CN112209967A - Chiral spiro monophosphine-oxazoline ligand and preparation method thereof - Google Patents
Chiral spiro monophosphine-oxazoline ligand and preparation method thereof Download PDFInfo
- Publication number
- CN112209967A CN112209967A CN201910631270.5A CN201910631270A CN112209967A CN 112209967 A CN112209967 A CN 112209967A CN 201910631270 A CN201910631270 A CN 201910631270A CN 112209967 A CN112209967 A CN 112209967A
- Authority
- CN
- China
- Prior art keywords
- substituted
- alkyl
- sec
- formula
- phenyl
- 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
- 239000003446 ligand Substances 0.000 title claims abstract description 43
- NHFAABIHBNXKDT-UHFFFAOYSA-N 4,5-dihydro-1,3-oxazole;phosphane Chemical compound P.C1CN=CO1 NHFAABIHBNXKDT-UHFFFAOYSA-N 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 40
- 125000003003 spiro group Chemical group 0.000 title claims abstract description 19
- -1 cyano, carboxyl Chemical group 0.000 claims abstract description 211
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 32
- 230000003287 optical effect Effects 0.000 claims abstract description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 12
- 239000001257 hydrogen Substances 0.000 claims abstract description 12
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims abstract description 11
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims abstract description 11
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 5
- 125000004185 ester group Chemical group 0.000 claims abstract description 4
- 125000002541 furyl group Chemical group 0.000 claims abstract description 3
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 3
- 125000001544 thienyl group Chemical group 0.000 claims abstract description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 12
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims description 10
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 claims description 9
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 8
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 claims description 8
- 238000006555 catalytic reaction Methods 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- ZDHXKXAHOVTTAH-UHFFFAOYSA-N trichlorosilane Chemical compound Cl[SiH](Cl)Cl ZDHXKXAHOVTTAH-UHFFFAOYSA-N 0.000 claims description 7
- 239000005052 trichlorosilane Substances 0.000 claims description 7
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 6
- 238000005886 esterification reaction Methods 0.000 claims description 6
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 6
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 6
- 229910052763 palladium Inorganic materials 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 claims description 5
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 238000006482 condensation reaction Methods 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 4
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 238000006722 reduction reaction Methods 0.000 claims description 4
- 238000007363 ring formation reaction Methods 0.000 claims description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- WJTCGQSWYFHTAC-UHFFFAOYSA-N cyclooctane Chemical compound C1CCCCCCC1 WJTCGQSWYFHTAC-UHFFFAOYSA-N 0.000 claims description 3
- 239000004914 cyclooctane Substances 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 125000005929 isobutyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC(*)=O 0.000 claims description 3
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000005932 isopentyloxycarbonyl group Chemical group 0.000 claims description 3
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000005933 neopentyloxycarbonyl group Chemical group 0.000 claims description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000005930 sec-butyloxycarbonyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 claims description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000005934 tert-pentyloxycarbonyl group Chemical group 0.000 claims description 3
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims description 2
- XKZQKPRCPNGNFR-UHFFFAOYSA-N 2-(3-hydroxyphenyl)phenol Chemical compound OC1=CC=CC(C=2C(=CC=CC=2)O)=C1 XKZQKPRCPNGNFR-UHFFFAOYSA-N 0.000 claims description 2
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 claims description 2
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000005244 neohexyl group Chemical group [H]C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000000542 sulfonic acid group Chemical group 0.000 claims description 2
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 3
- 125000004410 cyclooctyloxy group Chemical group C1(CCCCCCC1)O* 0.000 claims 1
- QIRAYNIFEOXSPW-UHFFFAOYSA-N dimepheptanol Chemical compound C=1C=CC=CC=1C(CC(C)N(C)C)(C(O)CC)C1=CC=CC=C1 QIRAYNIFEOXSPW-UHFFFAOYSA-N 0.000 claims 1
- 150000002148 esters Chemical group 0.000 claims 1
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 29
- 150000002431 hydrogen Chemical group 0.000 abstract description 6
- 229910052736 halogen Inorganic materials 0.000 abstract description 2
- 150000002367 halogens Chemical class 0.000 abstract description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 abstract description 2
- 125000000547 substituted alkyl group Chemical group 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 99
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 81
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 46
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 44
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
- 239000007787 solid Substances 0.000 description 34
- 235000019439 ethyl acetate Nutrition 0.000 description 29
- 238000003756 stirring Methods 0.000 description 25
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 23
- 239000003480 eluent Substances 0.000 description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 239000002904 solvent Substances 0.000 description 21
- 238000004809 thin layer chromatography Methods 0.000 description 18
- 239000003054 catalyst Substances 0.000 description 17
- 238000004440 column chromatography Methods 0.000 description 17
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
- 238000001816 cooling Methods 0.000 description 16
- 239000005457 ice water Substances 0.000 description 16
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- 239000012299 nitrogen atmosphere Substances 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 238000001514 detection method Methods 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 13
- 239000000741 silica gel Substances 0.000 description 13
- 229910002027 silica gel Inorganic materials 0.000 description 13
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 12
- 229940125782 compound 2 Drugs 0.000 description 11
- 238000002156 mixing Methods 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 238000010790 dilution Methods 0.000 description 10
- 239000012895 dilution Substances 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 239000012298 atmosphere Substances 0.000 description 6
- 230000003197 catalytic effect Effects 0.000 description 6
- 229940125904 compound 1 Drugs 0.000 description 6
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 6
