WO2004024663A1 - Procede de production metallo-organique de produits intermediaires organiques par des reactions d'echange halogene-metal - Google Patents

Procede de production metallo-organique de produits intermediaires organiques par des reactions d'echange halogene-metal Download PDF

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Publication number
WO2004024663A1
WO2004024663A1 PCT/EP2003/009251 EP0309251W WO2004024663A1 WO 2004024663 A1 WO2004024663 A1 WO 2004024663A1 EP 0309251 W EP0309251 W EP 0309251W WO 2004024663 A1 WO2004024663 A1 WO 2004024663A1
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WIPO (PCT)
Prior art keywords
arylaminoalkyl
halogen
alkyl
chlorine
aryl
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PCT/EP2003/009251
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German (de)
English (en)
Inventor
Andreas Meudt
Bernd Lehnemann
Michael Erbes
Klaus Forstinger
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Clariant Produkte Deutschland GmbH
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Clariant GmbH
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
    • C07C29/38—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones
    • C07C29/40—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones with compounds containing carbon-to-metal bonds
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/15—Preparation of carboxylic acids or their salts, halides or anhydrides by reaction of organic compounds with carbon dioxide, e.g. Kolbe-Schmitt synthesis

Definitions

  • the invention relates to a process for the preparation of organic compounds by producing aryllithium compounds and their reaction with suitable electrophiles, an intermediate aryllithium compound being generated first by reacting halogen aromatics with lithium metal (step 1 in equation I), which is then carried out in a halogen metal Exchange reaction is carried out with sufficiently reactive aromatic halogen compounds to form the desired lithium aromatics (step 2 in equation I), which are then reacted with an appropriate electrophile (step 3 in equation 1).
  • Step 1 creating the base lithium
  • halogen-metal exchange in which mostly bromoaromatics are reacted with n-butyllithium or phenyllithium at low temperatures.
  • the less reactive phenyllithium is particularly used on electron poor substrates, e.g. polyhalogenated benzenes or benzotrifluoride, and / or if a particularly high selectivity is required.
  • Li organyls can also be prepared by reacting aromatic bromates with lithium metal
  • lithium amides e.g. LDA or LiNSi
  • SCHLOSSER Superbases RLi / KOtBu
  • benzene deprotonation
  • phenyl halide metal-halogen exchange
  • Tolyllithium could be replaced. This would eliminate the problem of the gaseous butane (deprotonation) or halobutane (halogen-metal exchange with one equivalent of BuLi) that arises when using butyllithium, which has to be laboriously collected or flared in order to meet the strict pollution control regulations.
  • the present invention achieves all of these objects and relates to a process for the preparation of aryllithium compounds and their conversion with suitable electrophiles to give compounds of the formula (V) by reacting halogen aromatics (I) with lithium metal to form an aromatic lithium compound (II) (step 1 in equation 1 ), which reacts as a lithiation reagent with aromatic halogen compounds (III) with a halogen-metal exchange reaction to give the corresponding lithium aromatics (IV) (step 2 in equation 1), which in a further step with an appropriate electrophile to form the desired product (V ) can be reacted (step 3 in equation I), Step 1: creating the base lithium
  • Ar is phenyl, pyridyl or naphthyl, which are optionally substituted by a radical from the following group: ⁇ methyl, primary, secondary or tertiary alkyl, cycloalkyl, phenyl, substituted phenyl, aryl, heteroaryl, alkoxy, dialkylamino, alkylthio, fluoro, Bromo ⁇
  • Preferred compounds of the formula (III) which can be reacted by the process according to the invention are, for example, benzenes, pyridines, pyrimidines, pyrazines, pyridazines, furans, thiophenes, pyrroles, any N-substituted pyrroles or naphthalenes.
  • Examples include bromobenzene, 2-, 3- and 4-bromobenzotrifluoride, 2-, 3- and 4-chlorobenzotrifluoride, furan, 2-methylfuran, furfural acetals, thiophene, 2-methylthiophene, N-trimethylsilylpyrrole, 2,4-dichlorobromobenzene, Pentafluorobromobenzene, pentachlorobromobenzene and 4-bromo- or 4-iodobenzonitrile.
