WO2011009888A2 - Process for the production of substituted electron rich diphenylacetylenes - Google Patents
Process for the production of substituted electron rich diphenylacetylenes Download PDFInfo
- Publication number
- WO2011009888A2 WO2011009888A2 PCT/EP2010/060569 EP2010060569W WO2011009888A2 WO 2011009888 A2 WO2011009888 A2 WO 2011009888A2 EP 2010060569 W EP2010060569 W EP 2010060569W WO 2011009888 A2 WO2011009888 A2 WO 2011009888A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- phenyl
- alkyl
- compound
- branched
- Prior art date
Links
- 0 *c(cc1*)ccc1O Chemical compound *c(cc1*)ccc1O 0.000 description 2
- FYMYJWVDIMPSCJ-WAYWQWQTSA-N COc1cc(/C=C\c(cc2OC)cc(OC)c2OC)ccc1O Chemical compound COc1cc(/C=C\c(cc2OC)cc(OC)c2OC)ccc1O FYMYJWVDIMPSCJ-WAYWQWQTSA-N 0.000 description 1
- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Oc1ccc(/C=C/c2cc(O)cc(O)c2)cc1 Chemical compound Oc1ccc(/C=C/c2cc(O)cc(O)c2)cc1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 description 1
Classifications
-
- 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
- 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
- C07C41/20—Preparation of ethers by reactions not forming ether-oxygen bonds by hydrogenation of carbon-to-carbon double or triple bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
- C07C2603/74—Adamantanes
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K19/00—Liquid crystal materials
- C09K19/04—Liquid crystal materials characterised by the chemical structure of the liquid crystal components, e.g. by a specific unit
- C09K2019/0444—Liquid crystal materials characterised by the chemical structure of the liquid crystal components, e.g. by a specific unit characterized by a linking chain between rings or ring systems, a bridging chain between extensive mesogenic moieties or an end chain group
Definitions
- the present invention relates to an improved process for the production of substituted electron rich diphenylacetylenes (tolanes), which are starting materials for the production of stilbenes.
- the present invention relates to the process for production of a compound of formula (I)
- tolanes are characterized in that at least one of the phenyl rings is substituted by at least two substituents.
- the compounds according to formula (I) can be used as starting material for the production of the corresponding stilbenes.
- Some of the stilbenes are compounds with interesting pharmacological properties.
- Combretastatin A-4 is potent in regard to tubulin binding ability and it is also cytotoxic.
- Resveratrol is a well known nutritional supplement with healthy properties. Both compounds can be extracted from natural sources. For an industrial product extraction from natural sources is not suitable at all. Therefore these products are usually produced synthetically. Therefore there is always a need to simplify and optimize such processes of production or to provide new syntheses for the production.
- tolanes according to formula (I) For the production of tolanes according to formula (I) only synthesis using homogeneous catalytic systems are described. One of the most prominent ones is the Sonogashira coupling in which usually palladium catalysts under homogeneous conditions are used. Such a catalyst system is usually used in combination with a base and a halide salt of copper(l).
- the goal of the present invention was to find a process for the production of compounds of electron rich tolanes of formula (I), which does not have the disadvantages as mentioned above. Surprisingly it was found that when a heterogeneous catalytic system is used, the above mentioned disadvantages are overcome.