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 150000003413 spiro compounds Chemical class 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 5
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-Bis(diphenylphosphino)propane Substances C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 description 4
- BCJVBDBJSMFBRW-UHFFFAOYSA-N 4-diphenylphosphanylbutyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCCP(C=1C=CC=CC=1)C1=CC=CC=C1 BCJVBDBJSMFBRW-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- AVNRJUHUOZDFKS-UHFFFAOYSA-N phenyl(3-phenylphosphanylpropyl)phosphane Chemical compound C=1C=CC=CC=1PCCCPC1=CC=CC=C1 AVNRJUHUOZDFKS-UHFFFAOYSA-N 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 239000011261 inert gas Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- MPQXHAGKBWFSNV-UHFFFAOYSA-N oxidophosphanium Chemical compound [PH3]=O MPQXHAGKBWFSNV-UHFFFAOYSA-N 0.000 description 3
- LRYYUQJFQWSHNC-UHFFFAOYSA-N phenyl(4-phenylphosphanylbutyl)phosphane Chemical compound C=1C=CC=CC=1PCCCCPC1=CC=CC=C1 LRYYUQJFQWSHNC-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000010948 rhodium Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 2
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000011914 asymmetric synthesis Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 2
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 229910052703 rhodium Inorganic materials 0.000 description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 1
- IJXJGQCXFSSHNL-MRVPVSSYSA-N (2s)-2-amino-2-phenylethanol Chemical compound OC[C@@H](N)C1=CC=CC=C1 IJXJGQCXFSSHNL-MRVPVSSYSA-N 0.000 description 1
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical group C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- BSIMZHVOQZIAOY-SCSAIBSYSA-N 1-carbapenem-3-carboxylic acid Chemical compound OC(=O)C1=CC[C@@H]2CC(=O)N12 BSIMZHVOQZIAOY-SCSAIBSYSA-N 0.000 description 1
- VPMMJSPGZSFEAH-UHFFFAOYSA-N 2,4-diaminophenol;hydrochloride Chemical compound [Cl-].NC1=CC=C(O)C([NH3+])=C1 VPMMJSPGZSFEAH-UHFFFAOYSA-N 0.000 description 1
- ONPJWQSDZCGSQM-UHFFFAOYSA-N 2-phenylprop-2-enoic acid Chemical compound OC(=O)C(=C)C1=CC=CC=C1 ONPJWQSDZCGSQM-UHFFFAOYSA-N 0.000 description 1
- YFPJFKYCVYXDJK-UHFFFAOYSA-N Diphenylphosphine oxide Chemical compound C=1C=CC=CC=1[P+](=O)C1=CC=CC=C1 YFPJFKYCVYXDJK-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000011942 biocatalyst Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- WXMZPPIDLJRXNK-UHFFFAOYSA-N butyl(diphenyl)phosphane Chemical group C=1C=CC=CC=1P(CCCC)C1=CC=CC=C1 WXMZPPIDLJRXNK-UHFFFAOYSA-N 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 238000007036 catalytic synthesis reaction Methods 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- XPYGGHVSFMUHLH-UUSULHAXSA-N falecalcitriol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(O)(C(F)(F)F)C(F)(F)F)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C XPYGGHVSFMUHLH-UUSULHAXSA-N 0.000 description 1
- 238000009434 installation Methods 0.000 description 1
- 229960003376 levofloxacin Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- UMLJLONQGFCDLO-UHFFFAOYSA-N methyl-phenyl-propylphosphane Chemical compound CCCP(C)C1=CC=CC=C1 UMLJLONQGFCDLO-UHFFFAOYSA-N 0.000 description 1
- 125000001298 n-hexoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 125000005328 phosphinyl group Chemical group [PH2](=O)* 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 150000003303 ruthenium Chemical class 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000011995 wilkinson's catalyst Substances 0.000 description 1
- UTODFRQBVUVYOB-UHFFFAOYSA-P wilkinson's catalyst Chemical compound [Cl-].C1=CC=CC=C1P(C=1C=CC=CC=1)(C=1C=CC=CC=1)[Rh+](P(C=1C=CC=CC=1)(C=1C=CC=CC=1)C=1C=CC=CC=1)P(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 UTODFRQBVUVYOB-UHFFFAOYSA-P 0.000 description 1
Classifications
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
- C07F9/653—Five-membered rings
-
- 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
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
- B01J31/2442—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems
- B01J31/249—Spiro-condensed ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/5022—Aromatic phosphines (P-C aromatic linkage)
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
- C07F9/5325—Aromatic phosphine oxides or thioxides (P-C aromatic linkage)
-
- 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
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/82—Metals of the platinum group
- B01J2531/827—Iridium
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a chiral spiro monophosphine-oxazoline ligand, an intermediate and a preparation method thereof. Respectively are compounds with the structures shown in the formulas 1,2 and 3,
comprises a racemate and optical isomers thereof, wherein m and n are integers of 0 to 3; x is CR1’R2’、NR1’O or S; r1And R2Each independently is hydrogen, alkyl, phenyl, 1-naphthyl, 2-naphthyl, alkoxy, ester group substitutedAlkyl groups of (a); r is hydrogen, alkyl, substituted phenyl, substituted alkyl, alkoxy, phenyl, 1-naphthyl, 2-naphthyl, halogen, cyano, carboxyl and hydroxyl; r2Hydrogen, alkyl, phenyl, 1-naphthyl, 2-naphthyl, alkyl substituted phenyl; m' is P (O) (R)3)2Or P (R)3)2；R3Is alkyl, phenyl, 1-naphthyl, 2-naphthyl, substituted phenyl, furyl or thienyl; m is OTf, COOH or COOR5(ii) a OTf represents trifluoromethanesulfonic group, R5Is an alkyl group.
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to a chiral spiro monophosphine-oxazoline ligand, an intermediate and a preparation method thereof.
Background
Asymmetric catalytic reactions are a research hotspot in the field of organic synthesis, while asymmetric catalytic hydrogenation reactions are a research hotspot in the field of asymmetric catalytic synthesis. The asymmetric catalytic hydrogenation reaction has the characteristics of perfect atom economy, cleanness, high efficiency and the like, and is one of the most favored asymmetric synthesis methods.
In the early 60's of the 20 th century, it was unknown whether catalytic asymmetric hydrogenation was feasible, and whether it was possible to produce an excess of one enantiomer by catalytic asymmetric hydrogenation was demonstrated by William s. Experiments by William s. knowles compounds of the following formula a were published by Osborn and Wilkinson in 1966
Chiral phosphides synthesized with Horner and Mislow and having the structure shown in formula B
Is taken as a basis. William S. Knowles analysis after comparing results that were available to the pre-study person, presented his hypothesis that he speculates if the metal complexes of Osborn and Wilkinson (Ph)3P)3Substitution of the triphenylphosphine of RhCl by one of the enantiomers of the chiral phosphine compound, possibly results in a chiral structured catalyst made of transition metals enabling asymmetric synthesis. At the outset, William S. Knowles used (-) -methyl-n-propylphenylphosphine in place of triphenylphosphine in Wilkinson's catalyst and catalyzed hydrogenation of alpha-phenylacrylic acid using this as catalyst to give an enantiomerA 15% excess of hydrogenated products, an important breakthrough in research was reported in the journal literature Chem commu, 1968:1445 by William s.
