CN101646642A - 对映选择性制备光学活性4-羟基-2,6,6-三甲基环己-2-烯酮衍生物的方法 - Google Patents
对映选择性制备光学活性4-羟基-2,6,6-三甲基环己-2-烯酮衍生物的方法 Download PDFInfo
- Publication number
- CN101646642A CN101646642A CN200880010528A CN200880010528A CN101646642A CN 101646642 A CN101646642 A CN 101646642A CN 200880010528 A CN200880010528 A CN 200880010528A CN 200880010528 A CN200880010528 A CN 200880010528A CN 101646642 A CN101646642 A CN 101646642A
- Authority
- CN
- China
- Prior art keywords
- formula
- chph
- optical activity
- compound
- transition metal
- Prior art date
- Legal status (The legal status 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 status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims abstract description 48
- 230000003287 optical effect Effects 0.000 title claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- 229940022405 astaxanthin Drugs 0.000 claims abstract description 24
- 239000001168 astaxanthin Substances 0.000 claims abstract description 24
- 238000002360 preparation method Methods 0.000 claims abstract description 21
- 239000011734 sodium Substances 0.000 claims description 18
- 150000003624 transition metals Chemical class 0.000 claims description 16
- 230000002829 reductive effect Effects 0.000 claims description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- 229910052708 sodium Inorganic materials 0.000 claims description 10
- 229910052723 transition metal Inorganic materials 0.000 claims description 10
- 238000003786 synthesis reaction Methods 0.000 claims description 9
- 229910052707 ruthenium Inorganic materials 0.000 claims description 7
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 6
- 238000005984 hydrogenation reaction Methods 0.000 claims description 6
- 150000003333 secondary alcohols Chemical group 0.000 claims description 6
- 229910052700 potassium Inorganic materials 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 4
- 230000005595 deprotonation Effects 0.000 claims description 4
- 238000010537 deprotonation reaction Methods 0.000 claims description 4
- 150000001342 alkaline earth metals Chemical group 0.000 claims description 3
- 150000001450 anions Chemical class 0.000 claims description 3
- 229910052728 basic metal Inorganic materials 0.000 claims description 3
- 150000003818 basic metals Chemical class 0.000 claims description 3
- 229910052792 caesium Inorganic materials 0.000 claims description 3
- 229910052791 calcium Inorganic materials 0.000 claims description 3
- 229910052744 lithium Inorganic materials 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- 150000002894 organic compounds Chemical class 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 229910052701 rubidium Inorganic materials 0.000 claims description 3
