WO2011000532A2 - Procédé d’addition énantiosélective de nucléophiles carbonés organométalliques sur des trifluorométhylcétones et utilisation du procédé dans la synthèse d’inhibiteurs de la transcriptase inverse du vih - Google Patents

Procédé d’addition énantiosélective de nucléophiles carbonés organométalliques sur des trifluorométhylcétones et utilisation du procédé dans la synthèse d’inhibiteurs de la transcriptase inverse du vih Download PDF

Info

Publication number
WO2011000532A2
WO2011000532A2 PCT/EP2010/003907 EP2010003907W WO2011000532A2 WO 2011000532 A2 WO2011000532 A2 WO 2011000532A2 EP 2010003907 W EP2010003907 W EP 2010003907W WO 2011000532 A2 WO2011000532 A2 WO 2011000532A2
Authority
WO
WIPO (PCT)
Prior art keywords
zinc
group
alkyl
lower alkyl
alkenyl
Prior art date
Application number
PCT/EP2010/003907
Other languages
German (de)
English (en)
Other versions
WO2011000532A3 (fr
Inventor
Michael Nonnenmacher
Jörg Jung
Andreas Meudt
Original Assignee
Archimica Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Archimica Gmbh filed Critical Archimica Gmbh
Priority to EP10728609A priority Critical patent/EP2448917A2/fr
Publication of WO2011000532A2 publication Critical patent/WO2011000532A2/fr
Publication of WO2011000532A3 publication Critical patent/WO2011000532A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
    • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D265/18—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 2
    • 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
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a process for enantioselective addition reactions of organometallic nucleophiles with trifluoromethyl-substituted ketones.
  • the target compounds are tertiary alcohols which also include a particular class of substances which are suitable intermediates for the synthesis of benzoxazinones, which in turn are useful as inhibitors of human immunodeficiency virus reverse transcriptase.
  • Efavirenz is used as a potent inhibitor of human immunodeficiency virus (HIV) reverse transcriptase.
  • the manufacturing process involves a step of establishing a chiral center to which an amino-functional aryl group, an oxygen atom, a trifluoromethyl group and an alkynyl group are bonded.
  • a racemate resolution was carried out as a key step to obtain the desired S-enantiomer with high ee values of over 99%.
  • the inventive method meets all the requirements, since not only zinc salts such as inexpensive zinc (II) chloride can be used as a precursor for the formation of the chiral auxiliary complex, but also with standardized auxiliaries that are readily available in the market, excellent enantiomeric excesses are obtained. In addition, the process is very robust, provides virtually no secondary components and good yields. Summary of the invention:
  • the invention accordingly relates to a process for the preparation of compounds of the formula A1
  • R1 and R2 are independent of each other
  • terminal OH, NH 2 and NH-lower alkyl groups and acidic H atoms are unprotected or protected with a protective group
  • R3 and R4 independently of one another are C6-C14-aryl, C5-C13-heteroaryl, C1-C8-alkyl, C2-C8-alkenyl radicals or hydrogen and
  • R5 and R6 independently of one another are C6-C14-aryl, C5-C13-heteroaryl, C1-C8-
  • Alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl radicals or hydrogen are or
  • R5 and R6 together represent a C3-C7 alkylene or C3-C7 alkenylene radical
  • Configuration of the other center is a stereo center and has either the R or the S configuration
  • a second auxiliary selected from the group of alcohols, phenols, mercaptans,
  • Amines, carboxylic acids, urea derivatives or the nitrogen-containing, oxygen-containing or sulfur-containing heterocycles is selected,
  • R1-M in which R1 has the abovementioned meaning
  • M is selected from the group: lithium, sodium, potassium, magnesium halide, magnesium cyanide, magnesium lower alkyl alcoholate and then with a trifluoromethyl ketone
  • Heteroaryl is understood according to the invention to mean an aryl radical in which one or more carbon atoms are replaced by the heteroatoms N, S or O, where in the case of a plurality of heteroatoms they are identical or different.
  • halide is understood to mean fluoride, chloride, bromide, iodide, preferably chloride, bromide, iodide, very particularly preferably chloride or bromide.
  • lower alkyl is meant according to the invention a straight-chain or branched C 1 -C 4 -alkyl radical; preferably a methyl, ethyl, propyl, isopropyl or butyl radical; especially a methyl, ethyl or propyl radical.
  • a protective group is a carboxyl, preferably a 2,2-dimethylpropanoyl or an ethanoyl group, an alkoxycarbonyloxy, preferably a 2,2-dimethylpropanolylcarbonyloxy group, an alkoxymethyl,
  • the present invention thus relates to a process for the preparation of tertiary alcohols which carry a trifluoromethyl group;
  • the method is suitable tertiary alcohols of the formula