Although enantiomeric excesses are still low relative to current levels, this is a breakthrough in this direction. William S.Knowles and co-workers have finally prepared suitable catalysts capable of producing a greater proportion of beneficial isomers using [ Rh ((R) -DipAMP) COD in the course of increasing the catalytic efficiency of the catalyst by trial and error on the enantiomers of the phosphides of various structures]+BF- 4Is a catalyst, and takes achiral enamine as a starting material, and L-Dopa (an effective medicine for treating Parkinson's disease) with the structural formula as follows is obtained by one-step catalytic asymmetric hydrogenation reaction and one-step simple acidic hydrolysis reaction,
thus solving the key step of preparing L-Dopa industrially, the route is reported in journal literature Acc Chenm Res.1983,6:106 published by William S.Knowles in 1983, and the specific synthetic route is as follows:
the synthetic route was put into production in 1974 and was the first commercial drug synthesized by catalytic asymmetric reactions.
In 1980, another pioneer Ryoji Noyori and co-workers catalyzing asymmetric hydrogenation discovered a chiral diphosphine ligand represented by the structural formula BINAP,
the complex of any one enantiomer with rhodium has significantly greater activity than many other catalysts that catalyze asymmetric hydrogenation reactions.
His greatest contribution is to introduce the BINAP-Ru complex into the catalytic asymmetric hydrogenation reaction. These chiral ruthenium complexes are useful for stereoselectively catalyzing the hydrogenation of a series of unsaturated carboxylic acids. The stereoselectivity is much higher than that of rhodium catalyst. In addition, halogen-containing BINAP-Ru complex catalysts catalyze the hydrogenation of β -keto esters (enantiomeric excess up to 100%), with results even superior to many biocatalysts. This provides a powerful alternative for organic chemists to design synthetic routes.
Because of the high efficiency of the series of catalysts, the ratio of the catalyst to the catalyst can reach 1:10 in some reactions6The efficiency of (c). The reaction process is more economical, and simultaneously, the generation of harmful wastes is greatly reduced, thereby being beneficial to environmental protection. In addition, the corresponding enantiomer of BINAP can be conveniently selected according to the requirement, and the method is suitable for high-concentration (reactant concentration can reach 50%) organic solution, and has important significance for the production of medicines, pesticides, spices and the like. From the beginning of the 80 s of the 20 th century, Japan high sand company utilized this series of catalysts for the production of L-menthol. In addition, (R) -1, 2-propylene glycol (chiral intermediate for synthesizing antibacterial Levofloxacin) and azetidine (chiral intermediate for synthesizing antibiotic Carbapenem) can be put into industrial production and are also the outstanding roles of the series of catalysts.
In the field of asymmetric catalytic hydrogenation, although a plurality of chiral ligands and catalysts are reported, the catalyst system applied to asymmetric hydrogenation of unsaturated carboxylic acid compounds is still few overall. In view of the selection of multiple process routes in industrial production, there is a need to develop other, more and more efficient and highly selective chiral ligands and catalysts for asymmetric hydrogenation of unsaturated carboxylic acid compounds, which can be selected in industrial production.
Disclosure of Invention
The invention provides a chiral spiro monophosphine-oxazoline ligand, an intermediate and a preparation method thereof. Finally, the prepared chiral spiro monophosphine-oxazoline ligand has higher yield and optical purity, and a new intermediate is obtained. The novelty of the preparation method is shown, and the high-purity product proves that the preparation method has obvious technical effect.
In order to realize the technical purpose of the invention, the invention provides the following technical scheme:
the invention provides a chiral spirocyclic monophosphine-oxazoline ligand with the structure shown in the following formula 1,
including racemates and optical isomers thereof, wherein,
m, n are each independently an integer of 0, 1,2 or 3;
x is CR1’R2’、NR1’O or S; r1’And R2’Each independently is hydrogen, C1-C8Alkyl, phenyl, 1-naphthyl, 2-naphthyl, C1-C8Alkoxy of (5), by 1-3C2-C9Ester group substituted C of1-C8Alkyl groups of (a); r is hydrogen, C1-C8Alkyl of (C)1-C8Alkoxy, phenyl, or a substituted or unsubstituted alkoxy group of 1 to 5C1-C8Phenyl substituted by 1 to 5C1-C8Phenyl substituted by alkoxy, phenyl substituted by 1 to 5 phenyl, 1-naphthyl, 2-naphthyl, fluoro, chloro, bromo, iodo, cyano, carboxy, hydroxy, C substituted by 1 to 3 fluoro1-C8Alkyl of (2), C substituted by 1-3 chlorine1-C8Alkyl of (2), C substituted by 1-3 bromine1-C8Alkyl of (2), C substituted by 1-3 iodine1-C8Alkyl of (2), C substituted by 1-3 hydroxy groups1-C8Alkyl of (2), C substituted by 1-3 carboxyl groups1-C8Alkyl of (5) by 1-3C2-C9Ester group substituted C of1-C8Alkyl groups of (a); r2Is hydrogen, C1-C8Alkyl, phenyl, 1-naphthyl, 2-naphthyl, substituted by 1-5C1-C8Alkyl-substituted phenyl of (a); r3Is C1-C8Alkyl, phenyl, 1-naphthyl2-naphthyl, by 1-5C1-C8Phenyl substituted by alkoxy, phenyl substituted by 1 to 5 halogen groups, phenyl substituted by 1 to 5 amino, (C)1-C8Acyl) -amino substituted phenyl, di (C)1-C8Alkyl) amino-substituted phenyl, phenyl substituted with 1-5 hydroxy groups, phenyl substituted with 1-5 sulfonic acid groups, phenyl substituted with 1-5C1-C8Phenyl substituted by acyl, by 1-5C1-C8Phenyl substituted by 1 to 5C2-C9Phenyl, furyl, thienyl substituted by ester groups of (1);
said C is1-C8Alkyl of (a) is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, sec-pentyl, tert-pentyl, n-hexyl, isohexyl, neohexyl, sec-hexyl, tert-hexyl, n-heptyl, isoheptyl, neoheptyl, sec-heptyl, tert-heptyl, n-octyl, isooctyl, neooctyl, sec-octyl, tert-octyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane; preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptane, n-octyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane; more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptane, n-octyl, cyclopropane, cyclobutane, cyclopentane; more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropane; particularly preferably methyl, isopropyl, tert-butyl; most preferably methyl.
Said C is1-C8The alkoxy group of (A) is methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, cyclobutoxy, n-pentoxy, isopentoxy, neopentoxy, sec-pentoxy, tert-pentoxy, cyclopentoxy, n-hexoxy, isohexoxy, neohexoxy, sec-hexoxy, tert-hexoxy, cyclohexyloxy, n-heptoxy, isohexoxy, n-hexoxy, isopentexoxy, n-hexoxy, n,Neoheptyloxy, sec-heptyloxy, tert-heptyloxy, cycloheptyloxy, n-octyloxy, iso-octyloxy, neooctyloxy, sec-octyloxy, tert-octyloxy, cyclooctyloxy; preferably methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, cyclobutoxy, n-pentoxy, isopentoxy, neopentoxy, sec-pentoxy, tert-pentoxy, cyclopentoxy, n-hexoxy, isohexoxy, neohexoxy, sec-hexoxy, tert-hexoxy, cyclohexyloxy, n-heptoxy, isoheptoxy, neoheptoxy, sec-heptoxy, tert-heptoxy; more preferably methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, n-butoxy, tert-butoxy, cyclobutoxy, n-pentoxy, cyclopentoxy, n-hexoxy, cyclohexoxy, n-heptoxy; more preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy; particularly preferred are methoxy, ethoxy, and most preferred is methoxy.
Said C is2-C9The ester group of (a) is methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, cyclopropyloxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, cyclobutyloxycarbonyl, n-pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, sec-pentyloxycarbonyl, tert-pentyloxycarbonyl, cyclopentyloxycarbonyl, n-hexyloxycarbonyl, isohexyloxycarbonyl, neohexyloxycarbonyl, sec-hexyloxycarbonyl, tert-hexyloxycarbonyl, cyclohexyloxycarbonyl, n-heptyloxycarbonyl, isoheptyloxycarbonyl, neoheptyloxycarbonyl, sec-heptyloxycarbonyl, tert-heptyloxycarbonyl, cycloheptyloxycarbonyl, n-octyloxycarbonyl, isooctyloxycarbonyl, neooctyloxycarbonyl, sec-octyloxycarbonyl, tert-octyloxycarbonyl, cyclooctyloxycarbonyl; preferably methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, cyclopropyloxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, cyclobutyloxycarbonyl, n-pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, sec-pentyloxycarbonyl, tert-pentyloxycarbonyl, cyclopentyloxycarbonyl, n-hexyloxycarbonyl, isohexyloxycarbonyl, neohexyloxycarbonyl, sec-hexyloxycarbonyl, tert-hexyloxycarbonyl, cyclohexyloxycarbonyl, n-heptyloxycarbonyl, isoheptyloxycarbonylCarbonyl, neoheptyloxycarbonyl, sec-heptyloxycarbonyl, tert-heptyloxycarbonyl; more preferably methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, cyclopropyloxycarbonyl, isopropyloxycarbonyl, n-butoxycarbonyl, t-butoxycarbonyl, cyclobutyloxycarbonyl, n-pentyloxycarbonyl, cyclopentyloxycarbonyl, n-hexyloxycarbonyl, cyclohexyloxycarbonyl, n-heptyloxycarbonyl; more preferably methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, n-propoxycarbonyl; most preferred are methoxycarbonyl, ethoxycarbonyl.
Said C is1-C8The acyl group of (a) is formyl, acetyl, propionyl, n-butyryl, isobutyryl, n-valeryl, isovaleryl, sec-valeryl, pivaloyl, n-hexanoyl, isohexanoyl, neohexanoyl, sec-hexanoyl, n-heptanoyl, isoheptanoyl, neoheptanoyl, sec-heptanoyl, n-octanoyl, isooctanoyl, neooctanoyl, sec-octanoyl, 1-cyclopropylformyl, 1-cyclobutylformyl, 1-cyclopentylcarbonyl, 1-cyclohexylformyl, 1-cycloheptylcarbonyl; preferably formyl, acetyl, propionyl, n-butyryl, isobutyryl, n-pentanoyl, n-hexanoyl, n-heptanoyl, n-octanoyl, 1-cyclopropylformyl, 1-cyclobutylformyl, 1-cyclopentylcarbonyl, 1-cyclohexylformyl, 1-cycloheptylcarbonyl; more preferably formyl, acetyl, propionyl, n-butyryl, isobutyryl, n-valeryl, 1-cyclopropylformyl, 1-cyclobutylformyl, 1-cyclopentylcarbonyl; more preferably formyl, acetyl, propionyl, 1-cyclopropylformyl; most preferred are formyl, acetyl.
Preferably, the chiral spirocyclic monophosphine-oxazoline ligand having the structure of formula 1 above can be a compound having the structure of formula 1':
wherein, m, n, X, R3、R2Is as defined above, to R2With oxazoline rings
The key is
Key or
A key.
More preferably, the chiral spirocyclic monophosphine-oxazoline ligand with the structure of formula 1 may have a specific structure:
wherein R is3、R2Is as defined above, to R2With oxazoline rings
The key is
Key or
A key.
More preferably, the chiral spirocyclic monophosphine-oxazoline ligand with the structure of formula 1 has the following specific structure:
wherein R is3、R2Is as defined above, to R2With oxazoline rings
The key is
Key or
A key.
Particularly preferably, the chiral spirocyclic monophosphine-oxazoline ligand with the structure of the formula 1 has the following specific structure:
wherein R is3、R2The definition of (A) is as above.
Particularly preferably, the specific structure of the chiral spirocyclic monophosphine-oxazoline ligand with the structure of formula 1 is as follows:
most preferably, the chiral spirocyclic monophosphine-oxazoline ligand with the structure of formula 1 has the following specific structure:
in a second aspect, the present invention provides a chiral spirocyclic monophosphine-oxazoline ligand intermediate having the structure of formula 2,
including racemates and optical isomers thereof, wherein,
wherein, m, n, X, R3、R2The definition of (A) is as above.
Preferably, the chiral spirocyclic monophosphine-oxazoline ligand intermediate with the structure of formula 2 can be a compound with the structure of formula 2' as follows:
wherein, m, n, X, R3、R2Is as defined above, to R2With amide alcohols
The key is
Key or
A key.
More preferably, the specific structure of the chiral spirocyclic monophosphine-oxazoline ligand intermediate with the structure of formula 2 may be:
wherein R is3、R2Is as defined above, to R2With amide alcohols
The key is
Key or
A key.
More preferably, the specific structure of the chiral spirocyclic monophosphine-oxazoline ligand intermediate with the structure of formula 2 is as follows:
wherein R is3、R2Is as defined above, to R2With amide alcohols
The key is
Key or
A key.
Particularly preferably, the specific structure of the chiral spirocyclic monophosphine-oxazoline ligand intermediate with the structure of formula 2 is as follows:
wherein R is3、R2The definition of (A) is as above.
Particularly preferably, the specific structure of the chiral spirocyclic monophosphine-oxazoline ligand intermediate with the structure of formula 2 is as follows:
most preferably, the specific structure of the chiral spirocyclic monophosphine-oxazoline ligand intermediate with the structure of formula 2 is as follows:
in a third aspect, the present invention provides an intermediate of the structure of formula 3,
comprises racemate and optical isomer thereof, wherein M, n, R and X are defined as above, M is OTf, COOH or COOR5M' is P (O) (R)3)2Or P (R)3)2；R5Is C1-C8Alkyl of R3The definition of (A) is as above, OTf represents a trifluoromethanesulfonic group; said C is1-C8The alkyl group of (a) is as defined above.
Preferably, the structural intermediate of formula 3 may be a compound having a structure represented by formula 3-1, formula 3-2, formula 3-3, formula 3-4 below:
comprises thatSpiro and optical isomer, wherein m, n, R, X, OTf, R3，R5The definition of (A) is as above.
More preferably, the structural intermediate of formula 3 may be a structural compound of formula 3 '-1, formula 3' -2, formula 3 '-3, formula 3' -4, as follows:
wherein, m, n, R, X, OTf, R3，R5The definition of (A) is as above.
More preferably, the intermediate of the above structure of formula 3' -1 may be:
wherein, OTf, R3The definition of (1) is as above;
the intermediate of the above structure of formula 3' -2 may be:
wherein, OTf, R3The definition of (1) is as above;
the intermediate of the above structure of formula 3' -3 may be:
wherein R is3The definition of (1) is as above;
the intermediate of the above structure of formula 3' -4 may be:
wherein R is3The definition of (1) is as above;
particularly preferably, the intermediate of the above structure of formula 3' -1 may be:
wherein OTf is as defined above;
the intermediate of the above structure of formula 3' -2 may be:
wherein OTf is as defined above;
the intermediate of the above structure of formula 3' -3 may be:
the intermediate of the above structure of formula 3' -4 may be:
most preferably, the intermediate of the above structure of formula 3' -1 may be:
wherein OTf is as defined above;
the intermediate of the above structure of formula 3' -2 may be:
wherein OTf is as defined above;
the intermediate of the above structure of formula 3' -3 may be:
the intermediate of the above structure of formula 3' -4 may be:
the fourth aspect of the invention provides a preparation method of the chiral spiro monophosphine-oxazoline ligand with the structure of the formula 1.
The chiral spiro monophosphine-oxazoline ligand with the structure shown in the formula 1 is prepared by cyclization reaction of an intermediate with the structure shown in the formula 2, and the specific reaction formula is as follows:
comprises a racemate and optical isomers thereof, wherein m, n, X, R and R3、R2The definition of (1) is as above;
preferably, the reaction may be:
wherein, m, n, X, R3、R2Is as defined above, to R2With amide alcohols or linkages R2With oxazoline rings
The key is
Key or
A key.
More preferably, the reaction may be:
wherein R is3、R2Is as defined above, to R2With amide alcohols or linkages R2With oxazoline rings
The key is
Key or
A key.
More preferably, the reaction may be:
wherein R is3、R2Is as defined above, to R2With amide alcohols or linkages R2With oxazoline rings
The key is
Key or
A key.
Particularly preferably, the reaction may be:
wherein R is3、R2The definition of (A) is as above.
Particularly preferably, the reaction may be:
most preferably, the reaction may be:
further, the amide alcohol with the structure shown in the formula 2 can be prepared by performing acid-amine condensation reaction on an intermediate with the structure shown in the formula 3-4 and amino ethanol with the structure shown in the formula 4 substituted at the 2 position:
comprises racemate and optical isomers thereof, wherein m, n, R, X and R2，R3The definition of (1) is as above;
preferably, the reaction may be:
wherein, m, n, R, X, R2，R3Is as defined above for R2With amide alcohols or linkages R2With oxazoline rings
The key is
Key or
A key.
More preferably, the reaction may be:
wherein R is2，R3Is as defined above, to R2With amide alcohols
The key is
Key or
A key.
More preferably, the reaction may be:
most preferably, the reaction may be:
further, the structural intermediate of formula 3-4 can be prepared from the structural intermediate of formula 3-3 by hydrolysis reaction under alkaline condition:
comprises racemate and optical isomers thereof, wherein m, n, R, X and R5，R3The definition of (1) is as above;
preferably, the reaction may be:
wherein, m, n, R, X, R5，R3The definition of (1) is as above;
more preferably, the reaction may be:
wherein R is3The definition of (1) is as above;
more preferably, the reaction may be:
most preferably, the reaction may be:
further, the intermediate of formula 3-3 can be prepared from the intermediate of formula 3-2 by esterification reaction under the catalysis of palladium reagent:
comprises racemate and optical isomers thereof, wherein m, n, R, X, OTf and R3，R5The definition of (1) is as above;
preferably, the reaction may be:
wherein, m, n, R, X, OTf, R3，R5The definition of (1) is as above;
more preferably, the reaction may be:
wherein, OTf, R3The definition of (1) is as above;
more preferably, the reaction may be:
most preferably, the reaction may be:
further, the intermediate of the formula 3-2 can be prepared from the intermediate of the formula 3-1 by reduction reaction under the action of trichlorosilane:
comprises racemate and optical isomers thereof, wherein m, n, R, X, OTf and R3The definition of (1) is as above;
preferably, the reaction may be:
wherein, m, n, R, X, OTf, R3The definition of (1) is as above;
more preferably, the reaction may be:
wherein R is3The definition of (1) is as above;
more preferably, the reaction may be:
most preferably, the reaction may be:
the invention also provides a preparation method of the chiral spiro monophosphine-oxazoline ligand with the following formula 1 structure, which takes chiral spiro diphenol with the formula 6 structure as an initial raw material, and is prepared by esterification reaction with trifluoromethanesulfonic anhydride, coupling reaction under the catalysis of palladium reagent, reduction reaction under the action of trichlorosilane, esterification reaction under the catalysis of palladium reagent, hydrolysis reaction under alkaline condition, acid-amine condensation reaction with 2-substituted aminoethanol with the formula 4 structure to prepare amidol with the formula 2 structure, and finally cyclization reaction, wherein the reaction formula is as follows:
wherein OTf is trifluoromethanesulfonic group; r3Is selected from
Or
Preferably is
R2Is selected from
Preferably is
Connection R2With amide alcohols or linkages R2With oxazoline rings
The key is
Key or
A key.
