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WO2011113925A2 - Carbonylation de composés organiques de zinc - Google Patents

Carbonylation de composés organiques de zinc Download PDF

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Publication number
WO2011113925A2
WO2011113925A2 PCT/EP2011/054104 EP2011054104W WO2011113925A2 WO 2011113925 A2 WO2011113925 A2 WO 2011113925A2 EP 2011054104 W EP2011054104 W EP 2011054104W WO 2011113925 A2 WO2011113925 A2 WO 2011113925A2
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compound
compounds
formula
licl
organic
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WO2011113925A3 (fr
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Paul Knochel
Sebastian Bernhardt
Albrecht Metzger
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Ludwig-Maximilians-Universität München
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/12—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing organo-metallic compounds or metal hydrides
    • B01J31/122—Metal aryl or alkyl compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B49/00—Grignard reactions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
    • C07F3/06—Zinc compounds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
    • B01J2231/32—Addition reactions to C=C or C-C triple bonds
    • B01J2231/321—Hydroformylation, metalformylation, carbonylation or hydroaminomethylation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring

Definitions

  • the invention relates to processes for the preparation of organic compounds having at least one functional group, in particular of carboxylic acids, alcohols, esters, amides, ketones, aldehydes or amines, as well as compounds for their preparation and uses and the preparation of such compounds.
  • functional group in particular of carboxylic acids, alcohols, esters, amides, ketones, aldehydes or amines
  • Organometallic compounds are characterized by their high tolerance to functional groups and would therefore be ideally suited as nucleophiles for addition reactions to carbonyl groups.
  • organozinc compounds are normally inert to addition to carbonyl groups and provide only low yields. It is known that Lewis acids, such as CeCl 3 or LaCl 3 -2LiCl, must be used to increase the reactivity of carbonyl groups towards nucleophilic attack (Krasovskiy, 2006).
  • Organic carboxylic acids are of high economic importance, for example in the pharmaceutical field.
  • Examples of economically important carboxylic acids are Ibuprofen and phenylacetic acid derivatives (Martinez, 1993).
  • the known synthetic routes are often complicated and complicated or require toxic or expensive reagents.
  • the invention has for its object to provide methods and compounds which overcome the disadvantages mentioned above.
  • the invention is in particular the object of providing an efficient process for the production of organic carboxylic acids. It should be available in a simple manner and in an efficient process a variety of different organic carboxylic acids.
  • the method should preferably be feasible without toxic, aggressive or expensive reagents or catalysts. In particular, the use of precious metals should be avoided.
  • the method should also be energy efficient at low temperature and in a few steps within a short time feasible.
  • the invention addresses the problem of providing an efficient method for the synthesis of ibuprofen or similar organic carboxylic acids of pharmaceutical interest.
  • the invention is also based on the object to provide reagents which are suitable for the production of organic carboxylic acids. Furthermore, new efficient processes for the preparation of organic compounds having at least one functional group, in particular of carboxylic acids, alcohols, esters, amides, ketones, aldehydes or amines, as well as compounds for their preparation are to be provided.
  • the invention relates to a process for the preparation of organic carboxylic acids, comprising the steps a) providing a compound of the formula (Ia) or (Ib):
  • R, R 1 and R 2 are organic radicals which are selected independently of one another from benzyl, aryl, heteroaryl and alkyl radicals.
  • R 1 and R 2 are preferably identical, but they may also be different in a compound (Ib).
  • the halide X is preferably I, Br or Cl.
  • the halide Cl is preferably, in particular when using benzylic zinc reagents.
  • the zinc is bonded to carbon atoms.
  • the compounds are thus organometallischer nature.
  • the zinc in the compounds (Ia) and (Ib) is not bonded directly to a heteroaryl radical.
  • R, R 1 and R 2 are benzyl radicals wherein the aromatic ring of the benzyl radical is optionally substituted with at least one substituent R 4 selected as indicated below.
  • the length of the alkyl group is preferably between 1 and 10 carbon atoms, more preferably methyl, ethyl or propyl.
  • the alkoxy radical is preferably a methoxy or ethoxy radical.
  • the compound of the formula (Ia) or (Ib) is initially prepared in a step aO), starting from a compound of the formula (III):
  • R-X (III) by a reaction with magnesium, LiCl and ZnC .