  • an organometallic nucleophile is added to a trifluoromethyl ketone with the addition of a selectivity-controlling, enantiomerically pure or enantiomerically enriched auxiliary complex.
  • one or more substituents of the tertiary alcohol is an aryl or heteroaryl radical, and in a particularly preferred embodiment of the invention, this aryl radical in the 2-position bears an amino function relative to the keto group.
  • compounds of this type can be used for the synthesis of benzoxazinones which are used as inhibitors of the reverse transcriptase of the HI virus.
  • the process is easy to handle, stably reproducible, requires only stable, storable and reasonably priced raw materials and delivers good yields and high enantioselectivities up to 100%.
  • R1 is a substituted C2-alkynyl radical and in a particularly preferred embodiment, a cyclopropylethynyl radical.
  • R 2 is a divalent substituted aryl radical and in a particularly preferred embodiment a (2-amino-5-chlorophenyl) radical.
  • M is selected from the group: MgCl, MgBr and MgI
  • the zinc (II) salt is zinc (II) chloride, bromide, iodide, cyanide, trifluoromethanesulfonate, benzenesulfonate, toluenesulfonate, methanesulfonate, oxide, acetate, acetylacetonate, citrate, nitrate, phosphate, - hydrogen phosphate, dihydrogen phosphate, stearate, sulfate, hydrogen sulfate, carbonate, bicarbonate, tetrafluoroborate, trifluoroacetate.
  • it is zinc (II) chloride, bromide, iodide, trifluoromethanesulfonate, benzenesulfonate, toluenesulfonate or methanesulfonate, and in a most preferred embodiment, zinc (II) chloride or zinc (II) trifluoromethanesulfonate.
  • R3 phenyl
  • it is (1 R, 2S-1-phenyl-2- (1-pyrrolidinyl) -1-propanol of the formula
  • the reaction also takes place in the presence of an organic or inorganic base such as: amines, metal alkoxides, metal thiolates, metal amides, complex hydrides, metal hydrides, carbon bases such as methyllithium, butyllithium or tert-butyllithium, carbonates, phosphates, phosphazene bases and hydroxides.
  • an organic or inorganic base such as: amines, metal alkoxides, metal thiolates, metal amides, complex hydrides, metal hydrides, carbon bases such as methyllithium, butyllithium or tert-butyllithium, carbonates, phosphates, phosphazene bases and hydroxides.
  • a inorganic base from the group of metal hydrides and complex hydrides and in a particularly preferred embodiment with a metal hydride selected from the group NaH, KH, LiH, LiAlH 4 , NaBH 4 , NaBH 3 CN.
  • reaction is conveniently carried out in the presence of a second additive which is selected from the group of alcohols, phenols, mercaptans, amines, carboxylic acids, urea derivatives or the nitrogen-containing, oxygen-containing or sulfur-containing heterocycles.
  • a second additive which is selected from the group of alcohols, phenols, mercaptans, amines, carboxylic acids, urea derivatives or the nitrogen-containing, oxygen-containing or sulfur-containing heterocycles.
  • This is preferably an alcohol, particularly preferably tert-butanol, 2,2-dimethylpropan-1-ol or benzyl alcohol.
  • the process according to the invention is preferably carried out by initially adding 0.8 to 3 equivalents (all equivalent amounts based on organometallic nucleophile) of zinc salt, preferably 1 to 1.5 equivalents in an organic solvent, preferably a dialkyl ether, in an inertized stirred vessel and most preferably in tetrahydrofuran.
  • an organic solvent preferably a dialkyl ether
  • an inertized stirred vessel and most preferably in tetrahydrofuran.
  • To this solution are added at a temperature of -50 ° to +80 0 C, preferably at a temperature of -30 ° C to +30 0 C 0.8 to 3.6 equivalents, preferably 1 to 1 equivalent of the enantiomerically pure or 8 enantiomerically enriched auxiliaries and 0.8 to 3.6 equivalents, preferably 0.8 to 1, 5 equivalents of the second additive.
  • the invention further relates to the reaction of the compound of the formula
  • the organic phase is washed twice with 100 g of 2% hydrochloric acid, once with 60 g of saturated potassium bicarbonate solution and once with 30 g of water and about 150-18Og of solvent are distilled off until a thick slurry remains.
  • the product is precipitated by addition of 60 g of hexane, filtered off with suction and recrystallized from hexane.
  • the aqueous phase is extracted once more with 50 g of ethyl acetate and the combined organic phases are washed twice with 70 g of 2% hydrochloric acid, once with 30 g of saturated potassium bicarbonate solution and once with 30 g of water.
  • the organic phase is dried over sodium sulfate (about 10 g) and the resulting suspension is filtered through Celite. Then about 80 g of solvent are distilled off and replaced by 80 g of ethanol. The process is repeated a total of three times. This gives 5.89 g (93.8%) of the desired benzoxazinone in ⁇ 7% solution in ethanol.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

