with a compound of formula IIIa or depth, and then subjecting 3- [2- (3,4-dimethoxybenzoyl) -4.5 so prepared -dimethoxyphenyl] -pentan-2-one ketal of formula IV by hydrolysis.
Podľa variantu a) spôsobu prípravy podľa predloženého vynálezu sa atóm brómu v zlúčenine všeobecného vzorca II nahradí atómom alkalického kovu alebo atómom horčíka, potom sa týmto spôsobom pripravená zlúčenina obsahujúca alkalický kov alebo horčík nechá reagovať s AYV-dialkyl-amidom 3,4-dimetoxy-benzoovej kyseliny všeobecného vzorca Hla; uvedená zlúčenina môže byť pripravená z 3,4-dimetoxy-benzoovej kyseliny známym spôsobom.According to variant a) of the process according to the invention, the bromine atom in the compound of the formula II is replaced by an alkali metal or magnesium atom, then the alkali metal or magnesium compound prepared in this way is reacted with 3,4-dimethoxy- N, N-dialkyl amide. a benzoic acid of the formula IIIa; said compound may be prepared from 3,4-dimethoxybenzoic acid in a known manner.
Atóm brómu v zlúčenine všeobecného vzorca II sa nahradí atómom alkalického kovu (napr. sodík, draslík alebo lítium) alebo atómom horčíka Grignardovou reakciou. Je možné tiež vykonať výmenu brómu za lítium reakciou zlúčeniny všeobecného vzorca II s alkyllítiom (výhodne z?-butyllítiom alebo n-hexyllítiom). Alkyllítiová zlúčenina sa výhodne používa v roztoku pripravenom s alkánom, výhodne n-hexánom. Nahradenie atómu brómu lítiom je možné vykonať pri teplote medzi -78 °C a -10 °C, výhodne pri teplote asi -10 °C v bezvodom tetrahydrofuráne. Pripravená zlúčenina obsahujúca alkalický kov alebo horčík, výhodne zlúčenina obsahujúca lítium, sa potom nechá reagovať s približne ekvimolámym množstvom (výhodne 1,0 - 1,2 molárne množstvo) amidu všeobecného vzorca Illa. Je možné tiež výhodne vykonať reakciu zlúčeniny obsahujúcej lítium so zlúčeninou všeobecného vzorca Hla bez izolácie v reakčnej zmesi získanej počas prípravy uvedenej zlúčeniny obsahujúcej lítium. Reakciu je možné vykonať pri teplote pod 0 °C, výhodne pri teplote asi -20 °C. Týmto spôsobom pripravenú zlúčeninu všeobecného vzorca IV je možné izolovať z reakčnej zmesi.The bromine atom in the compound of formula II is replaced by an alkali metal atom (e.g., sodium, potassium or lithium) or a magnesium atom by a Grignard reaction. It is also possible to carry out the exchange of bromine for lithium by reacting a compound of formula II with an alkyl lithium (preferably from n-butyllithium or n-hexyllithium). The alkyl lithium compound is preferably used in a solution prepared with an alkane, preferably n-hexane. Replacement of the bromine atom with lithium can be carried out at a temperature between -78 ° C and -10 ° C, preferably at a temperature of about -10 ° C in anhydrous tetrahydrofuran. The prepared alkali metal or magnesium compound, preferably the lithium compound, is then reacted with an approximately equimolar amount (preferably 1.0-1.2 molar) of the amide of formula IIIa. It is also possible to advantageously carry out the reaction of a lithium-containing compound with a compound of the formula IIIa without isolation in the reaction mixture obtained during the preparation of said lithium-containing compound. The reaction may be carried out at a temperature below 0 ° C, preferably at about -20 ° C. The compound of formula (IV) thus prepared can be isolated from the reaction mixture.
Podľa variantu b) spôsobu prípravy podľa predloženého vynálezu sa atóm brómu v zlúčenine všeobecného vzorca II nahradí atómom alkalického kovu alebo horčíka, potom sa týmto spôsobom pripravená zlúčenina obsahujúca alkalický kov alebo horčík nechá reagovať s alkyl-3.4-dimetoxybenzoátom všeobecného vzorca Illb. čím sa získa zlúčenina všeobecného vzorca IV.According to process variant b) of the process according to the invention, the bromine atom in the compound of formula II is replaced by an alkali metal or magnesium atom, then the alkali metal or magnesium compound prepared in this way is reacted with an alkyl 3,4-dimethoxybenzoate IIIb. to give a compound of formula IV.