  • the radicals R- ⁇ - 5 represent substituents from the group ⁇ hydrogen, methyl, primary, secondary or tertiary, cyclic or acyclic alkyl radicals having 2 to 12 carbon atoms, in which one or more hydrogen atoms are optionally replaced by fluorine or chlorine, eg CF 3 , substituted cyclic or acyclic alkyl groups, alkoxy, dialkylamino, alkylamino, arylamino, diarylamino, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, alkylthio, arylthio, diarylphosphino, dialkylphosphino, alkylarylphosphino, dialkyl-, aryl-, aryl-, aryl-, alkyl-, aryl-, alkyl-, aryl-, alkyl- or monoarylaminocarbonyl, C0 2 -, alkyl or aryl
  • the lithium organyls prepared in this way can be reacted with any electrophilic compounds by methods of the prior art.
  • carbon electrophiles for example, C, C-
  • halogen aromatics All available fluorine, chlorine, bromine or iodine aromatics can be used as halogen aromatics (I), since lithium metal in ethereal solvents reacts easily with all halogen aromatics and in almost all cases with quantitative yields.
  • Chlorine or Aromatic bromines are used because iodine compounds are often expensive, fluorine compounds lead to the formation of LiF, which can lead to material problems in later aqueous work-ups as HF. In special cases, however, such halides can also be used advantageously.
  • the halogen aromatics can be used in pure isomers or as technical isomer mixtures, which is often even more cost-effective.
  • Aryl halides are preferably used which, after the halogen-metal exchange, are converted to aromatics or aryl halides which can be easily removed in the workup.
  • Isomerically pure chlorine or bromotoluenes the reaction products of which can be easily removed by distillation or azeotropic distillation, are particularly preferred.
  • Higher-boiling halogen aromatics can also be used for volatile products.
  • Suitable ethereal solvents are, for example, tetrahydrofuran, dioxane, diethyl ether, di-n-butyl ether, diisopropyl ether, diethylene glycol dibutyl or methyl ether or anisole; THF is preferably used.
  • the preferred reaction temperatures are between -120 and + 25 ° C, temperatures between -80 and 0 ° C are particularly preferred.
  • the aryl halide is first metered into the lithium metal in the ether, the lithium aromatic (II) initially forming. Subsequently, the halogen aromatic (III) to be metallized added and after the halogen-metal exchange of the electrophilic reactants.
  • the lithium can be used as a dispersion, powder, chips, sand, granules, pieces, bars or in some other form, the size of the lithium particles not being quality-relevant but merely influencing the reaction times. Smaller particle sizes are therefore preferred, for example granules, powders or dispersions.
  • the amount of lithium added is 1.95 to 2.5 mol, preferably 1.98 to 2.15 mol, per mole of halogen to be reacted.
  • Aromatics which can be used for halogen-metal exchange are initially all aromatic bromine and iodine compounds. It applies to chlorine compounds that those with activating, ie strongly electron-withdrawing substituents such as CF 3 radicals, can be lithiated in partially good yields.
  • the lithium aromatics (IV) generated according to the invention can be reacted with eiectrophilic compounds by the methods familiar to the person skilled in the art, carbon, boron and silicon electrophiles in particular being of interest to the pharmaceutical and agrochemical industry with regard to the required intermediates.
  • Alkali and alkaline earth salts of carboxylic acids (ArCHO for formates, ArCOCH 3 for
  • Aromatic nitriles (ArCOAr ' )
  • Alkylating agent Ar-alkyl
  • Trialkoxyboranes BF 3 * OR 2 , BF 3 * THF, BCI 3 or BBr 3 , particularly preferably trialkoxyboranes.
  • SiW 4 Compounds of the formula SiW 4 are used as silicon electrophiles, in which W independently of one another is the same or different (CrC 6 alkoxy), fluorine, chlorine, bromine, iodine, N (-C 6 alkyl) 2 or S (CrC 5 -AlkyI), tetraalkoxysilanes, tetrachlorosilanes or substituted alkyl- or aryl-halosilanes or substituted alkyl- or aryl-alkoxysilanes are preferred.
  • the workups are generally aqueous, with either water or aqueous mineral acids being metered in or the reaction mixture being metered into water or aqueous mineral acids.
  • the pH of the product to be isolated is set here, ie usually a slightly acidic, in the case of heterocycles also slightly alkaline pH.
  • the reaction products are obtained, for example, by extraction and evaporation of the organic phases, alternatively the organic solvents can also be distilled off from the hydrolysis mixture and the product which then precipitates can be obtained by filtration.
  • the purities of the products from the processes according to the invention are generally high, but a further purification step, for example by recrystallization with the addition of small amounts of activated carbon, may be required for special applications (pharmaceutical precursors).