L’invention concerne un procédé de production de composés de formule A1, dans laquelle l’atome de carbone auquel aussi bien le groupe CF3 que le groupe hydroxy sont liés est un stéréocentre qui présente la configuration R ou S et dans laquelle R1 et R2 sont indépendamment l’un de l’autre un radical alkyle en C1-C8, cycloalkyle en C3-C8, alcényle en C2-C8, cycloalcényle en C4-C8, alcynyle en C2-C8, aryle en C6-C14 ou hétéroaryle en C5-C13, les radicaux alkyle, alcényle et alcynyle étant linéaires ou ramifiés et tous les radicaux cités étant non substitués ou substitués une ou plusieurs fois par des substituants identiques ou différents choisis dans le groupe : halogénure, NO2, SO3H, SO3Na, SO3K, CN, OH, NH2, NH-alkyle inférieur, N-dialkyle inférieur, COOH, COO-alkyle inférieur, alkyle inférieur et cycloalkyle en C3-C6, et dans laquelle les groupes terminaux OH, NH2 et NH-alkyle inférieur et les atomes H acides sont non protégés ou protégés par un groupe protecteur, selon lequel un mélange d’un sel de zinc (II), d’un auxiliaire énantiomériquement pur ou énantiomériquement enrichi de formule (I), dans laquelle R3 et R4 représentent indépendamment l’un de l’autre des radicaux aryle en C6-C14, hétéroaryle en C5-C13, alkyle en C1-C8, alcényle en C2-C8 ou l’hydrogène et R5 et R6 représentent indépendamment l’un de l’autre des radicaux aryle en C6-C14, hétéroaryle en C5-C13, alkyle en C1-C8, alcényle en C2-C8, alcynyle en C2-C8 ou l’hydrogène, ou R5 et R6 représentent ensemble un radical alkylène en C3-C7 ou alcénylène en C3-C7, et au moins un des centres C1, C2, de préférence les deux, est un stéréocentre indépendamment de la configuration de l’autre centre et a la configuration R ou S, et d’un second auxiliaire, qui est choisi dans le groupe des alcools, phénols, mercaptans, amines, acides carboxyliques, dérivés d’urée ou des hétérocycles contenant de l’azote, contenant de l’oxygène ou contenant du soufre, est mis en réaction avec une base organique ou inorganique, puis ce mélange est mis en réaction avec un composé organométallique R1-M, dans lequel R1 a la signification susmentionnée et dans lequel M est choisi dans le groupe : lithium, sodium, potassium, halogénure de magnésium, cyanure de magnésium, alcoolate d’alkyle inférieur de magnésium, puis avec une trifluorométhylcétone (II), dans laquelle R2 a la signification susmentionnée.
PCT/EP2010/003907 2009-07-03 2010-06-25 Procédé d’addition énantiosélective de nucléophiles carbonés organométalliques sur des trifluorométhylcétones et utilisation du procédé dans la synthèse d’inhibiteurs de la transcriptase inverse du vih WO2011000532A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP10728609A EP2448917A2 (fr) 2009-07-03 2010-06-25 Procédé d addition énantiosélective de nucléophiles carbonés organométalliques sur des trifluorométhylcétones et utilisation du procédé dans la synthèse d inhibiteurs de la transcriptase inverse du vih