Zlúčenina všeobecného vzorca IV získaná pri reakcii podľa variantu a) alebo b) môže byť prípadne izolovaná a purifikovaná rekryštalizáciou. Izolovaný ketál všeobecného vzorca IV sa hydrolyzuje na zodpovedajúci ketón všeobecného vzorca I minerálnou kyselinou spôsobom všeobecne známym.The compound of formula IV obtained in the reaction according to variant a) or b) may optionally be isolated and purified by recrystallization. The isolated ketal of formula (IV) is hydrolyzed to the corresponding ketone of formula (I) by a mineral acid in a manner known per se.
Hydrolýza ketálu všeobecného vzorca IV môže byť vykonaná minerálnou kyselinou, predovšetkým zriedenou kyselinou sírovou alebo zriedenou kyselinou chlorovodíkovou, najvýhodnejšie zriedenou kyselinou sírovou. Reakciu je možné vykonať v dvojfázovej reakčnej zmesi, výhodne pri teplote 20 - 40 °C. Jedna fáza dvojfázového systému pozostáva z organického rozpúšťadla nemiešateľného s vodou (výhodne aromatické uhľovodíky, napr. benzén, toluén alebo xylén; alebo alifatické halogénované uhľovodíky, napr. dichlórmetán) a ďalšia fáza pozostáva z vodného kyslého roztoku. Reakciu je možné podporiť pridaním kieselgelu v dvoj až päťnásobnom množstve vzhľadom na zlúčeninu všeobecného vzorca IV.Hydrolysis of the ketal of formula IV can be carried out with a mineral acid, in particular dilute sulfuric acid or dilute hydrochloric acid, most preferably dilute sulfuric acid. The reaction may be carried out in a biphasic reaction mixture, preferably at a temperature of 20-40 ° C. One phase of the biphasic system consists of a water-immiscible organic solvent (preferably aromatic hydrocarbons, e.g. benzene, toluene or xylene; or aliphatic halogenated hydrocarbons, e.g. dichloromethane) and the other phase consists of an aqueous acidic solution. The reaction may be promoted by the addition of kieselgel in two to five times the amount of the compound of formula IV.
Zlúčenina všeobecného vzorca I môže byť tiež pripravená priamo, tzn. bez izolácie medziproduktu všeobecného vzorca IV. Túto reakciu je možné vykonať podrobením in situ pripravenej zlúčeniny všeobecného vzorca IV reakcii s kyselinou. V tomto prípade sa izoluje a purifikuje iba ketón všeobecného vzorca I.The compound of formula (I) may also be prepared directly, i. without isolation of the intermediate of formula IV. This reaction can be carried out by subjecting an in situ prepared compound of formula IV to an acid. In this case, only the ketone of formula I is isolated and purified.
Týmto spôsobom pripravená zlúčenina všeobecného vzorca I môže byť, pokiaľ je to potrebné, purifikovaná rekryštalizáciou z vhodného rozpúšťadla. Ako rekryštalizačné rozpúšťadlo môžu byť výhodne použité alifatické alkoholy s lineárnym alebo rozvetveným C i ^reťazcom. Týmto spôsobom pripravená zlúčenina všeobecného vzorca I má čistotu vyššiu než 98 % a výborne sa hodí na prípravu farmaceutický aktívneho konečného produktu, tofisopamu.The compound of formula (I) thus prepared can, if necessary, be purified by recrystallization from a suitable solvent. As a recrystallization solvent, linear or branched C 1-6 chain aliphatic alcohols may advantageously be used. The compound of formula I thus prepared has a purity of more than 98% and is well suited for the preparation of a pharmaceutically active end product, tofisopam.
Výhoda spôsobu podľa predloženého vynálezu spočíva v tom, že uľahčuje prípravu medziproduktu 3-[2-(3,4-dimetoxybenzoyl)-4,5-dimetoxyfenyl]-pentán-2-ónu všeobecného vzorca I použiteľného na výrobu tofisopamu s vysokými výťažkami, pričom sa používajú zlúčeniny prijateľné pre životné prostredie.An advantage of the process of the present invention is that it facilitates the preparation of intermediate 3- [2- (3,4-dimethoxybenzoyl) -4,5-dimethoxyphenyl] -pentan-2-one of formula I useful for the production of tofisopam in high yields, wherein: environmentally acceptable compounds are used.