  • the yields of the reaction products are 60 to 99%, typical yields are in particular 85 to 95%.
  • the process according to the invention opens up a very economical method for carrying out the transformation of aromatic halogen into any residues in a very economical way.
  • the reaction mixture is added to 120 g of water, the pH is adjusted to 6.3 with 37% HCl and the low boilers are distilled off at 45 ° C. under a slight vacuum.
  • the organic phase is separated off and the aqueous phase is extracted twice with 70 ml of toluene each time. After vacuum fractionation, 27.9 g of 4-trifluoromethylacetophenone are obtained from the combined organic phases as a colorless liquid (0.148 mol, 87.2%), GC purity> 98% a / a.
  • the solution is allowed to warm to room temperature with stirring, hydrolyzed with 100 g of water, the pH of the aqueous phase is adjusted to conc. Hydrochloric acid to 4.5-5 and separates the phases.
  • the aqueous phase is extracted with 50 ml of toluene. Vacuum fractionation gives 10.4 g (0.707 mol, 70.7%) of 3-cyanobenzoic acid from the combined organic phases. GC purity> 98% a / a.
  • a solution of 0.105 mol of 4-tolyllithium in THF is prepared in accordance with the procedure given in Example 2.
  • 24.7 g (0.100 ml) of bromopentafluorobenzene are added dropwise over 15 minutes and the mixture is stirred for a further 45 minutes at -55 ° C.
  • 11.6 g (0.200 mol) of propionaldehyde are added over 20 min and the mixture is allowed to warm to room temperature.
  • the reaction mixture is hydrolyzed by carefully adding 100 ml of 2N hydrochloric acid and the phases are separated.
  • aqueous phase is extracted again with 50 ml of toluene and the combined organic phases are distilled in vacuo after addition of 0.1 g of light magnesium oxide to avoid elimination. 19.2 g (0.085 mol, 84.9%) of 1-pentafluorophenylpropanoI are obtained, HPLC purity> 97% a / a.
  • a solution of 0.105 mol of 4-tolyllithium in THF is prepared in accordance with the instructions given in Example 2.
  • 17.5 g (0.100 mol) of 4-fluorobromobenzene are added dropwise at -70 ° C. over 15 minutes and the mixture is stirred at this temperature for 45 minutes.
  • 4.5 g (0.050 mol) of dimethyl carbonate are quickly added dropwise and the reaction mixture is warmed to room temperature over 6 h.
  • the crude product is distilled in vacuo.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé pour produire des composés d'aryllithium et pour faire réagir ces composés avec des réactifs électrophiles appropriés de façon à produire des composés de formule (V) par la mise en réaction d'aromates halogénés (I) avec du métal lithium pour former un composé de lithium aromatique (II) réagissant, en tant que réactif de lithiation, avec des composés halogénés aromatiques (III) par une réaction d'échange halogène-métal pour former les aromates de lithium correspondants (IV), ces derniers pouvant être mis en réaction, au cours d'une étape ultérieure, avec un réactif électrophile correspondant pour former le produit souhaité (V). Ledit procédé est représenté par l'équation (I) suivante, dans laquelle Ar désigne phényle, pyridyle ou naphtyle éventuellement substitués par un reste du groupe constitué par méthyle, alkyle primaire, secondaire ou tertiaire, cycloalkyle, phényle, phényle substitué, aryle, hétéroaryle, alcoxy, dialkylamino, alkylthio, fluoro, bromo ; Hal<1> = fluor, chlore, brome ou iode ; Hal<2> = chlore, brome ou iode ; les restes X1-5 représentent indépendamment carbone ou le reste XiRi (i = 1-5) signifie azote ou deux XiRi adjacents, reliés par une liaison double formique, peuvent signifier ensemble O (furane), S (thiophène), NRH ou NR (pyrroles). Les restes R1-5 représentent des substituants du groupe constitué par hydrogène, méthyle, des restes alkyle primaire, secondaire ou tertiaire, cycliques ou acycliques présentant 2 à 12 atomes de carbone, un ou plusieurs atomes d'hydrogène étant éventuellement remplacés par fluor ou chlore, p. ex. CF3, des groupes alkyle cycliques ou acycliques substitués, alcoxy, dialkylamino, alkylamino, arylamino, diarylamino, phényle, phényle substitué, hétéroaryle, hétéroaryle substitué, alkylthio, arylthio, diarylphosphino, dialkylphosphino, alkylarylphosphino, dialkyl-, arylalkyl- ou diarylaminocarbonyl, monoalkyl- ou monoarylaminocarbonyle, CO2<->, alkyl- ou aryloxycarbonyle, hydroxyalkyle, alcoxyalkyle, fluor ou chlore, nitro, cyano, aryl- ou alkylsulfone, aryl- ou alkylsulfonyle ou deux restes R1-5 adjacents peuvent correspondre ensemble à un cycle aromatique, hétéroaromatique ou aliphatique condensé.
PCT/EP2003/009251 2002-08-31 2003-08-21 Procede de production metallo-organique de produits intermediaires organiques par des reactions d'echange halogene-metal Ceased WO2004024663A1 (fr)