Most preferably, the compound having the structure of formula 1 is prepared by the following steps:
the invention provides a chiral spiro monophosphine-oxazoline ligand, an intermediate and a preparation method thereof. The chiral spiro monophosphine-oxazoline ligand finally prepared by the preparation method provided by the invention has higher yield and purity, and a new intermediate is obtained. The results show that the preparation method of the chiral spiro monophosphine-oxazoline ligand is a route with industrial advantages.
Detailed Description
For further understanding of the present invention, the following examples are provided to illustrate the preparation of the chiral spirocyclic monophosphine-oxazoline ligands of the present invention. It is to be understood that these examples are described merely to illustrate the features of the present invention in further detail, and not as limitations of the invention or of the scope of the claims appended hereto.
General description:
the following abbreviations are used in the examples and have the following meanings:
Tf2o is trifluoromethanesulfonic anhydride, Py is pyridine, OTf is trifluoromethanesulfonic group, dppb is 4-diphenylphosphinobutane, DIPEA is diisopropylethylamine, Xyl is 3, 5-dimethylphenyl, DTB is 3, 5-di-tert-butylphenyl, dppp is 1, 3-diphenylphosphinopropane, DMSO is dimethyl sulfoxide, TLC is thin-layer chromatography, HOBt is 1-hydroxybenzotriazole,DCC is N, N' -dicyclohexylcarbodiimide, Ph is phenyl, Bn is benzyl, DMAP is 4-dimethylpyridine, MsCl is methanesulfonyl chloride, NMR is nuclear magnetic resonance, ee is enantiomeric excess, HPLC is high performance liquid chromatography.
The solvent is purified and dried by standard operation before use; the reagents used are either commercially available or synthesized according to established literature methods and purified before use.
EXAMPLE 1 preparation of Compound 5
To a 500mL reaction flask were added (S, S, S) -6(17.5g, 60mmol), pyridine (14.1mL, 175.0mmol), and 200mL freshly distilled CH2Cl2Trifluoromethanesulfonic anhydride (25.5mL, 150mmol) was added dropwise at 0 deg.C, and the mixture was stirred at room temperature overnight. Adding diluted hydrochloric acid to quench the reaction, adjusting the pH of the water phase to 6-7, and adjusting the pH to CH2Cl2And (4) extracting. The organic phase was saturated NaHCO3The solution and saturated brine were washed successively, and dried over anhydrous sodium sulfate. The filtrate was concentrated and subjected to silica gel column chromatography to obtain 32.0 g of a pale yellow solid (eluent: n-hexane/ethyl acetate 10/1), yield: 96%.
Example 2: compound 3-1 (R)3Ph) preparation
A250 mL reaction flask was charged with bis (trifluoromethanesulfonate) 5(15.0g, 27.0mmol) of the spiro compound, diphenylphosphine oxide (7.0g, 35.0mmol), palladium acetate (303mg, 1.35mmol), 1, 4-diphenylphosphinobutane (dppb, 576mg, 1.35mmol), and 70mL of anhydrous DMSO. Diisopropylethylamine (19mL, 108.0mmol) was added with stirring and heated to 100 deg.C for 6 hours. Cooling to room temperature, adding EtOAc/water for dilution, filtering, removing solvent from the filtrate, and performing silica gel column chromatography (eluent: n-hexane/ethyl acetate 5/1) to obtain 15.0g with a yield of 91%; a pale yellow solid.
Example 3 Compound 3-1 (R)3Para Xyl) preparation
A250 mL reaction flask was charged with bis (trifluoromethanesulfonate) 5(15.0g, 27.0mmol) of a spiro compound, bis (3, 5-dimethylphenyl) phosphinyl (9.0g, 35.0mmol), palladium acetate (303mg, 1.35mmol), 1, 4-diphenylphosphinobutane (dppb, 576mg, 1.35mmol), and 70mL of anhydrous DMSO. Diisopropylethylamine (19mL, 108.0mmol) was added with stirring and heated to 100 deg.C for 6 hours. Cooling to room temperature, adding EtOAc/water for dilution, filtering, removing solvent from the filtrate, and performing silica gel column chromatography (eluent: n-hexane/ethyl acetate 5/1) to obtain 15.4 g with a yield of 86%; a pale yellow solid.
Example 4 Compound 3-1 (R)3Preparation of ═ DTB)
A250 mL reaction flask was charged with bis (trifluoromethanesulfonate) 5(15.0g, 27.0mmol) of a spiro compound, bis (3, 5-tert-butylphenyl) phosphinyl (14.9g, 35.0mmol), palladium acetate (303mg, 1.35mmol), 1, 4-diphenylphosphinobutane (dppb, 576mg, 1.35mmol), and 70mL of anhydrous DMSO. Diisopropylethylamine (19mL, 108.0mmol) was added with stirring and heated to 100 deg.C for 6 hours. Cooling to room temperature, adding EtOAc/water for dilution, filtering, removing solvent from the filtrate, and performing silica gel column chromatography (eluent: n-hexane/ethyl acetate 5/1) to obtain 26.8 g with a yield of 92%; a pale yellow solid.
Example 5 Compound 3-2 (R)3Ph) preparation
A250 mL reaction flask was charged with monophosphine oxide 3-1 (R) of the spiro compound3Ph) (15.0g, 25.0mmol) and 80mL of anhydrous toluene. Diisopropylethylamine (19mL, 108.0mmol), trichlorosilane (7.8mL,75mmol) were added with stirring under inert gas, and the reaction was heated to 100 ℃ in an oil bath for 6 hours. Cooling to room temperature, adding EtOAc for dilution, adding 12M sodium hydroxide solution (5mL) dropwise, filtering, removing the solvent from the filtrate, and subjecting the filtrate to silica gel column chromatography (eluent: n-hexane/ethyl acetate 10/1) to obtain 11.9 g, yield: 80 percent; a white solid.
Example 6 Compound 3-2 (R)3Para Xyl) preparation
A250 mL reaction flask was charged with monophosphine oxide 3-1 (R) of the spiro compound3Xyl) (16.6g, 25.0mmol) and 100mL of anhydrous toluene. Diisopropylethylamine (19mL, 108.0mmol), trichlorosilane (7.8mL,75mmol) were added with stirring under inert gas, and the reaction was heated to 100 ℃ in an oil bath for 6 hours. Cooling to room temperature, adding EtOAc for dilution, adding 12M sodium hydroxide solution (5mL) dropwise, filtering, removing the solvent from the filtrate, and subjecting the filtrate to silica gel column chromatography (eluent: n-hexane/ethyl acetate 10/1) to obtain 14.3 g, yield: 88 percent; a white solid.
Example 7 Compound 3-2 (R)3Preparation of ═ DTB)
A250 mL reaction flask was charged with monophosphine oxide 3-1 (R) of the spiro compound3DTB) (16.6g, 25.0mmol) and 100mL of anhydrous toluene. Diisopropylethylamine (19mL, 108.0mmol), trichlorosilane (7.8mL,75mmol) were added with stirring under inert gas, and the reaction was heated to 100 ℃ in an oil bath for 6 hours. Cooling to room temperature, adding EtOAc for dilution, adding 12M sodium hydroxide solution (5mL) dropwise, filtering, removing the solvent from the filtrate, and subjecting the filtrate to silica gel column chromatography (eluent: n-hexane/ethyl acetate 10/1) to obtain 18.8 g, yield: 92 percent; a white solid.
Example 8 Compound 3-3 (R)3Ph) preparation
To a 500mL two-necked flask was added compound 3-3 (R)3Ph) (10.0g,16.9mmol), palladium acetate (584mg,2.6mmol) and 1, 3-diphenylphosphinopropane (dppp,1073mg,2.6mmol), and the system was replaced with a CO atmosphere by installing a reflux condenser, an aspirator and a stopper. Methanol (60mL), DMSO (150mL) and triethylamine (50mL) were added and mixed well with stirring. The oil bath was heated to 80 ℃ for 24 hours and the TLC follow-up was checked until the reaction was complete. The system was replaced with a nitrogen atmosphere, and the solvent was removed by concentration under reduced pressure. Dichloromethane was added to the residual reaction solution to dilute, silica gel was added to the reaction solution, the mixture was concentrated, and then dry column chromatography (eluent: n-hexane/ethyl acetate: 20/1) was performed to obtain 7.3g of a yellow solid, yield: 86 percent.
Example 9 Compound 3-3 (R)3Para Xyl) preparation
To a 500mL two-necked flask was added compound 3-2 (R)3Xyl) (11.0g,16.9mmol), palladium acetate (584mg,2.6mmol) and 1, 3-diphenylphosphinopropane (dppp,1073mg,2.6mmol), and the system was replaced with a CO atmosphere by installing a reflux condenser, an aspirator and a stopper. Methanol (60mL), DMSO (150mL) and triethylamine (50mL) were added and mixed well with stirring. The oil bath was heated to 80 ℃ for 24 hours and the TLC follow-up was checked until the reaction was complete. The system was replaced with a nitrogen atmosphere, and the solvent was removed by concentration under reduced pressure. Dichloromethane was added to the residual reaction solution to dilute, silica gel was added to the reaction solution, the mixture was concentrated, and then dry column chromatography (eluent: n-hexane/ethyl acetate: 20/1) was performed to obtain 8.3g of a yellow solid, yield: 88 percent.
Example 10 Compounds 3-3 (R)3Preparation of ═ DTB)
To a 500mL two-necked flask was added compound 3-2 (R)3DTB) (13.8g,16.9mmol), palladium acetate (584mg,2.6mmol) and 1, 3-diphenylphosphinopropane (dppp,1073mg,2.6mmol), and the system was replaced with a CO atmosphere by installing a reflux condenser, an aspirator and a stopper. Methanol (60mL), DMSO (150mL) and triethylamine (50mL) were added and mixed well with stirring. The oil bath was heated to 80 ℃ for 24 hours and the TLC follow-up was checked until the reaction was complete. The system was replaced with a nitrogen atmosphere, and the solvent was removed by concentration under reduced pressure. Dichloromethane was added to the residual reaction solution to dilute, silica gel was added to the reaction solution, the mixture was concentrated, and then dry column chromatography (eluent: n-hexane/ethyl acetate: 20/1) was performed to obtain 11.0g of a yellow solid, yield: 90 percent.
Example 11 Compounds 3-4 (R)3Ph) preparation
To a 500mL two-necked flask was added compound 3-3 (R)3Ph) (7.3g,14.5mmol) and methanol (150mL), cooled in an ice-water bath, 60% KOH aqueous solution (30mL) was added, a reflux condenser tube was installed, and the system was replaced with a nitrogen atmosphere. After stirring and mixing evenly, the mixture is heated to 100 ℃ by oil bath for 24 hours of reaction, and TLC tracking detection is carried out until the reaction is complete. The reaction was stopped, the system was cooled in an ice-water bath, and concentrated hydrochloric acid was added dropwise to a pH of 3 to 4, to precipitate a large amount of white solid in the system. Adding dichloromethane to the residual reaction solution for dilution, stirring to dissolve the solid, then layering, extracting the water phase twice with dichloromethane, combining the organic phases, washing with saturated salt water once, and drying with anhydrous sodium sulfate. Suction filtration, concentration of the filtrate, and column chromatography (eluent: n-hexane/ethyl acetate 10/1) gave 6.7g of a white solid, yield: 95 percent.