- 229910052712 strontium Inorganic materials 0.000 claims description 3
- 150000001413 amino acids Chemical class 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- UOPFIWYXBIHPIP-SFTDATJTSA-N n-[(1s,2s)-2-amino-1,2-diphenylethyl]-4-methylbenzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N[C@@H](C=1C=CC=CC=1)[C@@H](N)C1=CC=CC=C1 UOPFIWYXBIHPIP-SFTDATJTSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- JEBFVOLFMLUKLF-IFPLVEIFSA-N Astaxanthin Natural products CC(=C/C=C/C(=C/C=C/C1=C(C)C(=O)C(O)CC1(C)C)/C)C=CC=C(/C)C=CC=C(/C)C=CC2=C(C)C(=O)C(O)CC2(C)C JEBFVOLFMLUKLF-IFPLVEIFSA-N 0.000 description 12
- 229910052717 sulfur Inorganic materials 0.000 description 12
- MQZIGYBFDRPAKN-ZWAPEEGVSA-N astaxanthin Chemical compound C([C@H](O)C(=O)C=1C)C(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)C(=O)[C@@H](O)CC1(C)C MQZIGYBFDRPAKN-ZWAPEEGVSA-N 0.000 description 10
- 235000013793 astaxanthin Nutrition 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- 239000000047 product Substances 0.000 description 9
- 235000021466 carotenoid Nutrition 0.000 description 6
- 150000001747 carotenoids Chemical class 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- -1 fatty acid ester Chemical class 0.000 description 6
- 239000007791 liquid phase Substances 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000002243 precursor Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 3
- MQZIGYBFDRPAKN-OXBRSLPGSA-N (6r)-6-hydroxy-3-[(1e,3e,5e,7e,9e,11e,13e,15e,17e)-18-[(4r)-4-hydroxy-2,6,6-trimethyl-3-oxocyclohexen-1-yl]-3,7,12,16-tetramethyloctadeca-1,3,5,7,9,11,13,15,17-nonaenyl]-2,4,4-trimethylcyclohex-2-en-1-one Chemical compound C([C@@H](O)C(=O)C=1C)C(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)C(=O)[C@H](O)CC1(C)C MQZIGYBFDRPAKN-OXBRSLPGSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 230000005526 G1 to G0 transition Effects 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- MQZIGYBFDRPAKN-UWFIBFSHSA-N astaxanthin Chemical compound C([C@H](O)C(=O)C=1C)C(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)C(=O)[C@@H](O)CC1(C)C MQZIGYBFDRPAKN-UWFIBFSHSA-N 0.000 description 2
- 150000001555 benzenes Chemical class 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- WTWBUQJHJGUZCY-UHFFFAOYSA-N cuminaldehyde Chemical compound CC(C)C1=CC=C(C=O)C=C1 WTWBUQJHJGUZCY-UHFFFAOYSA-N 0.000 description 2
- 125000003963 dichloro group Chemical group Cl* 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- QNVRIHYSUZMSGM-UHFFFAOYSA-N hexan-2-ol Chemical compound CCCCC(C)O QNVRIHYSUZMSGM-UHFFFAOYSA-N 0.000 description 2