Ďalšie detaily predloženého vynálezu je možné nájsť v nasledujúcich príkladoch, ktoré nemajú rozsah ochrany nijako limitovať.Further details of the present invention can be found in the following examples, which are not intended to limit the scope of protection in any way.
Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION
Príklad 1Example 1
3-[2-(3,4-dimetoxybenzoyl)-4.5-dimetoxyfenyl]-pentán-2-ón-etylén-ketál (IV)3- [2- (3,4-dimethoxybenzoyl) -4,5-dimethoxyphenyl] pentan-2-one ethylene ketal (IV)
17,26 g (0.05 mol) z 3-(2-bróm-4,5-dimetoxyfenyl)-pentán-2-ón-etylén-ketálu (II) sa rozpustilo v 173 ml bezvodého tetrahydrofuránu, potom bol roztok ochladený na teplotu -78 °C pomocou suchého ľadu. Za miešania bol počas 45 minút pridaný 2,5 M roztok butyllítia (0,06 mol) v 24 ml hexánu. Po pridaní bola zmes miešaná ďalšie 2 hodiny pri teplote -78 °C, potom bolo pridané 10,46 g (0,05 mol) yV,?V-dimetylamid 3,4-dimetoxybenzoovej kyseliny (Illa). Po 20 minútach reakcie bola teplota pomaly zvýšená na izbovú. Po 2 hodinovej reakcii bola zmes zmiešaná s nasýteným roztokom chloridu amónneho a extrahovaná etylacetátom. Etylacetátová fáza bola premývaná nasýteným roztokom chloridu sodného a sušená nad síranom horčenatým, filtrovaná a filtrát odparený. Surový produkt bol purifikovaný rekryštalizáciou. Týmto spôsobom sa pripravilo 9,0 g požadovanej zlúčeniny.17.26 g (0.05 mol) of 3- (2-bromo-4,5-dimethoxyphenyl) -pentan-2-one-ethylene-ketal (II) was dissolved in 173 ml of anhydrous tetrahydrofuran, then the solution was cooled to - 78 ° C using dry ice. With stirring, a 2.5 M solution of butyllithium (0.06 mol) in 24 ml of hexane was added over 45 minutes. After addition, the mixture was stirred for a further 2 hours at -78 ° C, then 10.46 g (0.05 mol) of N, N -dimethylamide of 3,4-dimethoxybenzoic acid (IIIa) was added. After 20 minutes of reaction, the temperature was slowly raised to room temperature. After 2 hours of reaction, the mixture was treated with saturated ammonium chloride solution and extracted with ethyl acetate. The ethyl acetate phase was washed with saturated sodium chloride solution and dried over magnesium sulfate, filtered and the filtrate evaporated. The crude product was purified by recrystallization. 9.0 g of the title compound are obtained.
Výťažok 42 %, Teplota topenia: 165 - 166 °C.Yield 42%, mp: 165-166 ° C.
IR(KBr):l 638 cm’1.IR (KBr): 1638 cm -1 .
lH NMR (DMSO-d6, TMS. Í400): 7,35 (d,J=l,9 Hz. 1H), 7,20 (dd,J=l,9, 8,4 Hz, 1H), 7,08 (s.lH), 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 (m,lH), 1,00 (s, 3H), 0.56 (t, J=7,4 Hz, 3H) ppm. 1 H NMR (DMSO-d 6 , TMS, 400400): 7.35 (d, J = 1.9 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 (m, 1H), 1.00 (s, 3H) 0.56 (t, J = 7.4Hz, 3H) ppm.
I3C NMR (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. 13 C NMR (DMSO-d 6 , 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.