  • the compound R-X is a bromide, in particular an aryl bromide. These are generally cheaper and better available than the comparable iodides.
  • the zinc compounds used in the present process are prepared by direct insertion of magnesium metal into organic halogen compounds in the presence of ZnCl 2 and LiCl (exemplified in Scheme 1).
  • ZnCl 2 is prepared by direct insertion of magnesium metal into organic halogen compounds in the presence of ZnCl 2 and LiCl (exemplified in Scheme 1).
  • R aryl, benzyl, alk
  • Scheme 1 Exemplary preparation of organozinc compounds by direct magnesium insertion in the presence of ZnCl 2 and LiCl.
  • R may also have other meanings, for example heteroaryl.
  • the preparation of the compounds (Ia) and (Ib) takes place in a one-pot process.
  • one-pot processes are generally advantageous since expensive purification steps are eliminated and comparatively simple devices can be used.
  • the further conversion to organic carboxylic acids or other organic compounds takes place.
  • organozinc compounds of the composition RZnX-LiCl with MgCl 2 powder or a solution of MgCl 2 in THF (Scheme 2, Equation 1).
  • the advantage of the one-pot process lies in the significantly shorter reaction times and lower temperatures required for the preparation and in the possibility of displaying diorganozinc species.
  • the preparation of aromatic zinc compounds by the in situ methodology is also possible starting from aryl bromides. It is also possible to react Grignard compounds of the type RMgX-LiCl with ⁇ 2 solution to give compounds of the type Ia and Ib (Scheme 2, Equation 2).
  • there is a restriction here with respect to the functional groups since it is assumed that an organomagnesium compound is used.
  • R aryl, benzyl, alkyl
  • R aryl, alkyl
  • X Cl, Br, I Scheme 2: Further Exemplary Representation of Zinc Compounds of Composition Ia and Ib.
  • R can also have other meanings, for example heteroaryl or benzyl.
  • the one-pot process resulting from the transmetalation reaction also MgCl 2 coordinates in the form of complex aggregates of the composition RZnX-MgCl 2 -LiCl or R ⁇ Zn-MgC ⁇ -LiCl in spatial proximity to the zinc atom.
  • This coordination sphere then allows the addition of C0 2 (Scheme 2a), carbonyl compounds, and imines under Lewis acid activation, probably via six-membered transition states.
  • Scheme 2a Lewis acid-mediated addition of organozinc reagents to CO 2 .
  • R aryl, benzyl, alkyl
  • X Cl, Br, I Scheme 3: Exemplary addition of organozinc compounds to CO 2 - representation of carboxylic acids. R can also have other meanings, for example heteroaryl.
  • the invention also provides a compound of the formula (Ib):
  • R 1 and R 2 are organic radicals and X is a halide.
  • the radicals R 1 , R 2 and X are preferably selected as indicated above.
  • the invention also provides a process for preparing a compound of the formula (Ib), where a compound of the formula (III):
  • R benzyl, aryl, heteroaryl, alkyl
  • FG OMe, CF 3, Hai, C0 2 Et, CN, SMe, HNBoc, TMS, NR 2, OTIPS
  • the compounds of the formula (Ib) have good stability.
  • the organozinc species were usually prepared on a 20 mmol scale and then consumed within a period of 2-3 weeks. During this period, no significant change in concentration could be detected by titration with iodine.
  • the compounds of formula (Ib) according to the invention may generally be used for the preparation of organic compounds having functional groups such as carboxylic acids, esters, ketones, imides, alcohols, amides or amines, e.g. be used with the use of carbon dioxide, carbonyl compounds, isocyanates or imines.
  • ketones or aldehydes can be used as starting materials for the preparation of alcohols.
  • the reaction with imines allows the preparation of amines.
  • the reaction with isocyanates allows the preparation of amides.
  • the further esterification or amidation of the products allows the synthesis of esters and amides.
  • the starting materials used are compounds R-X as described above. The procedure can be analogous to the procedures of Metzger, 2008 and Piller, 2008.
  • reactions with further starting compounds, such as nitriles, epoxides, thioesters, etc. are also conceivable.
  • the compound (Ia) is 1- (4'-isobutylphenyl) ethyl-Zn-Cl-MgCl 2 -LiCl and the compound (II) is ibuprofen.
  • Ibuprofen is an important medicine that has anti-inflammatory, analgesic and anti-pyretic effects.
  • the synthesis relies entirely on the use of toxic and costly reagents and also does not use environmentally questionable transition metal based catalyst systems such as palladium catalysts.
  • this newly developed ibuprofen synthesis offers a more cost-efficient and ecologically safer access to ibuprofen (8) in a very high yield (Scheme 5).
  • ibuprofen The synthesis of ibuprofen is based on the commercially available 4-isobutylacetophenone
  • the process according to the invention is used for the preparation of phenylacetic acid derivatives.
  • the starting compound of the formula (III) is then a compound aryl / heteroaryl-CH 2 -X or a derivative thereof.