- ZOCHHNOQQHDWHG-UHFFFAOYSA-N hexan-3-ol Chemical compound CCCC(O)CC ZOCHHNOQQHDWHG-UHFFFAOYSA-N 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 238000013507 mapping Methods 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000012429 reaction media Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 229960000371 rofecoxib Drugs 0.000 description 2
- 150000003304 ruthenium compounds Chemical class 0.000 description 2
- YAYGSLOSTXKUBW-UHFFFAOYSA-N ruthenium(2+) Chemical class [Ru+2] YAYGSLOSTXKUBW-UHFFFAOYSA-N 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- MQZIGYBFDRPAKN-GNBIBNSWSA-N (6s)-6-hydroxy-3-[(1e,3e,5e,7e,9e,11e,13e,15e,17e)-18-[(4r)-4-hydroxy-2,6,6-trimethyl-3-oxocyclohexen-1-yl]-3,7,12,16-tetramethyloctadeca-1,3,5,7,9,11,13,15,17-nonaenyl]-2,4,4-trimethylcyclohex-2-en-1-one Chemical compound C([C@@H](O)C(=O)C=1C)C(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)C(=O)[C@@H](O)CC1(C)C MQZIGYBFDRPAKN-GNBIBNSWSA-N 0.000 description 1
- AYJXHIDNNLJQDT-UHFFFAOYSA-N 2,6,6-Trimethyl-2-cyclohexene-1,4-dione Chemical compound CC1=CC(=O)CC(C)(C)C1=O AYJXHIDNNLJQDT-UHFFFAOYSA-N 0.000 description 1
- QNVRIHYSUZMSGM-LURJTMIESA-N 2-Hexanol Natural products CCCC[C@H](C)O QNVRIHYSUZMSGM-LURJTMIESA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical group CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 241000195493 Cryptophyta Species 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 241000168517 Haematococcus lacustris Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000003570 biosynthesizing effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical class CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 229910052735 hafnium Inorganic materials 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000013462 industrial intermediate Substances 0.000 description 1
- 150000002484 inorganic compounds Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910001867 inorganic solvent Inorganic materials 0.000 description 1
- 239000003049 inorganic solvent Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 229910052750 molybdenum Inorganic materials 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- QQZOPKMRPOGIEB-UHFFFAOYSA-N n-butyl methyl ketone Natural products CCCCC(C)=O QQZOPKMRPOGIEB-UHFFFAOYSA-N 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 229910052758 niobium Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 229910052762 osmium Inorganic materials 0.000 description 1