- the present invention relates to a process for the production of compounds of formula (I)
- R 1 is H; linear, branched or cyclic Ci-C 6 alkyl; tetrahydropyryl or -CH 2 - phenyl; preferably H; -CH 3 ; -CH 2 CH 3 , or -CH 2 -phenyl; more preferably H; -CH 3 ; or -CH 2 CH 3 ;
- R 2 is H or OR' 2 , wherein R' 2 is H; linear, branched or cyclic Ci-C 6 -alkyl or -CH 2 -phenyl; preferably R 2 is H or OR' 2 , wherein R' 2 is -CH 3 or -
- R 3 is H; linear, branched or cyclic Ci-C 6 alkyl; tetrahydropyryl or -CH 2 - phenyl; preferably H; -CH 3 ; -CH 2 CH 3 , or -CH 2 -phenyl; more preferably H; -CH 3 ; or -CH 2 CH 3 ;
- R 4 is H or OR' 4 , wherein R' 4 is H; linear, branched or cyclic Ci-C 6 -alkyl or -CH 2 -phenyl; preferably R 4 is H or OR' 4 , wherein R 4 is -CH 3 or -
- R 5 is H; linear, branched or cyclic Ci-C 6 alkyl; tetrahydropyryl or -CH 2 - phenyl; preferably H; -CH 3 ; -CH 2 CH 3 , or -CH 2 -phenyl; more preferably H; -CH 3 ; or -CH 2 CH 3 ; wherein a compound of formula (Na) or (lib)
- X is -I; -Br; -Cl; or -N 2 , is reacted with a compound of formula (Ilia) or (MIb)
- the linear, branched and cyclic Ci-C 6 -alkyl groups (in the definition of R-i, R 2 , R' 2 , R 3 , R 4 , R 4 and R 5 ) can also be substituted. Suitable substituents are d-C 4 alkoxy (preferably -OCH 3 and -OCH 2 CH 3 ) and aryl. In case one or more linear, branched and cyclic C-i-C 6 -alkyl groups are substituted by at least one substituent, then the substituent is chosen from the group consisting of Ci-C 4 alkoxy (preferably -OCH 3 and -OCH 2 CH 3 ) and aryl.
- the -CH 2 -phenyl groups (in the definition of R 1 , R 2 , R' 2 , R 3 , R 4 , R' 4 and R 5 ) can also be substituted.
- Suitable substituents are C 1 -C 4 alkyl (preferably -CH 3 and - CH 2 CH 3 ) and aryl.
- the substituent is chosen from the group consisting of CrC 4 alkyl (preferably -CH 3 and -CH 2 CH 3 ); C- ⁇ -C 4 alkoxy (preferably -OCH 3 and - OCH 2 CH 3 ) and aryl.
- a preferred embodiment of the present invention is a process for the production of a compound of formula (I) as described above, wherein a compound of formula (Ha) is reacted with a compound of formula (Ilia).
- Another preferred embodiment of the present invention is a process for the production of a compound of formula (I) as described above, wherein a compound of formula (Mb) is reacted with a compound of formula (IMb).
- Preferred compounds, which are produced according to the process of the present invention, are compounds of formula (Ia)
- R-i, R3 and R 5 are independently from each other H; linear, branched or cyclic d- Ce-alkyl; tetrahydropyryl or-CH 2 -phenyl.
- R-i, R 3 and R 5 are independently from each other H; -CH 3 or -CH 2 CH 3 . More preferably R-i, R 3 and R 5 are H. Further more preferably Ri, R 3 and R 5 are CH 3 .
- the linear, branched and cyclic Ci-C6-alkyl groups (in the definition of R-i, R 3 and R 5 ) can also be substituted. Suitable substituents are Ci-C 4 alkoxy (preferably -OCH 3 and -OCH 2 CH 3 ) and aryl. In case one or more linear, branched and cyclic C-i-Ce-alkyl groups are substituted by at least one substituent, then the substituent is chosen from the group consisting of Ci-C 4 alkoxy (preferably -OCH 3 and -OCH 2 CH 3 ) and aryl.
- the -CH 2 -phenyl groups (in the definition of Ri, R 3 and R 5 ) can also be substituted.
- Suitable substituents are d-C 4 alkyl (preferably -CH 3 and -CH 2 CH 3 ) and aryl. In case one or more -CH 2 -phenyl groups are substituted by at least one substituent, then the substituent is chosen from the group consisting of d-C 4 alkyl (preferably -CH 3 and -CH 2 CH 3 ); d-C 4 alkoxy (preferably -OCH 3 and - OCH 2 CH 3 ) and aryl.
- R-i, R'2, R3, R'4 and R5 are independently from each other H; linear, branched or
- R' 2 , R3, R 4 ', and R 5 are independently from each other -CH 3 or -CH 2 CH 3 , and Ri is H. More preferably R' 2 , R 3 , R' 4 and R 5 are independently from each other -CH 3 or -CH 2 CH 3 , and Ri is H. Most preferably Ri is H and R' 2 , R 3 , R' 4 and R 5 are -CH 3 .