Príklad 2Example 2
3-[2-(3,4-dimetoxybenzoyl)-4.5-dimetoxyfenyl]-pentán-2-ón-etylén-ketál (IV)3- [2- (3,4-dimethoxybenzoyl) -4,5-dimethoxyphenyl] pentan-2-one ethylene ketal (IV)
Požadovaná látka bola pripravená podľa príkladu 1 s výnimkou toho, že reakcia bola vykonávaná pri teplote -20 °C. Týmto spôsobom sa pripravilo 6.9 g požadovanej zlúčeniny. Výťažok 32 %. Teplota topenia: 164 - 166 °C.The title compound was prepared according to Example 1 except that the reaction was carried out at -20 ° C. 6.9 g of the title compound are obtained. Yield 32%. Melting point: 164-166 ° C.
Príklad 3Example 3
3-[2-(3,4-dimetoxybenzoyl)-4,5-dimetoxyľenyl]-pentán-2-ón-etylén-ketál (IV)3- [2- (3,4-dimethoxybenzoyl) -4,5-dimethoxyphenyl] -pentan-2-one ethylene ketal (IV)
Požadovaná látka bola pripravená podľa príkladu 1 s výnimkou toho, že 2,5 molárny hexánový roztok butyllítia bol nahradený 2,5 molárnym hexánovým roztokom hexyllítia. Reakcia bola vykonávaná pri teplote -78 °C. Týmto spôsobom sa pripravilo 8,6 g požadovanej zlúčeniny. Výťažok 40 %.The title compound was prepared according to Example 1, except that the 2.5 molar hexane solution of butyllithium was replaced by the 2.5 molar hexane solution of hexyllithium. The reaction was carried out at -78 ° C. 8.6 g of the title compound are obtained. Yield 40%.
Príklad 4Example 4
3-[2-(3,4-dimetoxybenzoyl)-4,5-dimetoxyfenyl]-pentán-2-ón-etylén-ketál (IV)3- [2- (3,4-Dimethoxybenzoyl) -4,5-dimethoxyphenyl] -pentan-2-one ethylene ketal (IV)
Požadovaná látka bola pripravená podľa príkladu 1 s výnimkou toho, že 2,5 molárny hexánový roztok butyllítia bol nahradený 2,5 molárnym hexánovým roztokom hexyllítia. Reakcia bola vykonávaná pri teplote -20 °C. Týmto spôsobom sa získalo 6,2 g požadovanej zlúčeniny. Výťažok bol 29 %.The title compound was prepared according to Example 1, except that the 2.5 molar hexane solution of butyllithium was replaced by the 2.5 molar hexane solution of hexyllithium. The reaction was carried out at -20 ° C. 6.2 g of the title compound are obtained. The yield was 29%.
Príklad 5Example 5
3-[2-(3,4-dimetoxybenzoyl)-4.5-dimetoxyfenyl]-pentán-2-ón-etylén-ketál (IV)3- [2- (3,4-dimethoxybenzoyl) -4,5-dimethoxyphenyl] pentan-2-one ethylene ketal (IV)
Požadovaná látka bola pripravená podľa príkladu 1 s výnimkou toho, že miesto /VjV-dimetylamidu 3,4-dimetoxybenzoovej kyseliny (Hla) sa použilo 9,8 g (0,05 mol) metyl-3,4-dimetoxybenzoátu. Týmto spôsobom bolo získané 6,9 g požadovanej zlúčeniny. Výťažok bol 32 %. Teplota topenia: 164 - 166 °C.The title compound was prepared according to Example 1 except that 9.8 g (0.05 mol) of methyl 3,4-dimethoxybenzoate was used in place of N, N-dimethylamide of 3,4-dimethoxybenzoic acid (IIIa). 6.9 g of the title compound are obtained. The yield was 32%. Melting point: 164-166 ° C.