- 150000002926 oxygen Chemical class 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- XOJVVFBFDXDTEG-UHFFFAOYSA-N pristane Chemical compound CC(C)CCCC(C)CCCC(C)CCCC(C)C XOJVVFBFDXDTEG-UHFFFAOYSA-N 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 229910052702 rhenium Inorganic materials 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000010421 standard material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229910052715 tantalum Inorganic materials 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 238000009901 transfer hydrogenation reaction Methods 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- 229940087652 vioxx Drugs 0.000 description 1
- 229910052726 zirconium Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
- C07C403/24—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by six-membered non-aromatic rings, e.g. beta-carotene
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- 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
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及对映选择性制备式(I)或(Ia)的光学活性4-羟基-2,6,6-三甲基环己-2-烯酮衍生物的方法和包括制备式(I)化合物方法的制备式(III)的(3S,3′S)-虾青素的方法。
Description
本发明涉及对映选择性制备式(I)或(Ia)的光学活性4-羟基-2,6,6-三甲基环己-2-烯-1-酮衍生物的方法以及包括制备式(I)化合物的方法的制备式(III)的(3S,3′S)-虾青素的方法。
由于其在3和3′位置的两个手性中心,虾青素(3,3′-二羟基-β,β′-胡萝卜素-4,4′-二酮)可以按下面构型异构体的形式存在:(3S,3′S)、(3R,3′R)、(3S,3′R)和(3R,3′S)。后两种构型异构体相同并且构成内消旋形式(类胡萝卜素手册(Carotenoids Handbook),2004,Main List Nr.405)。
所有三种形式均可在自然源中找到(Carotenoids Handbook,2004,Main List No.404,405,406)。从外消旋前体开始的化学全合成产生(3S,3′S)-虾青素、内消旋虾青素和(3R,3′R)-虾青素的1∶2∶1混合物(TheEFSA Journal,2005,291,12,Deutsche Lebensmittel-Rundschau,2004,100,437,Helvetica Chimica Acta,1981,64,2436)。
然而,(3S,3′S)构型异构体特别重要。其由绿藻(雨生红球藻(Haematococcus Pluvialis))以对映体纯的形式生物合成(J.AppliedPhycology,1992,4,165;Phytochemistry,1981,20,2561)。
来自绿藻的(S,S)-虾青素用作对人体健康具有积极作用的食品增补剂(J.Nat.Prod.,2006,69,443)。此外,其适合于完全阻止罗非考昔(rofecoxib)(Vioxx)的不利助氧化作用(J.Cardiovasc.Pharmacol.,2006,47Suppl 1,第7页)。
然而,鉴于绿藻中(S,S)-虾青素的低浓度(J.Agric.Food Chem.,1998,46,3371),这种活性成分的可获得性非常有限。另外,藻类中的该活性成分以单脂肪酸酯和二脂肪酸酯及游离虾青素的混合物存在,这对分离和纯化造成相当大程度的复杂性(特别参见Phytochemistry,20,11,2561(1981);J.Applied Phycology,4,2,165(1992))。为了能够提供较大量和高纯度的(S,S)-虾青素,化学全合成是所选技术。
文献中描述了(S,S)-虾青素的各种合成方法。一种策略在于使用非对映盐(Helvetica Chimica Acta,1981,64,2447)或非对映酯(Helvetica ChimicaActa,1981,64,2419)将外消旋前体拆分成光学对映体。还报导了外消旋前体的微生物光学拆分。这些方法的特别不利之处在于产生(R,R)-虾青素的对映体是不可用的或者可仅非常困难地进行再循环。
另一合成策略在于通过微生物法或酶法获得对映体纯的合成单元(Helvetica Chimica Acta,1978,61,2609,Helvetica Chimica Acta,1981,64,2405)。因为这些单元具有过低的氧化态,因此必须在多步合成中将它们转化为(S,S)-虾青素前体。
首先,WO 2006/039685在图II中描述了将酮异佛尔酮两步对映选择性氢化为对映体纯的C9-二醇,由该C9-二醇基于Helv.Chim.Acta,1978,61,2609中描述的方法再氧化一个羟基后在多步合成中获得(S,S)-虾青素前体。此外,WO 2006/039685描述了将式(II-a)的C9-烯醇醚对映选择性催化转移氢化为相应式(I-b)的对映体纯的醇。
所述氢化催化剂是具有手性配体的金属,优选具有光学活性胺作为配体的钌催化剂。这种方法的不利之处在于使用式(II-OH)的工业中间体的氧受保护的衍生物,其带来额外的合成复杂性。
本发明的目的是由工业上可获得的起始材料开始开发制备用于(S,S′)-虾青素或(R,R′)-虾青素合成的尽可能为对映体纯形式的光学活性中间体的简单且经济有效的方法,其可无任何问题地并入“外消旋”虾青素的现有工业全合成中(类胡萝卜素(Carotenoids)第2卷,1996,259;纯粹和应用化学(Pure and Applied Chemistry),2002,74,2213)。
该目的通过在还原剂RA和手性过渡金属催化剂存在下使式(II)的三甲基环己-2-烯-1,4-二酮衍生物反应产生式(I)或(Ia)化合物而对映选择性制备式(I)或(Ia)的光学活性4-羟基-2,6,6-三甲基环己-2-烯-1-酮衍生物的方法得以实现:
其中在式(D、(Ia)和(II)中:
R1为碱金属M1或碱土金属片段M2 1/2或(M2)+X-,其中M1为Li、Na、K、Rb或Cs,M2为Mg、Ca、Sr或Ba,X-为单电荷阴离子,式(II)化合物1位的羰基在手性过渡金属催化剂存在下优先氢化为式(I)的仲(4S)-醇或优先氢化为式(Ia)的仲(4R)-醇,并且如果合适,从反应平衡中至少部分地除去被氧化的还原剂RA。
在本发明方法中,使用式(II)化合物并且制备式(I)或(Ia)化合物,其中R1为碱金属M1或碱土金属片段M2 1/2或(M2)+X-,其中M1为Li、Na、K、Rb或Cs,优选Na或K,特别为Na,M2为Mg、Ca、Sr或Ba,特别为Mg,X-1为单电荷阴离子如卤离子、乙酸根或磷酸二氢根。R1优选为Na或K,特别为Na。
在本发明方法中,在手性过渡金属催化剂存在下将式(II)化合物转化为式(I)或(Ia)化合物。
适合于将碳原子4上的酮基还原成仲醇的手性过渡金属催化剂优选包含过渡金属原子和至少一个光学活性手性配体。有用的过渡金属原子原则上是所有过渡金属,例如Ti、Zr、Hf、V、Nb、Ta、Cr、Mo、W、Mn、Re、Fe、Ru、Os、Co、Rh、Ir、Ni、Pd、Pt、Cu、Ag或Au,其可形成合适的手性过渡金属催化剂。
在本发明方法中,特别优选是使用包含过渡金属原子和至少一个光学活性手性配体的手性过渡金属催化剂,其中所述过渡金属原子为钌。可例如通过使合适的钌化合物如[RuX2(η6-Ar)]2与合适的手性配体反应获得优选的手性钌催化剂,其中X是卤素原子例如氟、氯、溴或碘,Ar是苯或取代的苯衍生物,特别是被C1-C4烷基取代的苯衍生物。
在手性钌催化剂中,光学活性手性配体优选为光学活性胺或光学活性氨基酸。可与合适的钌化合物,特别是[RuX2(η6-Ar)]2反应产生催化活性配合物的光学活性胺的实例例如为H2N-CHPh-CHPh-OH、H2N-CHMe-CHPh-OH、MeHN-CHMe-CHPh-OH或TsNH-CHPh-CHPh-NH2,特别为(1S,2S)-N-对甲苯磺酰基-1,2-二苯基乙二胺或(1R,2R)-N-对甲苯磺酰基-1,2-二苯基乙二胺。
特别优选其中光学活性手性配体可通过H2N-CHPh-CHPh-OH、H2N-CHMe-CHPh-OH、MeHN-CHMe-CHPh-OH或TsNH-CHPh-CHPh-NH2的单去质子化,特别是通过(1S,2S)-N-对甲苯磺酰基-1,2-二苯基乙二胺或(1R,2R)-N-对甲苯磺酰基-1,2-二苯基乙二胺的单去质子化获得的手性钌催化剂。
当例如在本发明的方法中使用(1S,2S)-N-对甲苯磺酰基-1,2-二苯基乙二胺作为光学活性手性配体时,以高对映体纯度获得式(I)化合物:
而在使用(1R,2R)-N-对甲苯磺酰基-1,2-二苯基乙二胺在的情形中,所得光学活性手性配体是式(Ia)化合物。
在本发明方法中,所用还原剂RA原则上可以是无机或有机化合物,例如氢气或醇。在本发明方法中,所用还原剂RA优选是包含至少一个伯醇或仲醇官能团CH(OH)的有机化合物,例如异丙醇、2-丁醇、2-戊醇、2-己醇或3-己醇,特别是异丙醇。可将在本发明方法中形成的被氧化的还原剂RA(例如在使用异丙醇作为还原剂RA的情形中的丙酮)至少部分地从反应介质或者从反应平衡中除去。当还原剂RA是仲醇时,通常还将其称作牺牲醇,并且将相应形成的氧化产物称作牺牲酮。
通常在液相中即在至少一种溶剂或溶剂混合物中进行本发明方法。液相优选包含至少一种有机溶剂,此时液相通常包含大于50体积%的有机溶剂。作为无机溶剂,液相特别可包含水。根据不同溶剂的液相组成,液相可以是单相、双相或多相系统。优选在单相系统中进行本发明方法,此时所用溶剂特别是仲醇(特别是异丙醇)与水的混合物。
在本发明方法中,可将形成的氧化产物至少部分地从反应介质或者从反应平衡中除出。在仲醇如异丙醇作为还原剂(RA)的情形中,形成的所谓牺牲酮(在异丙醇作为牺牲醇的情形中为丙酮)的除去可按各种方式进行,例如通过选择性膜或者通过萃取或蒸馏方法。
本发明方法有利地在0℃-150℃,优选10℃-85℃,更优选15℃-75℃的温度下进行。
在本发明方法中,将光学活性化合物理解为指表现出对映体富集的对映体。在本发明方法中,优选获得至少70%ee,优选最小80%ee,更优选最小90%ee,最优选最小98%ee的对映体纯度。
本发明方法制备的式(I)或(Ia)化合物可通过酸化转化为相应的二醇,例如(4S)-3,4-二羟基-2,6,6-三甲基环己-2-烯酮,其可通过已知的方法如萃取或沉淀获得。一种分离酸化后可获得的式(I-OH)或(Ia-OH)的二醇的方法原则上可按Helv,Chim.Acta 64,2436,1981中所述进行。
在除去有机溶剂或者在用水稀释后,可首先将产物溶液调节到1-3的pH,优选pH 1。优选用无机酸如盐酸或硫酸,更优选用硫酸进行酸化。产物一般沉淀析出并且可取出,或者用与水不混溶的有机溶剂反复萃取酸性产物溶液。这里的合适溶剂是氯代烃,特别是二氯甲烷,醚,例如MTBE或二异丙基醚,以及乙酸乙酯。该萃取可分批或连续进行。通过在酸化前浓缩水相或者通过“盐析”来支持产物的萃取;然而,这些操作对于从反应溶液中取出产物并非是必需的。