- the linear, branched and cyclic C r C 6 -alkyl groups (in the definition of R 1 , R' 2 , R 3 , R 4 and R 5 ) can also be substituted.
- Suitable substituents are Ci-C 4 alkoxy (preferably -OCH 3 and -OCH 2 CH 3 ) and aryl.
- the substituent is chosen from the group consisting of C r C 4 alkoxy (preferably -OCH 3 and -OCH 2 CH 3 ) and aryl.
- the -CH 2 -phenyl groups (in the definition of R 1 , R 2 , R' 2 , R 3 , R 4 , R 4 and R 5 ) can also be substituted.
- Suitable substituents are C 1 -C 4 alkyl (preferably -CH 3 and -CH 2 CH 3 ) and aryl.
- the substituent is chosen from the group consisting of CrC 4 alkyl (preferably -CH 3 and -CH 2 CH 3 ); C r C 4 alkoxy (preferably -OCH 3 and -OCH 2 CH 3 ) and aryl.
- the process for the production of the present invention is catalyzed by a heterogeneous catalytic system.
- the catalytic system is a heterogeneous system with catalysts on a carrier for example, Pd/BaSO 4 , Pd/CaCO 3 , Pd/AI 2 O 3 , Pd/TiO 2 , Pd/SiC-2, Pd/ZnO, Pd/C with palladium loadings of 1 - 12 weight-% (wt-%), preferred 3 - 10 wt-%, based on the total weight of the catalytic system.
- the catalyst has a surface area (BET) of 5-400 m 2 /g, preferably 10-250 m 2 /g. These catalysts are known from the prior art and can therefore be prepared accordingly. Usually such catalytic systems are commercially available. In the process according to the present invention palladium on charcoal (Pd/C) is a preferred heterogeneous catalytic system.
- BET surface area
- reaction according to the present invention is carried out in polar organic solvents, preferred are non-protic solvents, such as DMF, NMP, triethylamine and pyrrolidine.
- non-protic solvents such as DMF, NMP, triethylamine and pyrrolidine.
- a base can be added to the solvent as well as ligands like triarylphosphines, trialkylphoshines or aminoethanol. It is obvious that also solvent mixtures can be used.
- a suitable reaction temperature for the process of production of compounds of formula (I) is from 25 0 C - 150 0 C, preferred 50 0 C - 120 0 C.
- the compounds of formula (I) as described and defined above are used for the manufacture of the corresponding stilbenes (formula (IV)). Such a transformation can be done according to reduction processes known from the prior art. But surprisingly a new and improved way for the synthesis of electron rich stilbenes from the corresponding tolanes using heterogeneous hydrogenation catalysts has been found.
- corresponding it is meant that all the substituents in formula (I) and formula (IV) are identical. It is only the triple bond which is transformed into a double bond.
- a further embodiment of the present invention is an inventive hydrogenation of compounds according to formula (I), for the manufacture of compounds of formula (IV)
- the compounds of formula (I) can be reduced to the corresponding stilbenes in presence of hydrogen and a heterogeneous catalytic system comprising palladium and lead (Pb) on calcium carbonate.
- the Pd/Pb content on CaCO 3 varies from 1 to 10 wt-%, based on the total weight of the catalytic system and the Pd/Pb ratio varies from 1 :1 to 0.5 to 5.
- the H 2 pressure in the hydrogenation process can be from 1 .1 bar - 10 bar, preferably 1 .1 bar - 6 bar.
- the reaction temperature in the hydrogenation process goes from 25 0 C to 80 0 C, preferred is 30 - 60 0 C.
- the hydrogenation process can be carried out in organic solvents, preferred are polar organic solvents, especially preferred are alcohols from C 2 -C 6 . It is obvious that also solvent mixtures can be used. But it is also possible to carry out the hydrogenation without any solvents. Such hydrogenations are more preferred than ones using a solvent.
- the following examples serve to illustrate the invention. The percentages are expressed in weight percentages and the temperatures are degrees Celsius, if not otherwise defined. Examples
- the mixture was stirred under argon at 85 0 C (aluminum block temperature) for 17 hours.
- the reaction solution was cooled down to room temperature and then 10 ml of ethyl acetate were added. Afterwards the suspension was filtrated with a membrane filter (0.45 ⁇ m).