Príklad 6Example 6
3-(2-(3,4-dimetoxybenzoyl)-4.5-dimetoxyfenyl]-pentán-2-ón (I)3- (2- (3,4-dimethoxybenzoyl) -4,5-dimethoxyphenyl) pentan-2-one (I)
Do zmesi 25.0 g kieselgelu sa pridalo 100 ml dichlórmetánu a 2,5 ml z roztoku 15 hmotn. % kyseliny sírovej a 6,46 g (0,015 mol) 3-(2-(3,4-dimetoxybenzoyl)-4,5-dimetoxyfenyl]-pentán-2-ón-etylén-ketálu. Reakčná zmes bola miešaná pri izbovej teplote počas 2 hodín, potom bol kieselgel odfiltrovaný a premývaný dichlórmetánom. Dichlórmetánový roztok bol sušený nad síranom horečnatým a odparovaný. Surový produkt bol rekryštalizovaný. Týmto spôsobom sa získalo 5,4 g požadovanej zlúčeniny. Výťažok bol 93 %. Teplota topenia: 158 159 °C.To a mixture of 25.0 g of kieselgel was added 100 mL of dichloromethane and 2.5 mL of a 15 wt. % of sulfuric acid and 6.46 g (0.015 mol) of 3- (2- (3,4-dimethoxybenzoyl) -4,5-dimethoxyphenyl] pentan-2-one ethylene ketal. The reaction mixture was stirred at room temperature for After 2 hours, the silica gel was filtered off and washed with dichloromethane, the dichloromethane solution was dried over magnesium sulphate and evaporated, the crude product recrystallized to give 5.4 g of the title compound, yield 93%, mp 158-159 ° C.
Príklad 7Example 7
3-[2-(3,4-dimetoxybenzoyl)-4,5-dimetoxyfenyl]-pentán-2-ón (I)3- [2- (3,4-dimethoxybenzoyl) -4,5-dimethoxyphenyl] pentan-2-one (I)
Požadovaná látka bola pripravená podľa príkladu 6 s výnimkou toho, že zlúčenina všeobecného vzorca IV nebola purifikovaná, ale na kyslú hydrolýzu bol používaný surový produkt pripravený spôsobom podľa ktoréhokoľvek z príkladov 1-5. Iba zlúčenina vzorca I bola purifikovaná rekryštalizáciou. Týmto spôsobom sa pripravilo 6,2 - 9,6 g požadovanej zlúčeniny. Výťažok bol 32 - 50 % (vztiahnuté na zlúčeninu všeobecného vzorca II).The title compound was prepared according to Example 6 except that the compound of Formula IV was not purified, but the crude product prepared by the method of any one of Examples 1-5 was used for acid hydrolysis. Only the compound of formula I was purified by recrystallization. 6.2 - 9.6 g of the title compound are obtained. The yield was 32-50% (based on the compound of formula II).
Príprava východiskových látokPreparation of starting materials
Príklad 8Example 8
3-(2-bróm-4,5-dimetoxyfenyl)-pentán-2-ón-etylén-ketál (II)3- (2-Bromo-4,5-dimethoxyphenyl) -pentan-2-one ethylene ketal (II)
34,3 g (0.11 mol) 3-(2-bróm-4,5-dimetoxyfenyl)-pentán-2-ónu bolo rozpustených v 250 ml toluénu. Do roztoku 11,2 ml (0,20 mol) etylénglykolu sa pridalo 1,5 g p-toluénsulfónovej kyseliny. Aparatúra bola vybavená odlučovačom vody a reakčná zmes bola miešaná za zahrievania do varu, kým nebolo odseparované teoretické množstvo vody. Potom bola voda odstránená, toluénový roztok bol premývaný roztokom uhličitanu sodného bez kyseliny, sušený nad síranom horečnatým, filtrovaný a odparovaný vo vákuu. Týmto spôsobom sa získalo 38 g surového produktu, ktorý bol oddestilovaný pri 149 - 152 °C/12 Pa. Týmto spôsobom sa získalo 36,2 g chromatograficky čistého požadovaného produktu. Výťažok bol 92 %. Teplota topenia: 44 - 45 °C.34.3 g (0.11 mol) of 3- (2-bromo-4,5-dimethoxyphenyl) -pentan-2-one were dissolved in 250 ml of toluene. To a solution of 11.2 mL (0.20 mol) of ethylene glycol was added 1.5 g of p-toluenesulfonic acid. The apparatus was equipped with a water trap and the reaction mixture was stirred while heating to boiling until the theoretical amount of water was separated. After the water was removed, the toluene solution was washed with an acid-free sodium carbonate solution, dried over magnesium sulfate, filtered and evaporated in vacuo. In this way 38 g of crude product were obtained, which was distilled off at 149-152 ° C / 12 Pa. 36.2 g of chromatographically pure desired product are obtained. The yield was 92%. Melting point: 44 - 45 ° C.
IR (film): 2 962 (CH3O). 591 (C-Br) cnť1.IR (film): 2962 (CH 3 O). 591 (C-Br) tr 1 .
'H NMR (DMSO-d6. TMS. i400): 7.09 (s. 1H), 7.01 (s,lH). 3.94-3.77 (m,4H). 3,72 (s. 3H). 3.7l(s. 3H). 3.27 (dd. .1=3.4. 11.5 Hz. 1H). 1.92-1.85 (m. 1H). 1.64-1.56 (m. III). 1.07 (s. 3H). 0.63 (t.J=7, 4 Hz. 3H) ppm.1 H NMR (DMSO-d 6 , TMS, i400): 7.09 (s, 1H), 7.01 (s, 1H). 3.94-3.77 (m. 4H). 3.72 (s, 3H). 3.7l (s, 3H). 3.27 (dd, J = 3.4, 11.5 Hz, 1H). 1.92-1.85 (m, IH). 1.64-1.56 (m, III). 1.07 (s, 3H). 0.63 (t J = 7.4 Hz, 3H) ppm.
l3C NMR (DMSO-d6, TMS. Í400): 148.3, 148.1, 132,1, 116.6, 115,1. 111.9. 110.8, 65,2. 64,4. 13 C NMR (DMSO-d 6 , TMS, 400400): 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.55.8, 55.7, 53.3. 23.3, 22.8, 11.9 ppm.
Elementárna analýza:Elemental analysis:
Vypočítané: C 52.19 %, H 6,13 %, Br 23.14 %.Calculated: C 52.19%, H 6.13%, Br 23.14%.
Namerané: C 52.36 %, H 6.12 %, Br 23. 23 %.Found: C 52.36%, H 6.12%, Br 23, 23%.
Claims (17)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU0204342A HU227044B1 (en) | 2002-12-16 | 2002-12-16 | Process for producing 3-[2-(3,4-dimethoxybenzoyl)-4,5-dimethoxyphenyl]-pentan-2-one |
| 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 |
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| SK702005A3 true SK702005A3 (en) | 2005-09-08 |
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| SK70-2005A SK702005A3 (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 |
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| EP (1) | EP1575890A1 (en) |
| JP (1) | JP4437093B2 (en) |
| KR (1) | KR100936306B1 (en) |
| AU (2) | AU2002361068A1 (en) |
| BG (1) | BG109230A (en) |
| CZ (1) | CZ2005388A3 (en) |
| EA (1) | EA007788B1 (en) |
| HU (1) | HU227044B1 (en) |
| PL (1) | PL376530A1 (en) |
| SK (1) | SK702005A3 (en) |
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| WO (2) | WO2004054951A1 (en) |
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| 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 |
| 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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| WO2003050092A2 (en) * | 2001-12-13 | 2003-06-19 | EGIS Gyógyszergyár Rt. | Process for the preparation of tofisopam and new intermediates |
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- 2002-12-31 CZ CZ2005388A patent/CZ2005388A3/en unknown
- 2002-12-31 AU AU2002361068A patent/AU2002361068A1/en not_active Abandoned
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- 2002-12-31 EP EP02791921A patent/EP1575890A1/en not_active Withdrawn
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| Publication number | Publication date |
|---|---|
| KR20050085686A (en) | 2005-08-29 |
| AU2003292449A1 (en) | 2004-07-09 |
| JP4437093B2 (en) | 2010-03-24 |
| HUP0204342A3 (en) | 2004-11-29 |
| HU0204342D0 (en) | 2003-02-28 |
| WO2004054951A1 (en) | 2004-07-01 |
| KR100936306B1 (en) | 2010-01-12 |
| WO2004054952A1 (en) | 2004-07-01 |
| EA007788B1 (en) | 2007-02-27 |
| PL376530A1 (en) | 2006-01-09 |
| JP2006509814A (en) | 2006-03-23 |
| EP1575890A1 (en) | 2005-09-21 |
| CZ2005388A3 (en) | 2005-09-14 |
| HUP0204342A2 (en) | 2004-07-28 |
| AU2002361068A1 (en) | 2004-07-09 |
| UA78634C2 (en) | 2007-04-10 |
| HU227044B1 (en) | 2010-05-28 |
| EA200500966A1 (en) | 2005-12-29 |
| BG109230A (en) | 2006-04-28 |
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