  • the reaction of benzylic zinc compounds of the formula (Ia) or (Ib) with C0 2 allows the preparation of phenylacetic acid derivatives of type 9, which are common target molecules of pharmaceutical chemistry.
  • Scheme 6 Exemplary general representation of type 9 phenylacetic acid derivatives.
  • the inventive method for producing a variety of organic acids can be used.
  • the process is used for the preparation of ibuprofen, naproxen, fluribiprofen, carprofen, phenylacetic acid or derivatives of these acids.
  • the process of the present invention application with the zinc reagents used differs markedly from organozinc species that result from metallation reactions with the zinc amide base (tmp) 2 Zn-2MgCl 2 -2LiCl. Since it is only possible with the help of Zinka- midbase to metallate electron-deficient aromatic or heteroaromatic systems, only aromatic zinc reagents with highly electron-withdrawing functional groups or very electron-poor heterocyclic zinc reagents can be obtained in this way. However, due to their electronic properties, these zinc species are not reactive enough to react with the electrophile CO 2 . Consequently, even in these substrate classes, the metallation method does not represent an alternative to the oxidative additions used here for the preparation of the zinc reagents.
  • carboxylic acids were synthesized according to the method of the present invention with CO2.
  • Table 1 shows the reactions. Indicated are also the reaction times and yields.
  • MeO MeO "MeO kZn-2MgBrCl-2LiCl 12/50 ° C C0 2 H 76
  • the innovation and the advantage of the invention on the one hand is that the reactions can be carried out under relatively mild conditions without transition metal catalysis in the toxicologically acceptable solvent THF. Furthermore, it was shown that functionalized benzylic zinc reagents of the composition RZnCl LiCl (R: benzyl), which had been prepared by zinc insertion in the presence of LiCl, showed no reactivity towards CO 2 in THF.
  • LiCl (1.06 g, 25.0 mmol) was dried in a Schlenk tube for 10 min at 500 ° C under high vacuum and then dissolved under argon in THF (10 ml).
  • ZnCl 2 (11.0 mL, 11.0 mmol, 1.00 M in THF) and magnesium turnings (0.61 g, 25.0 mmol) were added and the reaction mixture was cooled to 25 ° C with a water bath.
  • 1- (1-Chloro-ethyl) -4-isobutyl-benzene (6, 1.97 g, 10.0 mmol) was added dropwise and the Reaction mixture stirred for 2 h at room temperature.
  • the titration of the zinc reagent 7 against iodine gave a concentration of 0.33 M (7.2 mmol, 72%).
  • a Schlenk tube was heated in a high vacuum and filled with pre-dried via calcium chloride C0 2 gas.
  • 1- (4'-Isobutylphenyl) ethylzinc chloride-magnesium chloride-lithium chloride (7.6ml, 0.32M in THF, 1.8mmol) was added and C0 2 gas was bubbled through the solution for 5 min.
  • the reaction mixture was stirred for 12 h at 25 ° C and then heated to 50 ° C for 12 h.
  • Diethyl ether (20ml) was added and the organic phase extracted with 2M NaOH (3x20ml).
  • the combined aqueous phases were acidified with 2 M HCl (pH ⁇ 5) and extracted with diethyl ether (3 ⁇ 20 ml).
  • the reaction according to the invention with the electrophile C0 2 was carried out starting from monobenzylic zinc reagents of the composition RZnCl-MgCl 2 -LiCl (prepared according to Metzger, 2008) and bisbenzylic zinc reagents in a comparative experiment.
  • 4-fluorobenzylzinc chloride-magnesium chloride-lithium chloride with CO 2 after 12 h at 50 ° C (4-fluoro-phenyl) -acetic acid (2), it could be isolated in 61% yield (see Scheme 7 below).
  • bis (2-fluorobenzylzinc) magnesium chloride-lithium chloride (3) could (2-fluoro-phenyl) -acetic acid (4) after 6 h at room temperature in 100% yield isolated.
  • the comparative experiment demonstrates that bisbenzylic zinc reagents of the present invention the composition R 2 Zn-2 2MgCl -2LiCl a higher reactivity toward C0 2 having as the primary benzylic zinc reagent composition RZnCl-MgCl 2 -LiCl.
  • the diaryl zinc reagent 6a was obtained by reaction of 4-bromoanisole (1.0 equiv.) With Mg (2.5 equiv.), LiCl (0.75 equiv.), And ZnCl 2 (0.55 equiv.) In THF at 25 ° C over 2 h.
  • the corresponding diaryl zinc reagent 6a containing MgX 2 (X: Cl, Br; 2.0 equiv) reacts with ketone 2b within 2 h at 25 ° C and both Ar groups are transferred to the ketone (Equation 2, Scheme 8) ).
  • Bisarylic zinc compounds of type 6 Ar 2 Zn-2MgX 2 -2LiCl, 0.6 equiv.
  • both Ar groups are transferred during the carbonyl addition reaction.
  • the addition of i? Z ' s- (4-methoxyphenyl) zinc-2MgX 2 -LiCl (6a) to aliphatic ketones such as dicyclopropyl ketone (2h) or cyclopentanone (2i) occur within 2 h and 12 h respectively and lead to the Alcohols 3h-i in 84-87% yield (entries 2-3).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de production de composés organiques présentant au moins un groupe fonctionnel, notamment des acides carboxyliques, alcools, esters, amides, cétones, aldéhydes ou amines, ainsi que des composés destinés à leur production. L'invention porte également sur des utilisations et sur la production de tels composés.
PCT/EP2011/054104 2010-03-18 2011-03-18 Carbonylation de composés organiques de zinc WO2011113925A2 (fr)