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DE10240261.2 2002-08-31
DE10240261A DE10240261A1 (de) 2002-08-31 2002-08-31 Verfahren zur metallorganischen Herstellung organischer Zwischenprodukte über Halogen-Metall-Austauschreaktionen

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7196089B2 (en) 2003-01-29 2007-03-27 Asterand Uk Limited EP4 receptor antagonists
US7417068B2 (en) 2003-10-16 2008-08-26 Asterand Uk Limited EP4 receptor antagonists
US7456176B2 (en) 2004-04-08 2008-11-25 Targegen, Inc. Benzotriazine inhibitors of kinases
US7528143B2 (en) 2005-11-01 2009-05-05 Targegen, Inc. Bi-aryl meta-pyrimidine inhibitors of kinases
WO2009089310A1 (fr) * 2008-01-11 2009-07-16 Dow Agrosciences Llc Procédé pour la déprotonation et la fonctionnalisation sélectives de 1-fluoro-2-substitué-3-chlorobenzènes
US8133900B2 (en) 2005-11-01 2012-03-13 Targegen, Inc. Use of bi-aryl meta-pyrimidine inhibitors of kinases
US8372971B2 (en) 2004-08-25 2013-02-12 Targegen, Inc. Heterocyclic compounds and methods of use
US8604042B2 (en) 2005-11-01 2013-12-10 Targegen, Inc. Bi-aryl meta-pyrimidine inhibitors of kinases
US8884034B2 (en) 2009-07-08 2014-11-11 Dermira (Canada), Inc. TOFA analogs useful in treating dermatological disorders or conditions
US10391094B2 (en) 2010-11-07 2019-08-27 Impact Biomedicines, Inc. Compositions and methods for treating myelofibrosis
CN112028739A (zh) * 2019-06-04 2020-12-04 湖北大学 邻二卤代芳烃化合物功能化的方法
CN114805019A (zh) * 2022-04-25 2022-07-29 华东师范大学 一种基于连续流反应技术合成2-芳基-1-环己醇的方法

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
A. N. DOBRODEI, A. V. EL'TSOV, RUSS. J. GEN. CHEM., vol. 70, no. 1, 2000, pages 158 - 159 *
A. P. BATALOV, RUSS. J. PHYS. CHEM. (ENGL. TRANSL.), vol. 63, no. 2, 1989, pages 192 - 195 *
ACTA CHEM. SCAND, vol. 3, 1949, pages 655 *
DATABASE CROSSFIRE BEILSTEIN [online] Beilstein Institut zur Förderung der Chemischen Wissenschaften, Frankfurt am Main, DE; XP002263004, Database accession no. 3666487,653874 *
DATABASE CROSSFIRE BEILSTEIN [online] Beilstein Institut zur Förderung der Chemischen Wissenschaften, Frankfurt am Main, DE; XP002263005, Database accession no. 907180 *
DATABASE CROSSFIRE BEILSTEIN [online] Beilstein Institut zur Förderung der Chemischen Wissenschaften, Frankfurt am Main, DE; XP002263006, Database accession no. 2925155 *
DATABASE CROSSFIRE BEILSTEIN [online] Beilstein Institut zur Förderung der Chemischen Wissenschaften, Frankfurt am Main, DE; XP002263007, Database accession no. 8695618,8714834 *
DATABASE CROSSFIRE BEILSTEIN [online] Beilstein Institut zur Förderung der Chemischen Wissenschaften, Frankfurt am Main, DE; XP002263008, Database accession no. 2925302 *
GILMAN, SPATZ, J. AMER. CHEM. SOC., vol. 66, 1944, pages 621 *
L. S. LIEBESKIND, J. ZHANG, J. ORG. CHEM., vol. 56, no. 22, 1991, pages 6379 - 6385 *