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102009031861 2009-07-03
DE102009031861.5 2009-07-03

Publications (2)

Publication Number Publication Date
WO2011000532A2 true WO2011000532A2 (fr) 2011-01-06
WO2011000532A3 WO2011000532A3 (fr) 2011-05-05

Family

ID=43086064

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2010/003907 WO2011000532A2 (fr) 2009-07-03 2010-06-25 Procédé d’addition énantiosélective de nucléophiles carbonés organométalliques sur des trifluorométhylcétones et utilisation du procédé dans la synthèse d’inhibiteurs de la transcriptase inverse du vih

Country Status (2)

Country Link
EP (1) EP2448917A2 (fr)
WO (1) WO2011000532A2 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012097511A1 (fr) * 2011-01-19 2012-07-26 Lonza Ltd Dmp-266 par cyclisation
US8852553B2 (en) 2008-01-08 2014-10-07 Lantheus Medical Imaging, Inc. N-alkoxyamide conjugates as imaging agents
US9156756B2 (en) 2008-01-31 2015-10-13 Laurus Labs Private Limited Efficient process to induce enantioselectivity in procarbonyl compounds
CN109761829A (zh) * 2019-02-19 2019-05-17 盐城迪赛诺制药有限公司 一种高手性纯度依非韦伦中间体的制备方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105523984B (zh) * 2015-09-07 2018-05-11 赤峰艾克制药科技股份有限公司 （1r，2s）-1-苯基-2-（1-吡咯烷基）-1-丙醇的制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0582455A1 (fr) 1992-08-07 1994-02-09 Merck & Co. Inc. Benzoxazinones utilisées comme inhibiteurs de transcriptase inverse de HIV
WO1996037457A1 (fr) 1995-05-25 1996-11-28 Merck & Co., Inc. Synthese asymetrique de (-) 6-chloro-4-cyclopropyle-ethynyle-4-trifluoromethyle-1,4-dihydro-2h-3,1-benzoxazin-2-one
WO1998051676A1 (fr) 1997-05-16 1998-11-19 Merck & Co., Inc. Reaction d'addition enantioselective efficace a reactif de type complexe organate-zinc
EP1614672A1 (fr) 2003-04-04 2006-01-11 Shanghai Institute Of Organic Chemistry, Chinese Academy Of Sciences Ligand amino-alcool et son utilisation dans la preparation d'alcools tertiaires propargyliques et d'amines tertiaires par le biais d'une reaction d'addition eniantioselective
WO2009095931A2 (fr) 2008-01-31 2009-08-06 Aptuit Laurus Pvt Ltd Procédé efficace pour induire une énantiosélectivité dans des composés procarbonyles

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5663169A (en) * 1992-08-07 1997-09-02 Merck & Co., Inc. Benzoxazinones as inhibitors of HIV reverse transcriptase

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0582455A1 (fr) 1992-08-07 1994-02-09 Merck & Co. Inc. Benzoxazinones utilisées comme inhibiteurs de transcriptase inverse de HIV
WO1996037457A1 (fr) 1995-05-25 1996-11-28 Merck & Co., Inc. Synthese asymetrique de (-) 6-chloro-4-cyclopropyle-ethynyle-4-trifluoromethyle-1,4-dihydro-2h-3,1-benzoxazin-2-one
WO1998051676A1 (fr) 1997-05-16 1998-11-19 Merck & Co., Inc. Reaction d'addition enantioselective efficace a reactif de type complexe organate-zinc
EP1614672A1 (fr) 2003-04-04 2006-01-11 Shanghai Institute Of Organic Chemistry, Chinese Academy Of Sciences Ligand amino-alcool et son utilisation dans la preparation d'alcools tertiaires propargyliques et d'amines tertiaires par le biais d'une reaction d'addition eniantioselective
WO2009095931A2 (fr) 2008-01-31 2009-08-06 Aptuit Laurus Pvt Ltd Procédé efficace pour induire une énantiosélectivité dans des composés procarbonyles