- the solution was treated 12 ml of hydrochloric acid solution (10 %, 34.3 mmol). Then an extraction was performed by extracting twice with 10 ml of ethyl acetate. The organic solutions were dried with sodium sulfate and afterwards concentrated at 40 0 C at 180 mbar. The dark yellow crude material was purified by chromatography with ethyl acetate n-heptane in a ratio of 5:95. The fractions were collected and concentrated at 40 0 C and 90 mbar. The isolated fractions were analysed by GC-MS and NMR.
- the autoclave was pressurized with 2 bara H 2 and the stirrer was set to 1000 rpm.
- the reaction mixture was stirred under 2 bara H 2 at 60 0 C for 3.3 minutes. Then the autoclave was opened. The content was sucked, filtrated over a 0.45 ⁇ m filter and washed with 4 ml of ethanol.
- the mixture was concentrated at 40 °C and 120 mbar.
- the isolated crude product was analyzed by GC/MS and NMR. The total yield calculated with GC/MS was 45 %.
- the mixture was stirred under argon at 85 0 C (aluminum block temperature) for 17 hours.
- the reaction solution was cooled to room temperature and then 10 ml of ethyl acetate were added. Afterwards the suspension was filtrated with a membrane filter (0.45 ⁇ m).
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2012521031A JP2012533600A (en) | 2009-07-22 | 2010-07-21 | Method for producing electron-rich substituted diphenylacetylenes |
CN2010800338198A CN102625792A (en) | 2009-07-22 | 2010-07-21 | Process for the production of substituted electron rich diphenylacetylenes |
US13/386,385 US20130131390A1 (en) | 2009-07-22 | 2010-07-21 | Process for the production of substituted electron rich diphenylacetylenes |
BR112012001511A BR112012001511A2 (en) | 2009-07-22 | 2010-07-21 | process for the production of electron-rich substituted diphenylacetylenes. |
EP10740576A EP2456742A2 (en) | 2009-07-22 | 2010-07-21 | Process for the production of substituted electron rich diphenylacetylenes |
KR1020187003692A KR20180018830A (en) | 2009-07-22 | 2010-07-21 | Process for the production of substituted electron rich diphenylacetylenes |
IN578DEN2012 IN2012DN00578A (en) | 2009-07-22 | 2010-07-21 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP09166121.5 | 2009-07-22 | ||
EP09166121 | 2009-07-22 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2011009888A2 true WO2011009888A2 (en) | 2011-01-27 |
WO2011009888A3 WO2011009888A3 (en) | 2011-10-06 |
Family
ID=43244855
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2010/060569 WO2011009888A2 (en) | 2009-07-22 | 2010-07-21 | Process for the production of substituted electron rich diphenylacetylenes |
Country Status (8)
Country | Link |
---|---|
US (1) | US20130131390A1 (en) |
EP (1) | EP2456742A2 (en) |
JP (1) | JP2012533600A (en) |
KR (2) | KR20120039033A (en) |
CN (1) | CN102625792A (en) |
BR (1) | BR112012001511A2 (en) |
IN (1) | IN2012DN00578A (en) |
WO (1) | WO2011009888A2 (en) |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2423337A1 (en) * | 2000-08-15 | 2002-02-21 | Northeastern Ohio Universities College Of Medicine | Methods for treating subjects infected with a herpes virus orneisseria gonorrheae |
JP4778710B2 (en) * | 2005-01-14 | 2011-09-21 | 宇部興産株式会社 | Coupling reaction using a flow reactor packed with palladium catalyst |
WO2008157745A1 (en) * | 2007-06-20 | 2008-12-24 | Kent State University | Ascorbate, vitamin k3 and hydroxytolans in the treatment of cancer |
KR100878394B1 (en) * | 2008-01-31 | 2009-01-13 | 한림대학교 산학협력단 | A synthesis of piceatannol |
-
2010
- 2010-07-21 BR BR112012001511A patent/BR112012001511A2/en not_active IP Right Cessation
- 2010-07-21 EP EP10740576A patent/EP2456742A2/en not_active Withdrawn
- 2010-07-21 WO PCT/EP2010/060569 patent/WO2011009888A2/en active Application Filing
- 2010-07-21 US US13/386,385 patent/US20130131390A1/en not_active Abandoned
- 2010-07-21 IN IN578DEN2012 patent/IN2012DN00578A/en unknown