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7196089B2 (en) 2003-01-29 2007-03-27 Asterand Uk Limited EP4 receptor antagonists
US7858644B2 (en) 2003-01-29 2010-12-28 Asterand Uk Limited EP4 receptor antagonists
US7528157B2 (en) 2003-01-29 2009-05-05 Asterand Uk Limited EP4 receptor antagonists
US7507754B2 (en) 2003-01-29 2009-03-24 Asterand Uk Limited EP4 receptor antagonists
US7417068B2 (en) 2003-10-16 2008-08-26 Asterand Uk Limited EP4 receptor antagonists
US7569602B2 (en) 2003-10-16 2009-08-04 Asterand Uk Limited Furan derivatives as EP4 receptor antagonists
US7456176B2 (en) 2004-04-08 2008-11-25 Targegen, Inc. Benzotriazine inhibitors of kinases
US8481536B2 (en) 2004-04-08 2013-07-09 Targegen, Inc. Benzotriazine inhibitors of kinases
US8372971B2 (en) 2004-08-25 2013-02-12 Targegen, Inc. Heterocyclic compounds and methods of use
US7528143B2 (en) 2005-11-01 2009-05-05 Targegen, Inc. Bi-aryl meta-pyrimidine inhibitors of kinases
US8604042B2 (en) 2005-11-01 2013-12-10 Targegen, Inc. Bi-aryl meta-pyrimidine inhibitors of kinases
US8133900B2 (en) 2005-11-01 2012-03-13 Targegen, Inc. Use of bi-aryl meta-pyrimidine inhibitors of kinases
US7825246B2 (en) 2005-11-01 2010-11-02 Targegen, Inc. Bi-aryl meta-pyrimidine inhibitors of kinases
US8138199B2 (en) 2005-11-01 2012-03-20 Targegen, Inc. Use of bi-aryl meta-pyrimidine inhibitors of kinases
WO2009089310A1 (fr) * 2008-01-11 2009-07-16 Dow Agrosciences Llc Procédé pour la déprotonation et la fonctionnalisation sélectives de 1-fluoro-2-substitué-3-chlorobenzènes
CN101970446A (zh) * 2008-01-11 2011-02-09 陶氏益农公司 对1-氟-2-取代的-3-氯苯选择性脱质子化和官能化的方法
AU2009204153B2 (en) * 2008-01-11 2013-08-01 Corteva Agriscience Llc Process for the selective deprotonation and functionalization of 1-Fluoro-2-substituted-3-chlorobenzenes
KR20100114893A (ko) * 2008-01-11 2010-10-26 다우 아그로사이언시즈 엘엘씨 1-플루오로-2-치환된-3-클로로벤젠의 선택적 탈양성자화 및 관능화 방법
EA020444B1 (ru) * 2008-01-11 2014-11-28 ДАУ АГРОСАЙЕНСИЗ ЭлЭлСи 1-фтор-2-замещенные-3-хлорбензолы, содержащие заместитель в положении, соседнем с замещающим атомом фтора
KR101599566B1 (ko) 2008-01-11 2016-03-03 다우 아그로사이언시즈 엘엘씨 1-플루오로-2-치환된-3-클로로벤젠의 선택적 탈양성자화 및 관능화 방법
US8884034B2 (en) 2009-07-08 2014-11-11 Dermira (Canada), Inc. TOFA analogs useful in treating dermatological disorders or conditions
US9434718B2 (en) 2009-07-08 2016-09-06 Dermira (Canada), Inc. TOFA analogs useful in treating dermatological disorders or conditions
US9782382B2 (en) 2009-07-08 2017-10-10 Dermira (Canada), Inc. TOFA analogs useful in treating dermatological disorders or conditions
US10391094B2 (en) 2010-11-07 2019-08-27 Impact Biomedicines, Inc. Compositions and methods for treating myelofibrosis
CN112028739A (zh) * 2019-06-04 2020-12-04 湖北大学 邻二卤代芳烃化合物功能化的方法
CN114805019A (zh) * 2022-04-25 2022-07-29 华东师范大学 一种基于连续流反应技术合成2-芳基-1-环己醇的方法
CN114805019B (zh) * 2022-04-25 2024-03-12 华东师范大学 一种基于连续流反应技术合成2-芳基-1-环己醇的方法

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