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
A. S. THOMPSON ET AL., TETRAHEDRON LETT., vol. 36, 1995, pages 8937 - 8940
L. TAN ET AL., ANGEW. CHEM. INT. ED., vol. 38, 1999, pages 711 - 713
S. D. YOUNG ET AL., ANTIMICROBAL AGENTS AND CHEMOTHERAPY, vol. 39, 1995, pages 2602 - 2605

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8852553B2 (en) 2008-01-08 2014-10-07 Lantheus Medical Imaging, Inc. N-alkoxyamide conjugates as imaging agents
US9156756B2 (en) 2008-01-31 2015-10-13 Laurus Labs Private Limited Efficient process to induce enantioselectivity in procarbonyl compounds
WO2012097511A1 (fr) * 2011-01-19 2012-07-26 Lonza Ltd Dmp-266 par cyclisation
CN109761829A (zh) * 2019-02-19 2019-05-17 盐城迪赛诺制药有限公司 一种高手性纯度依非韦伦中间体的制备方法

Also Published As

Publication number Publication date
WO2011000532A3 (fr) 2011-05-05
EP2448917A2 (fr) 2012-05-09

Similar Documents

Publication Publication Date Title
DE2503815C2 (de) Indazol-Derivate, Verfahren zu ihrer Herstellung und Arzneimittel
DE69824958T2 (de) Enantioselektive additions-reaktion mit hilfe eines organozink reagenzes
EP0794957B1 (fr) Procede de production de phosphines de metallocenyle optiquement actives
EP2448917A2 (fr) Procédé d addition énantiosélective de nucléophiles carbonés organométalliques sur des trifluorométhylcétones et utilisation du procédé dans la synthèse d inhibiteurs de la transcriptase inverse du vih
DE69710181T2 (de) 7-amino-2-heptenoate und ihre verwendung in der herstellung von methylphenidat
DE69118906T2 (de) Neue methoden zur katalytischen reduktion organischer substrate
DE69808093T2 (de) Verfahren zur herstellung von 2-substituierten 1-(tetrazol-5-yl)benzenverbindungen durch ortho-metallierung
DD202018A5 (de) Verfahren zur herstellung von 3,1-benzoxazin-2-onen
DE69518516T2 (de) Tetrahydroindenol[1,2-d][1,3,2]oxazaborole und deren verwendung als enantioselektive katalysatoren
DE2802864C2 (de) Verfahren zur Herstellung von 3-Isobutoxy-2-pyrrolidino-N-phenyl-N-benzylpropylamin
DE10150615A1 (de) Verfahren zur metallorganischen Herstellung organischer Zwischenprodukte
EP1070718B1 (fr) Procede de production de composes de grignard et nouveaux composes de grignard
EP1713800B1 (fr) Procede pour produire un derive de 2-(ethoxymethyl)-tropane
CH493517A (de) Verfahren zur Herstellung von Derivaten des 4-(2,6-Dioxo-3-piperidyl)-piperidins
DE4232505A1 (de) Verfahren zur Reduktion von Carbonsäuren oder Carbonsäurederivaten sowie neue Verbindungen
EP1010689A1 (fr) Cycloheptènes substitués, production et utilisation
DE2431201A1 (de) 4-aryldecahydro-1h-pyrrolo eckige klammer auf 3,4-f eckige klammer zu chinolinderivate, verfahren zu ihrer herstellung und arzneimittel
DE1468624C3 (fr)
EP1043306A2 (fr) Dérivés 3-Amino-3-arylpropan-1-ol leur préparation et leur usage
DE1645952A1 (de) Naphthalinderivate und Verfahren zur Herstellung solcher Verbindungen
DE2621539A1 (de) Eckige klammer auf (2-oxepanyliden) -methyl eckige klammer zu -triphenylphosphoniumsalze
WO2009141110A1 (fr) Procédé de synthèse sélective d'acétate de 3-alpha-hydroxychloromadinone
DE2505143A1 (de) Verfahren zur herstellung von spiro-(4,5)-decanderivaten
EP1076646A1 (fr) Procede pour la production stereochimiquement controlee de composes azacycliques isomeriquement purs hautement substitues
DE957842C (de) Verfahren zur Herstellung von neuen Octahydropyridopyrimidinverbindungen

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10728609

Country of ref document: EP

Kind code of ref document: A2

WWE Wipo information: entry into national phase

Ref document number: 2010728609

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE