KR20050085686A - 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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- KR20050085686A KR20050085686A KR1020057011012A KR20057011012A KR20050085686A KR 20050085686 A KR20050085686 A KR 20050085686A KR 1020057011012 A KR1020057011012 A KR 1020057011012A KR 20057011012 A KR20057011012 A KR 20057011012A KR 20050085686 A KR20050085686 A KR 20050085686A
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- 238000000034 method Methods 0.000 title claims abstract description 34
- 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
- 238000002360 preparation method Methods 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 55
- 239000003513 alkali Substances 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 18
- 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 10
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical group [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 7
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- 229910052749 magnesium Inorganic materials 0.000 claims description 6
- 239000011541 reaction mixture Substances 0.000 claims description 6
- 150000001408 amides Chemical class 0.000 claims description 5
- 229910052744 lithium Inorganic materials 0.000 claims description 5
- 230000003301 hydrolyzing effect Effects 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
- 150000007522 mineralic acids Chemical class 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
- 150000002642 lithium compounds Chemical class 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000007858 starting material Substances 0.000 claims description 3
- 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 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 238000011065 in-situ storage Methods 0.000 claims description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims 1
- 239000005977 Ethylene Substances 0.000 claims 1
- 150000002641 lithium Chemical group 0.000 claims 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- -1 ethylene, trimethylene Chemical group 0.000 description 11
- 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 group [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 4
- WSSLDBVWUSSAGE-UHFFFAOYSA-N Veratrumsaeure-dimethylamid Natural products COC1=CC=C(C(=O)N(C)C)C=C1OC WSSLDBVWUSSAGE-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 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
- 125000000217 alkyl group Chemical group 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 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
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- RUJBDQSFYCKFAA-UHFFFAOYSA-N Tofisopam Chemical compound N=1N=C(C)C(CC)C2=CC(OC)=C(OC)C=C2C=1C1=CC=C(OC)C(OC)=C1 RUJBDQSFYCKFAA-UHFFFAOYSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 150000001805 chlorine compounds Chemical class 0.000 description 2
- 150000001844 chromium Chemical class 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000002050 international nonproprietary name Substances 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- BIGQPYZPEWAPBG-UHFFFAOYSA-N methyl 3,4-dimethoxybenzoate Chemical compound COC(=O)C1=CC=C(OC)C(OC)=C1 BIGQPYZPEWAPBG-UHFFFAOYSA-N 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
- 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
- JQNBCSPQVSUBSR-UHFFFAOYSA-N 2,3-dimethoxybenzoyl chloride Chemical compound COC1=CC=CC(C(Cl)=O)=C1OC JQNBCSPQVSUBSR-UHFFFAOYSA-N 0.000 description 1
- DAUAQNGYDSHRET-UHFFFAOYSA-N 3,4-dimethoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1OC DAUAQNGYDSHRET-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
- HRMXGYSYURYVCI-UHFFFAOYSA-N C1CC1=O.COC=1C=C(C(=O)C2=C(C=C(C(=C2)OC)OC)C(C(C)=O)CC)C=CC1OC Chemical compound C1CC1=O.COC=1C=C(C(=O)C2=C(C=C(C(=C2)OC)OC)C(C(C)=O)CC)C=CC1OC HRMXGYSYURYVCI-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
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- GPVDHNVGGIAOQT-UHFFFAOYSA-N Veratric acid Natural products COC1=CC=C(C(O)=O)C(OC)=C1 GPVDHNVGGIAOQT-UHFFFAOYSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000004821 distillation Methods 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
- 238000007429 general method Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical class C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- IZYBEMGNIUSSAX-UHFFFAOYSA-N methyl benzenecarboperoxoate Chemical compound COOC(=O)C1=CC=CC=C1 IZYBEMGNIUSSAX-UHFFFAOYSA-N 0.000 description 1
- KRKPYFLIYNGWTE-UHFFFAOYSA-N n,o-dimethylhydroxylamine Chemical compound CNOC KRKPYFLIYNGWTE-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 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
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229960002501 tofisopam Drugs 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
Abstract
Description
본 발명은 하기 화학식(I)의 3-[2-(3,4-다이메톡시-벤조일)-4,5-다이메톡시-페닐]-펜탄-2-온을 제조하는 신규한 방법에 관한 것이다.The present invention relates to a novel process for preparing 3- [2- (3,4-dimethoxy-benzoyl) -4,5-dimethoxy-phenyl] -pentan-2-one of formula (I) will be.
화학식(I)의 3-[2-(3,4-다이메톡시-벤조일)-4,5-다이메톡시-페닐]-펜탄-2-온은 국제 비 독점적 명칭(INN) 토피소팜(tofisopam)을 가진 항불안제 활성 성분 1-(3,4-다이메톡시-페닐)-4-메틸-5-에틸-7,8-다이메톡시-5H-2,3-벤조디아제핀을 제조하는데 유용한 중간체이다.3- [2- (3,4-dimethoxy-benzoyl) -4,5-dimethoxy-phenyl] -pentan-2-one of formula (I) is an international non-proprietary name (INN) topisopam ( antifibrillant active ingredient 1- (3,4-dimethoxy-phenyl) -4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine with tofisopam) .
HU 158,091에 따르면, 화학식(I)의 화합물은 크롬(VI) 산화물로 산화시켜서 다이이소호모유제놀로부터 제조되고 단지 저수율로 수득된다.According to HU 158,091, the compound of formula (I) is prepared from diisohomogenol by oxidation with chromium (VI) oxide and obtained only in low yield.
HU 194,529에 따르면, 1-(3,4-다이메톡시-페닐)-3-메틸-4-에틸-6,7-다이메톡시-이소크로만은 크롬(VI)산화물로 산화되어 수성 알칼리성 분해로 화학식(I)의 표제 화합물로 변환되는 상응하는 벤조피릴륨 염이 된다.According to HU 194,529, 1- (3,4-dimethoxy-phenyl) -3-methyl-4-ethyl-6,7-dimethoxy-isochroman is oxidized to chromium (VI) oxide to give an aqueous alkaline decomposition To the corresponding benzopyryllium salt converted to the title compound of formula (I).
이 두 공지된 방법은 산화 반응에서 환경에 유해한 고독성 크로뮴 염이 형성된다는 공통된 단점을 가진다. 상기 크로뮴 염의 저장, 중화 및 재활용은 환경 보호를 위하여 심각한 문제이다.These two known methods have a common drawback that, in the oxidation reaction, highly toxic chromium salts which are harmful to the environment are formed. Storage, neutralization and recycling of the chromium salts are a serious problem for environmental protection.
HU 187,161은 공지된 방법의 상기 단점을 제거하는 것을 목표로 한다. HU 187,161에 따르면, 화학식(I)의 화합물은 탈 크로뮴 방법의 도움으로 알루미늄(III)클로라이드의 존재에서 3-(3,4-다이메톡시-페닐)-펜탄-2-온을 3,4-다이메톡시-벤조일 클로라이드와 반응시키고 알칼리성 매질에서 형성된 벤조피릴륨 염을 분해시켜서 제조된다.HU 187,161 aims to obviate the above drawbacks of known methods. According to HU 187,161, the compound of formula (I) converts 3- (3,4-dimethoxy-phenyl) -pentan-2-one in the presence of aluminum (III) chloride with the help of a dechromium method to 3,4- Prepared by reaction with dimethoxy-benzoyl chloride and decomposition of the benzopyryllium salt formed in the alkaline medium.
상기 방법의 단점은 출발 물질로서 사용된 3,4-다이메톡시-벤조일 클로라이드가 매우 분해되기 쉽고 반응에서 형성된 프리에델-크래프츠 생성물은 크게 오염되어 다루기 힘들고 이의 정제가 심각한 문제를 발생시킨다.A disadvantage of this method is that the 3,4-dimethoxy-benzoyl chloride used as starting material is very susceptible to decomposition and the Friedel-Crafts product formed in the reaction is heavily contaminated and difficult to handle and its purification causes serious problems.
공지된 방법의 상기 단점을 제거하고, 환경 친화적이며 공지된 방법보다 보다 우수한 수율 및 보다 고순도를 가진 화학식(I)의 목적하는 화합물을 수득하는 화학식(I)의 3-[2-(3,4-다이메톡시-벤조일)-4,5-다이메톡시-페닐]-펜탄-2-온을 제조하는 탈 크로뮴 방법을 제공하는 것이 본 발명의 목적이다. 3- [2- (3,4) of formula (I) which eliminates the above drawbacks of known processes and obtain the desired compounds of formula (I) which are environmentally friendly and have better yields and higher purity than known methods It is an object of the present invention to provide a dechromium method for preparing -dimethoxy-benzoyl) -4,5-dimethoxy-phenyl] -pentan-2-one.
상기 목적은 본 발명의 방법으로 해결된다.This object is solved by the method of the present invention.
발명의 요약Summary of the Invention
본 발명에 따르면 하기 화학식(I)의 3-[2-(3,4-다이메톡시-벤조일)-4,5-다이메톡시-페닐]-펜탄-2-온을 제조하는 방법이 제공되고, 하기 화학식(II)의 화합물로부터 출발하여,According to the present invention there is provided a process for preparing 3- [2- (3,4-dimethoxy-benzoyl) -4,5-dimethoxy-phenyl] -pentan-2-one of formula (I) Starting from the compound of formula (II)
a) 상기 화학식(II)의 화합물중에 브롬 원자를 알칼리 또는 마그네슘 원자로 치환하고; 이와 같이 수득된 알칼리 또는 마그네슘 화합물을 대략 등몰량의 하기 화학식(IIIa)의 산 아미드와 반응시키고 이와 같이 수득된 하기 화학식(IV)의 화합물을 가수분해시키거나;a) replacing the bromine atom with an alkali or magnesium atom in the compound of formula (II); The alkali or magnesium compound thus obtained is reacted with an approximately equimolar amount of the acid amide of formula IIIa and the compound of formula IV thus obtained is hydrolyzed;
b) 상기 화학식(II)의 화합물중의 브롬 원자를 알칼리 또는 마그네슘 원자로 치환하고; 이와 같이 수득된 알칼리 또는 마그네슘 화합물을 대략 등몰량의 하기 화학식(IIIb)의 에스테르와 반응시키고 이와 같이 수득된 상기 화학식(IV)의 화합물을 가수분해시킨다.b) replacing the bromine atom in the compound of formula II with an alkali or magnesium atom; The alkali or magnesium compound thus obtained is reacted with an approximately equimolar amount of the ester of formula (IIIb) and the compound of formula (IV) thus obtained is hydrolyzed.
상기 식에서,Where
R1 및 R2 각각이 C1-4-알킬이거나 함께 C2-6-알킬렌을 형성하고,Each of R 1 and R 2 is C 1-4 -alkyl or together forms C 2-6 -alkylene,
R3, R4 및 R5는 C1-4-알킬이다.R 3 , R 4 and R 5 are C 1-4 -alkyl.
본 특허 명세서에서 사용되는 용어는 하기와 같이 해석된다:The terminology used in this patent specification is interpreted as follows:
용어 "C1-4-알킬"은 1개 내지 4개의 탄소 원자를 함유하는 선형 또는 분지형 사슬 알킬 기와 관련된다(예를 들어, 메틸, 에틸, n-프로필, 이소프로필, n-부틸 등).The term “C 1-4 -alkyl” relates to linear or branched chain alkyl groups containing 1 to 4 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, etc.) .
용어 "C2-6-알킬렌"은 2개 내지 6개의 탄소 원자를 함유하는 선형 또는 분지형 사슬 알킬렌 기와 관련된다(예를 들어, 에틸렌, 트리메틸렌 등).The term “C 2-6 -alkylene” relates to linear or branched chain alkylene groups containing 2 to 6 carbon atoms (eg ethylene, trimethylene, etc.).
화학식(II)의 3-(2-브로모-4,5-다이메톡시-페닐)-펜탄-2-온 케탈의 합성 및 특징규명은 2001년 12월 13일에 출원된 동시 계속중인 헝거리 특허 출원 시리즈 제 01/05326호 및 제 01/05327호에 개시되어 있다.Synthesis and characterization of 3- (2-bromo-4,5-dimethoxy-phenyl) -pentan-2-one ketal of formula (II) is a concurrent patent application filed December 13, 2001 Application series 01/05326 and 01/05327 are disclosed.
일반적으로 사용된 방법에 따르면, 다이아릴 케톤은 아릴 금속 화합물을 방향족 니트릴과 반응시키고 형성된 이민을 가수분해하여 아릴 금속 화합물로부터 제조된다. 그러나, 상기 일반적인 방법은 화학식(I)의 3-[2-(3,4-다이메톡시-벤조일)-4,5-다이메톡시-페닐]-펜탄-2-온 대신에 선행 기술을 기초로 다소 이소퀴놀린 유도체 형성이 예상될 수 있기 때문에 3-[2-(3,4-다이메톡시-벤조일)-4,5-다이메톡시-페닐]-펜탄-2-온를 제조하는데 응용될 수 없다[Khim. Geterosikl. Soedin, (1988), (1), 134-5].According to the commonly used method, diaryl ketones are prepared from aryl metal compounds by reacting aryl metal compounds with aromatic nitriles and hydrolyzing the imines formed. However, this general method is based on the prior art instead of 3- [2- (3,4-dimethoxy-benzoyl) -4,5-dimethoxy-phenyl] -pentan-2-one of formula (I). It can be applied to prepare 3- [2- (3,4-dimethoxy-benzoyl) -4,5-dimethoxy-phenyl] -pentan-2-one since some isoquinoline derivative formation can be expected. None [Khim. Geterosikl. Soedin, (1988), (1), 134-5].
아릴 금속 화합물을 일반적으로 사용되는 베인렙 아미드(Weinreb amides)(N-메틸-N-메톡시-아미드)와 반응시키는 경우에 화학식(IV)의 화합물 형성이 예상될 수 있다. 그러나 상기 반응물을 사용하는 것은 합성을 매우 비싸고 비경제적이게 한다[Bioorganic and Medicinal Chemistry Letters(1993), 1991-2].Compound formation of formula (IV) can be expected when the aryl metal compound is reacted with commonly used Weinreb amides (N-methyl-N-methoxy-amide). However, using the reactants makes synthesis very expensive and uneconomical [Bioorganic and Medicinal Chemistry Letters (1993), 1991-2].
아릴 금속 화합물을 산 클로라이드와 반응시켜서 화학식(IV)의 화합물을 합성하는 것은 산 클로라이드가 용이하게 분해되기 쉽고 상당하게 수율을 감소시키고 부반응 속도를 증가시키는 무기산으로 일반적으로 오염되기 때문에 가능하지 않다.The synthesis of compounds of formula (IV) by reacting aryl metal compounds with acid chlorides is not possible because acid chlorides are easily contaminated and are generally contaminated with inorganic acids, which significantly reduce yields and increase side reaction rates.
화학식(IV)의 화합물은 용이하게 화학식(IIIa)의 아미드 및 화학식(IIIb)의 에스테르의 도움으로 제조될 수 있어서, 화학식(IIIa) 및 화학식(IIIb)의 상기 화합물은 케톤기 형성을 위하여 금속 유기 화학에서 지금까지는 일반적으로 사용되지 않았다.Compounds of formula (IV) can be readily prepared with the aid of amides of formula (IIIa) and esters of formula (IIIb), so that the compounds of formulas (IIIa) and (IIIb) are metal organic for the formation of ketone groups. Not commonly used in chemistry until now.
본 발명은 목적하는 화학식(I)의 3-[2-(3,4-다이메톡시-벤조일)-4,5-다이메톡시-페닐]-펜탄-2-온이 화학식(II)의 3-(2-브로모-4,5-다이메톡시-페닐)-펜탄-2-온 케탈로부터 형성된 알칼리 또는 마그네슘 화합물을 화학식(IIIa) 및 (IIIb)의 화합물과 반응시킨 후에 이와 같이 가수분해하여 수득된 화학식(IV)의 3-[2-(3,4-다이메톡시-벤조일)-4,5-다이메톡시-페닐]-펜탄-2-온 케탈을 처리하여 용이하게 제조될 수 있다.The invention provides that 3- [2- (3,4-dimethoxy-benzoyl) -4,5-dimethoxy-phenyl] -pentan-2-one of formula (I) is a compound of formula (II). Alkali or magnesium compounds formed from-(2-bromo-4,5-dimethoxy-phenyl) -pentan-2-one ketal are reacted with the compounds of formulas (IIIa) and (IIIb) and then hydrolyzed as such It can be easily prepared by treating 3- [2- (3,4-dimethoxy-benzoyl) -4,5-dimethoxy-phenyl] -pentan-2-one ketal of the obtained formula (IV). .
본 발명의 방법의 변형 a)에 따르면 화학식(II)의 화합물중에서 브롬 원자는 알킬리 또는 마그네슘 원자로 치환된 후에 이와 같이 수득된 알칼리 또는 마그네슘 화합물을 화학식(IIIa)의 3,4-다이메톡시-벤조산-N,N-다이알킬-아미드와 반응시키고 상기 화합물이 공지된 방법으로 3,4-다이메톡시-벤조산으로부터 제조될 수 있다.According to variant a) of the process of the invention, the bromine atom in the compound of formula (II) is substituted with an alkyl or magnesium atom and thus the alkali or magnesium compound thus obtained is substituted with 3,4-dimethoxy- of formula (IIIa). Reaction with benzoic acid-N, N-dialkyl-amides and the compounds can be prepared from 3,4-dimethoxy-benzoic acid by known methods.