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DE102010003015.5 2010-03-18
DE102010003015A DE102010003015A1 (de) 2010-03-18 2010-03-18 Carbonylierung von organischen Zinkverbindungen

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2746259A1 (fr) 2012-12-21 2014-06-25 Basf Se Composés de [1,2,4]triazole et d'imidazole substitués
EP2746260A1 (fr) 2012-12-21 2014-06-25 Basf Se Composés de [1,2,4]triazole et d'imidazole substitués
CN106518655A (zh) * 2016-09-08 2017-03-22 山东理工大学 一种通过添加晶形控制剂自水溶液中制备片状布洛芬晶体的方法

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US5068448A (en) 1989-12-04 1991-11-26 Hoechst Celanese Corporation Process for the production of 4'-isobutylacetophenone

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US5068448A (en) 1989-12-04 1991-11-26 Hoechst Celanese Corporation Process for the production of 4'-isobutylacetophenone

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2746259A1 (fr) 2012-12-21 2014-06-25 Basf Se Composés de [1,2,4]triazole et d'imidazole substitués
EP2746260A1 (fr) 2012-12-21 2014-06-25 Basf Se Composés de [1,2,4]triazole et d'imidazole substitués
CN106518655A (zh) * 2016-09-08 2017-03-22 山东理工大学 一种通过添加晶形控制剂自水溶液中制备片状布洛芬晶体的方法
CN106518655B (zh) * 2016-09-08 2019-01-04 山东理工大学 一种通过添加晶形控制剂自水溶液中制备片状布洛芬晶体的方法

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DE102010003015A1 (de) 2011-11-17

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