在本发明方法中,可以基于反应中所用式(II)底物(例如其中R2=Na)为60%-大于95%,优选80%-大于95%的产率制备式(I)或(Ia)产物,并且在后处理后可以式(I-OH)或(Ia-OH)二醇将其分离。该二醇可以大于98%ee的对映体纯度获得。如果需要,其可通过根据Helv.Chim.Acta 64,2436,1981的结晶法进行纯化,但在根据Helv.Chim.Acta 64,2447,1981的S,S′-虾青素的进一步合成中,优选不进行进一步纯化操作而进行使用。
本发明方法可分批、半分批或连续进行。
本发明还提供了通过在本发明方法中在(3S,3′S)-虾青素全合成的一个反应步骤中制备上述本发明方法制备的式(I)化合物而制备式(III)的(3S,3′S)-虾青素的方法。
(3R,3′R)-虾青素可类似地使用式(Ia)化合物进行制备。
制备式(II)起始化合物的合成步骤和经由几个步骤将式(I)或式(Ia)的对映体纯化合物转化为式(III)的(3S,3′S)-虾青素或(3R,3′R)-虾青素的合成步骤原则上可从文献获知。如文献(WO 2006/039685;Helv.Chim.Acta,1981,64,2447;ibid.,1981,64,2405)中对于各种情形所述,没有外消旋化地将通过式(II)化合物(其中R2优选为Na)的对映选择性还原获得的式(I)或式(Ia)的光学纯化合物转化为(3S,3′S)-虾青素或(3R,3′R)-虾青素。这些方法对应于工业虾青素合成(Carotenoids,第2卷,1996,259;Pure and Appl.Chem.,2002,74,2213),并且提供至(3S,3′S)-虾青素的在技术和经济上有利的路线。
本发明方法的优点在于以高对映体纯度简便地获得式(I)或(Ia)化合物,同时这些化合物的产率良好。
本发明通过以下实施例进行描述,然而所述实施例不限制本发明。
实施例
实施例1化合物(I-OH)、(Ia-OH)和(II-OH)的分析
反应物和产物浓度可通过HPLC测定。根据固定相和流动相的选择,还有可能测定ee及浓度。
固定相:Chiralpak AS-RH,150*4.6mm,Daicel,加热至40℃
流动相:洗脱液A:10mM KH2PO4
洗脱液B:CH3CN
梯度:时间[min] A[%] B[%] 流速[ml/min]
0 90 10 0.5
10 90 10 0.5
11 60 40 0.5
20 60 40 0.5
流速:0.5ml/min
检测:在260nm处进行UV检测
保留时间:
(Ia-OH)(4R)-(+)-3,4-二羟基-2,6,6-三甲基环己-2-烯酮:约9.3min
(I-OH)(4S)-(-)-3,4-二羟基-2,6,6-三甲基环己-2-烯酮:约9.8min
(II-OH)2-羟基-3,5,5-三甲基环己-2-烯-1,4-二酮:约17.6min
使用标准材料建立校正序列,借助于此可测定未知样品的浓度并且能够归属对映异构体。
实施例2:(4S)-4-羟基-2,6,6-三甲基-1-氧代环己-2-烯-3-醇钠(I-Na)的制备
在氮气气氛下,首先加入10ml异丙醇和26.8mg(1S,2S)-(+)-N-对甲苯磺酰基-1,2-二苯基乙二胺及11.8mg二氯(对异丙基苯)钌(II)二聚体。在氮气下将该混合物加热至80℃并保持30min,然后冷却至20℃并与2.4ml3,5,5-三甲基-1,4-二氧代环己-2-烯-2-醇钠(II-Na)在2.4ml异丙醇中的脱气水溶液混合。在加入1.8ml 0.1M的氢氧化钾的异丙醇溶液后,将该混合物在40℃下搅拌24小时。在酸化后,通过HPLC分析发现化合物(II-Na)已定量地转化并且手性醇(I-Na)具有大于90%ee的对映体纯度。
实施例3:(4R)-4-羟基-2,6,6-三甲基-1-氧代环己-2-烯-3-醇钠(Ia-Na)的制备
类似于实施例2,通过使26.8mg(1R,2R)-(-)-N-对甲苯磺酰基-1,2-二苯基乙二胺与11.8mg二氯(对异丙基苯)钌(II)二聚体反应制备手性催化剂,并且根据实施例2,将其用于将化合物(II-Na)还原成化合物(Ia-OH),实现定量转化并且产物具有大于90%ee的对映体纯度。
实施例4:(4S)-4-羟基-2,6,6-三甲基-1-氧代环己-2-烯-3-醇钠(I-Na)的制备
类似于实施例2,使用十分之一量的实施例2的催化剂(S/C 1000:1)进行化合物(II-Na)的还原。通过HPLC分析监控的反应在24小时后给出72%的转换率,在48小时后完全转化并具有相同的对映体过量。
Claims (9)
1.一种通过在还原剂RA和手性过渡金属催化剂存在下使式(II)的三甲基环己-2-烯-1,4-二酮衍生物反应产生式(I)或(Ia)化合物而对映选择性制备式(I)或(Ia)的光学活性4-羟基-2,6,6-三甲基环己-2-烯-1-酮衍生物的方法:
其中在式(I)、(Ia)和(II)中:
R1为碱金属M1或碱土金属片段M2 1/2或(M2)+X-,其中M1为Li、Na、K、Rb或Cs,M2为Mg、Ca、Sr或Ba,X-为单电荷阴离子,
式(II)化合物1位的羰基在手性过渡金属催化剂存在下优先氢化为式(I)的仲(4S)-醇或优先氢化为式(Ia)的仲(4R)-醇,并且如果合适,从反应平衡中至少部分地除去被氧化的还原剂RA。
2.根据权利要求1的方法,其中所用还原剂RA是包含至少一个伯醇或仲醇官能团CH(OH)的有机化合物,特别是异丙醇。
3.根据权利要求1或2的方法,其式(I)、(Ia)和(II)中的R1是钠。
4.根据权利要求1至3中任一项的方法,其中手性过渡金属催化剂包含过渡金属原子和至少一个光学活性手性配体。
5.根据权利要求4的方法,其中过渡金属原子是钌。
6.根据权利要求5的方法,其中光学活性手性配体是光学活性胺或光学活性氨基酸。
7.根据权利要求5的方法,其中光学活性手性配体是通过H2N-CHPh-CHPh-OH、H2N-CHMe-CHPh-OH、MeHN-CHMe-CHPh-OH或TsNH-CHPh-CHPh-NH2的单去质子化获得的。
8.根据权利要求5的方法,其中光学活性手性配体是通过(1S,2S)-N-对甲苯磺酰基-1,2-二苯基乙二胺或(1R,2R)-N-对甲苯磺酰基-1,2-二苯基乙二胺的单去质子化获得的。
9.一种制备(3S,3′S)-虾青素的方法,其中在(3S,3′S)-虾青素全合成的一个反应步骤中,根据前述权利要求中的任一项制备权利要求1制备的式(I)化合物。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP07105089.2 | 2007-03-28 | ||
EP07105089 | 2007-03-28 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN101646642A true CN101646642A (zh) | 2010-02-10 |
Family
ID=39587937
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN200880010528A Pending CN101646642A (zh) | 2007-03-28 | 2008-02-22 | 对映选择性制备光学活性4-羟基-2,6,6-三甲基环己-2-烯酮衍生物的方法 |
Country Status (5)
Country | Link |
---|---|
US (1) | US20100041922A1 (zh) |
EP (1) | EP2142494A1 (zh) |
CN (1) | CN101646642A (zh) |
TW (1) | TW200909406A (zh) |
WO (1) | WO2008116714A1 (zh) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103980270A (zh) * | 2014-05-19 | 2014-08-13 | 埃斯特维华义制药有限公司 | 一种(r)-3-奎宁醇的制备方法 |
CN110088094A (zh) * | 2016-12-19 | 2019-08-02 | 巴斯夫欧洲公司 | 制备立体异构纯c9-缩醛的方法 |
CN110121489A (zh) * | 2016-12-19 | 2019-08-13 | 巴斯夫欧洲公司 | 制备(4s)-或(4r)-3,4-二羟基-2,6,6-三甲基环己-2-烯酮的方法 |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101535495A (zh) * | 2006-11-10 | 2009-09-16 | 巴斯夫欧洲公司 | 使用固氮弓菌苯基乙醇脱氢酶制备(4s)-3,4-二羟基-2,6,6-三甲基-环己-2-烯酮及其衍生物的方法 |
CN106795109B (zh) * | 2014-08-12 | 2019-09-27 | 巴斯夫欧洲公司 | 用于由虾红素制备虾青素的方法 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE102004022686A1 (de) * | 2004-05-05 | 2005-11-24 | Basf Ag | Verfahren zur Herstellung optisch aktiver Alkohole |
US20060111580A1 (en) * | 2004-10-01 | 2006-05-25 | Lockwood Samuel F | Methods for the synthesis of chiral dihydroxy ketone intermediates useful for the chiral synthesis of carotenoids |
CN101535495A (zh) * | 2006-11-10 | 2009-09-16 | 巴斯夫欧洲公司 | 使用固氮弓菌苯基乙醇脱氢酶制备(4s)-3,4-二羟基-2,6,6-三甲基-环己-2-烯酮及其衍生物的方法 |
-
2008
- 2008-02-22 CN CN200880010528A patent/CN101646642A/zh active Pending
- 2008-02-22 EP EP08717062A patent/EP2142494A1/de not_active Withdrawn
- 2008-02-22 US US12/593,466 patent/US20100041922A1/en not_active Abandoned
- 2008-02-22 WO PCT/EP2008/052202 patent/WO2008116714A1/de active Application Filing
- 2008-03-27 TW TW097111046A patent/TW200909406A/zh unknown
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103980270A (zh) * | 2014-05-19 | 2014-08-13 | 埃斯特维华义制药有限公司 | 一种(r)-3-奎宁醇的制备方法 |
CN110088094A (zh) * | 2016-12-19 | 2019-08-02 | 巴斯夫欧洲公司 | 制备立体异构纯c9-缩醛的方法 |
CN110121489A (zh) * | 2016-12-19 | 2019-08-13 | 巴斯夫欧洲公司 | 制备(4s)-或(4r)-3,4-二羟基-2,6,6-三甲基环己-2-烯酮的方法 |
Also Published As
Publication number | Publication date |
---|---|
US20100041922A1 (en) | 2010-02-18 |
EP2142494A1 (de) | 2010-01-13 |
WO2008116714A1 (de) | 2008-10-02 |
TW200909406A (en) | 2009-03-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Huo et al. | Bimetallic catalysis in stereodivergent synthesis | |
CN101646642A (zh) | 对映选择性制备光学活性4-羟基-2,6,6-三甲基环己-2-烯酮衍生物的方法 | |
Hennig et al. | Synthesis of (R)-and (S)-4-hydroxyisophorone by ruthenium-catalyzed asymmetric transfer hydrogenation of ketoisophorone | |
Broadley et al. | Stereoselective preparation of β-amino-acyl iron complexes for β-lactam synthesis | |
Schmidt et al. | Diarylmethanols by catalyzed asymmetric aryl transfer reactions onto aldehydes using boronic acids as aryl source | |
CN102971285A (zh) | 一种用于生产肉毒碱的方法 | |
CN105330515A (zh) | 一种光学纯香茅醇的制备方法 | |
CN111099989B (zh) | S-3-环己烯甲酸及其精制方法 | |
CN109651115B (zh) | 一种制备l-薄荷酮的方法 | |
CN108083980A (zh) | 一种制备光学纯l-薄荷醇的方法 | |
Inoue et al. | Chiral Phebox–rhodium complexes as catalysts for asymmetric direct aldol reaction | |
Ros et al. | Stereoselective synthesis of syn β-hydroxy cycloalkane carboxylates: transfer hydrogenation of cyclic β-keto esters via dynamic kinetic resolution | |
Li et al. | Copper catalyzed tandem asymmetric conjugate addition–cyclization reaction in the presence of chiral phosphoramidite ligands | |
Huang et al. | Zirconium‐Catalyzed Asymmetric Carboalumination of Alkenes: ZACA–Lipase‐Catalyzed Acetylation Synergy | |
Tedeschi et al. | 1, 4-Diynes from alkynyl–propargyl coupling reactions | |
Villano et al. | Pronounced asymmetric amplification in the aldol condensation of Chan's diene promoted by a Ti (IV)/BINOL complex | |
Chaudhari et al. | Multiphase catalysis and reaction engineering for emerging pharmaceutical processes | |
Szőllősi et al. | Reactions of chlorine substituted (E)-2, 3-diphenylpropenoic acids over cinchonidine-modified Pd: Enantioselective hydrogenation versus hydrodechlorination | |
Kawai et al. | Synthesis of novel C2-symmetric chiral crown ethers and their application to enantioselective trifluoromethylation of aldehydes and ketones | |
CN109096137A (zh) | 一种精异丙甲草胺的合成方法 | |
De Luca et al. | Base-free Asymmetric Transfer Hydrogenation of 1, 2-Di-and Monoketones Catalyzed by a Chiral Iron (II) Hydride | |
Lu et al. | A robust Ru-PNNP catalyst system for the asymmetric hydrogenation of α, β-unsaturated ketones to allylic alcohol | |
De Oliveira et al. | An efficient synthesis of enantiopure (+)-and (−)-syn-1, 3-amino alcohols with a norbornane framework and their application in the asymmetric addition of ZnEt2 to benzaldehyde | |
CN109574797A (zh) | 一种手性苄醇的制备方法 | |
US9340479B2 (en) | Methods of synthesizing alpha acids and substantially enantiomerically pure compositions thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20100210 |