- 2010-07-21 JP JP2012521031A patent/JP2012533600A/en active Pending
- 2010-07-21 CN CN2010800338198A patent/CN102625792A/en active Pending
- 2010-07-21 KR KR1020127004475A patent/KR20120039033A/en active Application Filing
- 2010-07-21 KR KR1020187003692A patent/KR20180018830A/en not_active Application Discontinuation
Non-Patent Citations (1)
Title |
---|
None |
Also Published As
Publication number | Publication date |
---|---|
KR20180018830A (en) | 2018-02-21 |
WO2011009888A3 (en) | 2011-10-06 |
JP2012533600A (en) | 2012-12-27 |
BR112012001511A2 (en) | 2019-09-24 |
CN102625792A (en) | 2012-08-01 |
EP2456742A2 (en) | 2012-05-30 |
US20130131390A1 (en) | 2013-05-23 |
KR20120039033A (en) | 2012-04-24 |
IN2012DN00578A (en) | 2015-06-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2658773C (en) | Asymmetric hydrogenation of 1,1,1-trifluoroacetone | |
US20160152550A1 (en) | Method for producing optically active 2,3-dihydrofarnesal | |
US20060004213A1 (en) | 1-Acetoxy-3-(substituted phenyl)propene compounds | |
CN107935971B (en) | Preparation method of (S) -3-hydroxytetrahydrofuran | |
KR101492225B1 (en) | Method for Synthesizing 4-O-Methylhonokiol | |
EP2456742A2 (en) | Process for the production of substituted electron rich diphenylacetylenes | |
Barbero et al. | Arenediazonium o-benzenedisulfonimides in Heck-type arylation of allylic alcohols | |
CN109020816B (en) | Method for obtaining 3-hydroxy-2, 2, 4-trimethyl pentanoic acid-2-methyl propyl ester from alcohol ester twelve-process wastewater | |
CN104529908B (en) | A kind of preparation method of rosuvastain calcium | |
CN106957235B (en) | A kind of preparation method of tamoxifen | |
JP5448572B2 (en) | Acetyl compound, method for producing the acetyl compound, and method for producing a naphthol compound using the acetyl compound | |
KR101659624B1 (en) | Method for preparation of -thujaplicin | |
KR100966027B1 (en) | The novel preparation method of decursin and decursin analoges | |
KR101558733B1 (en) | Effective synthetic method of natural product moracin N | |
EP2876108B1 (en) | Compounds of chiral aromatic spiroketal diphosphine ligands, preparation methods and uses thereof | |
CN112125793B (en) | 2, 4-Di-n-octoxybenzophenone and synthetic method and application thereof | |
CN116284031A (en) | Preparation method of R-glabridin | |
CN101525281B (en) | Synthetic method of natural products of AB5046A and AB5046B with herbicidal activity | |
KR101477058B1 (en) | Method of preparing piridine derivatives | |
KR100531117B1 (en) | New 3,4-diexomethylene tetrahydropyrane derivatives, and process for preparing them | |
KR20050070068A (en) | Process for production of an acetylenic compound | |
JP2009078997A (en) | Manufacturing method of optically active massoia lactone | |
KR20040086915A (en) | Processes For Preparing Allylic alcohol Derivatives | |
CA2846264A1 (en) | Dimethyl-(3,3-difluoro-2,2-dihydroxyheptyl)phosphonate and processes for its preparation | |
MXPA05006877A (en) | PROCESS FOR THE SYNTHESIS OF 3,3A,6,6A-TETRAHYDRO-2H-CYCLOPENTAN aC¦B ! FURAN-2-ONE. |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 201080033819.8 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 10740576 Country of ref document: EP Kind code of ref document: A2 |
|
REEP | Request for entry into the european phase |
Ref document number: 2010740576 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2010740576 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2012521031 Country of ref document: JP Ref document number: 578/DELNP/2012 Country of ref document: IN |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 20127004475 Country of ref document: KR Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 13386385 Country of ref document: US |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112012001511 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: 112012001511 Country of ref document: BR Kind code of ref document: A2 Effective date: 20120123 |