화학식(II)의 화합물에서 브롬 원자는 알칼리(예를 들어, 나트륨, 칼륨 또는 리튬)원자 또는 그리그나드 반응(Grignard-reaction)의 도움으로 마그네슘 원자로 치환된다. 바람직하게는 브롬→리튬 교환 반응을 수행하여 진행할 수 있다. 이는 화학식(II)의 화합물을 알칼리 리튬(바람직하게는 n-부틸 리튬 또는 n-헥실 리튬)과 반응시켜서 수행될 수 있다. 알킬 리튬 화합물이 바람직하게는 알칸, 바람직하게는 n-헥산으로 형성되는 용액 중에서 사용된다. 리튬에 의한 브롬 원자의 치환은 무수 테트라하이드로푸란 중에서, -78℃ 내지 -10℃, -바람직하게는 약 -10℃-의 온도에서 수행될 수 있다. 그 후, 형성된 알칼리 또는 마그네슘 화합물 -유리하게는 리튬 화합물-은 대략 등몰량의 화학식(Ⅲa)의 아미드(바람직하게는 1.0-1.2의 몰량)과 반응시킨다. 바람직하게는 리튬 화합물을 상기 리튬 화합물의 제조 중에 수득된 반응 혼합물 중에서 분리하지 않고, 화학식(Ⅲa)의 화합물과 반응시킴으로서 진행시킬 수 있다. 상기 반응은 0℃ 미만, 바람직하게는 약 -20℃에서의 온도에서 수행될 수 있다. 이와 같이 형성된 화학식(IV)의 화합물은 반응 혼합물로부터 분리될 수 있다. Bromine atoms in the compounds of formula (II) are substituted with magnesium atoms with the aid of alkali (eg sodium, potassium or lithium) atoms or the Grignard-reaction. Preferably, bromine → lithium exchange may be performed. This can be done by reacting the compound of formula (II) with alkali lithium (preferably n-butyl lithium or n-hexyl lithium). Alkyl lithium compounds are preferably used in solutions formed of alkanes, preferably n-hexane. Substitution of the bromine atom by lithium can be carried out in anhydrous tetrahydrofuran at a temperature of -78 ° C to -10 ° C, preferably -10 ° C. The alkali or magnesium compound formed-advantageously the lithium compound-is then reacted with an approximately equimolar amount of an amide of formula (IIIa) (preferably molar amount of 1.0-1.2). Preferably, the lithium compound can be advanced by reacting with the compound of formula (IIIa) without separating in the reaction mixture obtained during the preparation of the lithium compound. The reaction can be carried out at a temperature below 0 ° C., preferably at about −20 ° C. The compound of formula (IV) thus formed may be separated from the reaction mixture.
본 발명의 방법의 변형 b)에 따르면, 화학식(II)의 화합물 중의 브롬 원자는 알칼리 또는 마그네슘 원자에 의해 치환되고, 이와 같이 수득된 알칼리 또는 마그네슘 화합물이 화학식(Ⅲb)의 알킬 3,4-다이메톡시-벤조에이트와 반응하여 화학식(IV)의 화합물을 수득한다.According to variant b) of the process of the invention, the bromine atom in the compound of formula (II) is substituted by an alkali or magnesium atom, and the alkali or magnesium compound so obtained is an alkyl 3,4-di of formula (IIIb) Reaction with methoxy-benzoate yields a compound of formula (IV).
반응의 변형 a) 또는 b)에서 수득된 화학식(IV)의 화합물은 재결정에 의해 임의로 분리되고 정제된다. 화학식(IV)의 분리된 케탈은 공지된 방법 그 자체로 무기산을 사용하여 화학식(I)의 상응하는 케톤으로 가수분해 된다. Compounds of formula (IV) obtained in variant a) or b) of the reaction are optionally isolated and purified by recrystallization. The separated ketals of formula (IV) are hydrolyzed to the corresponding ketones of formula (I) using inorganic acids by known methods per se.
화학식(IV)의 케탈의 가수분해는 바람직하게는 무기산, 특히 묽은 황산 또는 묽은 염산, 가장 유리하게는 묽은 황산을 사용하여 수행될 수 있다. 상기 반응은 2개 상 반응 혼합물, 바람직하게는 20-40℃에서 수행될 수 있다. 상기 2개 상 시스템 중 하나의 상은 물 비혼화성 유기용매 (바람직하게는 방향족 탄화수소, 예를 들어 벤젠, 톨루엔 또는 자일렌; 또는 지방족 할로겐화 탄화수소, 예를 들어 다이클로로 메탄)으로 구성되고, 다른 상은 산성 수용액으로 구성된다. 상기 반응은 화학식(IV)의 화합물에 대해 2 내지 5 배의 양으로 사용된 키에셀겔을 첨가하여 촉진시킬 수 있다.Hydrolysis of the ketal of formula (IV) can preferably be carried out using inorganic acids, in particular dilute sulfuric acid or dilute hydrochloric acid, most advantageously dilute sulfuric acid. The reaction can be carried out in a two phase reaction mixture, preferably at 20-40 ° C. One of the two phase systems consists of a water immiscible organic solvent (preferably aromatic hydrocarbons such as benzene, toluene or xylene; or aliphatic halogenated hydrocarbons such as dichloromethane) and the other phase is acidic. It consists of an aqueous solution. The reaction can be promoted by addition of the kielsel gel used in an amount of 2 to 5 times the amount of the compound of formula (IV).
화학식(I)의 화합물은 또한 직접적으로, 즉, 화학식(Ⅳ)의 중간체를 분리하지 않고 제조될 수 있다. 원위치에서 형성된 화학식(IV)의 화합물을 산으로 처리하여 진행할 수 있다. 이 경우, 단지 화학식(I)의 케톤만이 분리되고 정제된다. Compounds of formula (I) may also be prepared directly, ie without separating intermediates of formula (IV). The compounds of formula (IV) formed in situ can be treated with acid. In this case, only ketones of formula (I) are isolated and purified.
이와 같이 수득된 화학식(I)의 화합물은 정제될 수 있고, 요망되는 경우, 적합한 용매로 재결정화될 수 있다. 바람직하게는 재결정화 용매로서 C1-4 선형 또는 분지형 사슬 지방족 알콜이 사용될 수 있다. 이와 같이 수득된 화학식(I)의 화합물은 98% 초과의 순도를 가지고 약제학적으로 활성있는 토피소팜 최종 생성물의 제조에 우수하게 적합하다.The compound of formula (I) thus obtained can be purified and, if desired, recrystallized with a suitable solvent. Preferably C 1-4 linear or branched chain aliphatic alcohols can be used as the recrystallization solvent. The compounds of formula (I) thus obtained are well suited for the preparation of pharmaceutically active topisopam final products with a purity of more than 98%.
본 발명의 방법의 장점은 고수율을 가진 토피소팜의 제조에서 유용하고 환경 친화적 화합물을 사용하는 중간체 화학식(I)의 3-[2-(3,4-다이메톡시-벤조일)-4,5-다이메톡시-페닐]-펜탄-2-온을 제조하게 하는 것이다.The advantages of the process of the present invention are intermediates of formula (I) 3- [2- (3,4-dimethoxy-benzoyl) -4, which are useful in the preparation of toffeisopalm with high yields and using environmentally friendly compounds. 5-dimethoxy-phenyl] -pentan-2-one is prepared.
본 발명의 추가 세부사항은 실시예에서 보호 범위를 제한하지 않고 하기 실시예에서 발견될 것이다.Further details of the invention will be found in the following examples without limiting the scope of protection in the examples.
실시예 1Example 1
3-[2-(3,4-다이메톡시-벤조일)-4,5-다이메톡시-페닐]-펜탄-2-온-에틸렌 케탈(IV)3- [2- (3,4-Dimethoxy-benzoyl) -4,5-dimethoxy-phenyl] -pentan-2-one-ethylene ketal (IV)
3-(2-브로모-4,5-다이메톡시-페닐)-펜탄-2-온-에틸렌 케탈(II) 17.26g(0.05몰)을 무수 테트라하이드로푸란 173ml중에 용해시킨 후에 상기 용액을 드라이 아이스로 외부 냉각하에서 -78℃로 냉각하였다. 핵산 24ml중에 부틸 리튬(0.06몰) 2.5 몰용액을 45분이내로 교반하에서 첨가하였다. 첨가를 완료한 후에 혼합물을 -78℃에서 2시간의 추가 기간동안 교반시키고 3,4-다이메톡시-벤조산-N,N-다이메틸-아미드(IIIa) 10.46g(0.05몰)을 첨가하였다. 20분의 후반응 이후에 온도를 천천히 상온으로 상승시켰다. 2시간의 반응 기간 후에 혼합물을 포화 암모늄 클로라이드 용액으로 혼합시키고 에틸 아세테이트로 추출하였다. 에틸 아세테이트 상을 포화 염화 나트륨 용액으로 세척하고 마그네슘 설페이트로 건조하고, 여과하고, 여과물을 증발시켰다. 미정제 생성물을 재결정으로 정제하였다. 표제 화합물 9.0g을 수득하였다. 수율 42%. 융해점:165-166℃17.26 g (0.05 mole) of 3- (2-bromo-4,5-dimethoxy-phenyl) -pentan-2-one-ethylene ketal (II) was dissolved in 173 ml of anhydrous tetrahydrofuran and the solution was dried. Cool with ice to -78 ° C under external cooling. A 2.5 molar solution of butyl lithium (0.06 mole) in 24 ml of nucleic acid was added under 45 minutes with stirring. After the addition was complete the mixture was stirred at −78 ° C. for a further period of 2 hours and 10.46 g (0.05 mol) of 3,4-dimethoxy-benzoic acid-N, N-dimethyl-amide (IIIa) was added. After 20 minutes of reaction, the temperature was slowly raised to room temperature. After a 2 hour reaction period the mixture was mixed with saturated ammonium chloride solution and extracted with ethyl acetate. The ethyl acetate phase was washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and the filtrate was evaporated. The crude product was purified by recrystallization. 9.0 g of the title compound were obtained. Yield 42%. Melting Point: 165-166 ℃
실시예 2Example 2
3-[2-(3,4-다이메톡시-벤조일)-4,5-다이메톡시-페닐]-펜탄-2-온-에틸렌 케탈(IV)3- [2- (3,4-Dimethoxy-benzoyl) -4,5-dimethoxy-phenyl] -pentan-2-one-ethylene ketal (IV)
반응을 -20℃에서 수행하는 것을 제외하고 실시예 1에서 설명된 바와 같이 진행시켰다. 이와 같이, 표제 화합물의 6.9g을 수득하였다. 수율 32%. 융해점:164-166℃.The reaction proceeded as described in Example 1 except that the reaction was carried out at -20 ° C. This gave 6.9 g of the title compound. Yield 32%. Melting point: 164-166 ° C.
실시예 3Example 3
3-[2-(3,4-다이메톡시-벤조일)-4,5-다이메톡시-페닐]-펜탄-2-온-에틸렌 케탈(IV)3- [2- (3,4-Dimethoxy-benzoyl) -4,5-dimethoxy-phenyl] -pentan-2-one-ethylene ketal (IV)
부틸 리듐의 2.5 몰 헥산 용액을 헥실 리튬의 2.5 몰 헥산 용액으로 대체하고 상기 반응을 -78℃에서 수행하는 것을 제외하고는 실시예 1에서 설명된 바와 같이 진행하였다. 이와 같이 표제 화합물 8.6g을 수득하였다. 수율 40%.Proceed as described in Example 1 except that the 2.5 molar hexane solution of butyl lithium was replaced with a 2.5 molar hexane solution of hexyl lithium and the reaction was carried out at -78 ° C. This gave 8.6 g of the title compound. Yield 40%.
실시예 4Example 4
3-[2-(3,4-다이메톡시-벤조일)-4,5-다이메톡시-페닐]-펜탄-2-온-에틸렌 케탈(IV)3- [2- (3,4-Dimethoxy-benzoyl) -4,5-dimethoxy-phenyl] -pentan-2-one-ethylene ketal (IV)
부틸 리듐의 2.5 몰 헥산 용액을 헥실 리튬의 2.5 몰 헥산 용액으로 대체하고 상기 반응을 -20℃에서 수행하는 것을 제외하고는 실시예 1에서 설명된 바와 같이 진행하였다. 이와 같이 표제 화합물 6.2g을 수득하였다. 수율 29%.The procedure was as described in Example 1 except that the 2.5 mol hexane solution of butyl lithium was replaced with a 2.5 mol hexane solution of hexyl lithium and the reaction was carried out at -20 ° C. This gave 6.2 g of the title compound. Yield 29%.
실시예 5Example 5
3-[2-(3,4-다이메톡시-벤조일)-4,5-다이메톡시-페닐]-펜탄-2-온-에틸렌 케탈(IV)3- [2- (3,4-Dimethoxy-benzoyl) -4,5-dimethoxy-phenyl] -pentan-2-one-ethylene ketal (IV)
3,4-다이메톡시-벤조산-N,N-다이메틸 아미드(IIIa) 대신에 메틸-3,4-다이메톡시-벤조에이트 9.8g(0.05몰)을 사용하는 것을 제외하고 실시예 1에서 설명된 바와 같이 진행하였다. 이와 같이 표제 화합물의 6.9g을 수득하였다. 수율 32%. 융해점: 164-166℃.In Example 1, except that 9.8 g (0.05 mol) of methyl-3,4-dimethoxy-benzoate is used instead of 3,4-dimethoxy-benzoic acid-N, N-dimethyl amide (IIIa) Proceed as described. This gave 6.9 g of the title compound. Yield 32%. Melting point: 164-166 ° C.
실시예 6Example 6
3-[2-(3,4-다이메톡시-벤조일)-4,5-다이메톡시-페닐]-펜탄-2-온(I)3- [2- (3,4-Dimethoxy-benzoyl) -4,5-dimethoxy-phenyl] -pentan-2-one (I)
키에셀겔 25.0g의 혼합물에, 다이클로로 메탄 100ml 및 3-[2-(3,4-다이메톡시-벤조일)-4,5-다이메톡시-페닐]-펜탄-2-온-에틸렌 케탈의 15% 중량/부피 황산 용액 6.46g의 2.5ml를 첨가하였다. 반응 혼합물을 2시간 동안 상온에서 교반시킨 후에 키에셀겔을 여과하고 다이클로로 메탄으로 세척하였다. 다이클로로 메탄 용액을 마그네슘 설페이트로 건조하고 증발시켰다. 미정제 생성물을 재결정시켰다. 이와 같인 표제 화합물 5.4g을 수득하였다. 수율 93%. 융해점: 158-159℃To a mixture of 25.0 g of kiesel gel, 100 ml of dichloromethane and 3- [2- (3,4-dimethoxy-benzoyl) -4,5-dimethoxy-phenyl] -pentan-2-one-ethylene ketone 2.5 ml of 6.46 g of 15% weight / volume sulfuric acid solution of deaeration was added. After the reaction mixture was stirred at room temperature for 2 hours, the Kisselgel was filtered and washed with dichloromethane. The dichloromethane solution was dried over magnesium sulfate and evaporated. The crude product was recrystallized. 5.4 g of the title compound were obtained. Yield 93%. Melting Point: 158-159 ℃
실시예 7Example 7
3-[2-(3,4-다이메톡시-벤조일)-4,5-다이메톡시-페닐]-펜탄-2-온(I)3- [2- (3,4-Dimethoxy-benzoyl) -4,5-dimethoxy-phenyl] -pentan-2-one (I)
화학식(IV)의 화합물을 정제하지 않지만, 산성 가수분해에 대하여는 실시예 1 내지 실시예 5 중 어느 하나에 따른 방법에 의하여 수득된 미정제 생성물을 수득한다는 것을 제외하고는 실시예 6에서 설명된 바와 같이 진행하였다. 화학식(I)의 화합물이 재결정에 의하여 정제된 유일한 화합물이다. 이와 같이, 표제 화합물의 6.2 내지 9.6g을 수득하였다. 수율 32-50%(화학식(II)의 화합물과 관련됨).As described in Example 6, except that the compound of formula (IV) is not purified, but the acidic hydrolysis yields the crude product obtained by the method according to any one of Examples 1-5. Proceed together. Compounds of formula (I) are the only compounds purified by recrystallization. Thus, 6.2-9.6 g of the title compound were obtained. Yield 32-50% (relative to compound of formula II).
출발물질의 제조Preparation of Starting Material
실시예 8Example 8
3-(2-브로모-4,5-다이메톡시-페닐)-펜탄-2-온-에틸렌 케탈(II)3- (2-Bromo-4,5-dimethoxy-phenyl) -pentan-2-one-ethylene ketal (II)
3-(2-브로모-4,5-다이메톡시-페닐)-펜탄-2-온 34.3g(0.11몰)을 톨루엔 250ml중에 용해시켰다. 상기 용액에 에틸렌 글리콜 11.2ml(0.20 몰) 및 p-톨루엔-황산 1.5g을 첨가하였다. 장치에 수 분리기를 장착하고 반응 혼합물을 가열하에서 교반하여 물의 이론적인 양을 분리할 때까지 용융시켰다. 물을 제거하고 톨루엔 용액을 탄산 나트륨 용액으로 산이 없도록 세척하고 마그네슘 설페이트로 건조하고, 여과하고 진공에서 증발시켰다. 이와 같이 미정제 생성물 38g을 149 내지 152℃/12Pa에서 증류하여 수득하였다. 이와 같이 크로마토그래프에서 균일한 표제 생성물 36.2g을 수득하였다. 수율 92%. 융해점:44-45℃34.3 g (0.11 mol) of 3- (2-bromo-4,5-dimethoxy-phenyl) -pentan-2-one were dissolved in 250 ml of toluene. To the solution was added 11.2 ml (0.20 mol) of ethylene glycol and 1.5 g of p-toluene-sulfuric acid. The apparatus was equipped with a water separator and the reaction mixture was stirred under heating to melt until a theoretical amount of water was separated. The water was removed and the toluene solution was washed free of acid with sodium carbonate solution, dried over magnesium sulfate, filtered and evaporated in vacuo. Thus 38 g of crude product were obtained by distillation at 149-152 ° C./12 Pa. This gave 36.2 g of uniform title product in the chromatograph. Yield 92%. Melting Point: 44-45 ℃
원소 분석:Elemental Analysis:
계산치: C 52.19%, H 6.13%, Br 23.14%Calculated: C 52.19%, H 6.13%, Br 23.14%
실측치: C 52.36%, H 6.12%, Br 23.23%Found: C 52.36%, H 6.12%, Br 23.23%
Claims (17)
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| 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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