Example 12 Compounds 3-4 (R)3Para Xyl) preparation
To a 500mL two-necked flask was added compound 3-3 (R)3＝Xyl)(8.3g,14.9mmol) and methanol (150mL) were cooled in an ice-water bath, and 60% KOH aqueous solution (30mL) was added thereto, followed by installation of a reflux condenser and replacement of the system with a nitrogen atmosphere. After stirring and mixing evenly, the mixture is heated to 100 ℃ by oil bath for 24 hours of reaction, and TLC tracking detection is carried out until the reaction is complete. The reaction was stopped, the system was cooled in an ice-water bath, and concentrated hydrochloric acid was added dropwise to a pH of 3 to 4, to precipitate a large amount of white solid in the system. Adding dichloromethane to the residual reaction solution for dilution, stirring to dissolve the solid, then layering, extracting the water phase twice with dichloromethane, combining the organic phases, washing with saturated salt water once, and drying with anhydrous sodium sulfate. Suction filtration, concentration of the filtrate, and column chromatography (eluent: n-hexane/ethyl acetate 10/1) gave 7.8g of a white solid, yield: 96 percent.
Example 13 Compounds 3-4 (R)3Preparation of ═ DTB)
To a 500mL two-necked flask was added compound 3-3 (R)3DTB) (11.0g,15.2mmol) and methanol (150mL) were cooled in an ice-water bath, and a 60% KOH aqueous solution (30mL) was added thereto, followed by installing a reflux condenser and replacing the system with a nitrogen atmosphere. After stirring and mixing evenly, the mixture is heated to 100 ℃ by oil bath for 24 hours of reaction, and TLC tracking detection is carried out until the reaction is complete. The reaction was stopped, the system was cooled in an ice-water bath, and concentrated hydrochloric acid was added dropwise to a pH of 3 to 4, to precipitate a large amount of white solid in the system. Adding dichloromethane to the residual reaction solution for dilution, stirring to dissolve the solid, then layering, extracting the water phase twice with dichloromethane, combining the organic phases, washing with saturated salt water once, and drying with anhydrous sodium sulfate. Suction filtration, concentration of the filtrate, and column chromatography (eluent: n-hexane/ethyl acetate 10/1) gave 10.8g of a white solid, yield: 99 percent.
Example 14 Compound 2 (R)3＝Ph,R2H) preparation
Adding into 500mL two-mouth bottleCompound 2 (R)3＝Ph,R2H) (6.7g,13.7mmol), HOBt (4.6g,30.3mmol) and DCC (8.1g,39.4mmol), and replaced with a nitrogen atmosphere. While cooling in an ice-water bath, redistilled tetrahydrofuran (180mL) was added, and after stirring and mixing well, ethanolamine (1.9g,31.1mmol) was added. After the addition, the temperature naturally rises to room temperature, and the reaction is stirred, so that a large amount of white solid is generated in the system. TLC tracing detection until the reaction is complete. The reaction was stopped, and after removing part of the solvent by concentration, silica gel was added, and after concentration, column chromatography (eluent: n-hexane/ethyl acetate 5/1) was performed to obtain 7.3g of a yellow foamy solid, yield: 100 percent.
Example 15 Compound 2 (R)3＝Xyl,R2H) preparation
Add Compound 3-4 (R) to a 500mL two-necked flask3Xyl) (7.8g,14.3mmol), HOBt (4.6g,30.3mmol) and DCC (8.1g,39.4mmol), and the atmosphere was replaced with nitrogen. While cooling in an ice-water bath, redistilled tetrahydrofuran (180mL) was added, and after stirring and mixing well, ethanolamine (1.9g,31.1mmol) was added. After the addition, the temperature naturally rises to room temperature, and the reaction is stirred, so that a large amount of white solid is generated in the system. TLC tracing detection until the reaction is complete. The reaction was stopped, and after removing part of the solvent by concentration, silica gel was added, and after concentration, column chromatography (eluent: n-hexane/ethyl acetate 5/1) was performed to obtain 8.4g of a yellow foamy solid, yield: 100 percent.
Example 16 Compound 2 (R)3＝DTB,R2H) preparation
Add Compound 3-4 (R) to a 500mL two-necked flask3DTB) (10.8g,15.0mmol), HOBt (5.0g,33.2mmol) and DCC (8.9g,43.2mmol), and replaced with a nitrogen atmosphere. While cooling in an ice-water bath, redistilled tetrahydrofuran (180mL) was added, and after stirring and mixing well, ethanolamine (1.9g,31.1mmol) was added. After the addition is finished, the temperature naturally rises to room temperature, the reaction is stirred, and a large amount of white solids exist in the systemAnd (4) generating a body. TLC tracing detection until the reaction is complete. The reaction was stopped, and after removing part of the solvent by concentration, silica gel was added, and after concentration, column chromatography (eluent: n-hexane/ethyl acetate 4/1) was performed to obtain 11.4g of a yellow foamy solid, yield: 100 percent.
Example 17 Compound 2 (R)3＝DTB,R2Ph) preparation
Add Compound 2 (R) to a 500mL two-necked flask3＝DTB,R2Ph) (10.8g,15.0mmol), HOBt (5.0g,33.2mmol), DCC (8.9g,43.2mmol) and L-phenylglycinol (4.3g,31.1mmol), and replaced with a nitrogen atmosphere. Adding redistilled tetrahydrofuran (180mL) under the cooling of an ice water bath, naturally heating to room temperature after the addition, and stirring for reaction, wherein a large amount of white solid is generated in the system. TLC tracing detection until the reaction is complete. The reaction was stopped, and after removing part of the solvent by concentration, silica gel was added, and after concentration, column chromatography (eluent: n-hexane/ethyl acetate 5/1) was performed to obtain 12.5g of a white solid, yield: 100 percent.
Example 18 Compound 2 (R)3＝DTB,R2Preparation of ═ Bn)
Add Compound 2 (R) to a 500mL two-necked flask3＝DTB,R2N. (10.8g,15.0mmol), HOBt (5.0g,33.2mmol), DCC (8.9g,43.2mmol) and L-phenylaminol (4.7g,31.1mmol), and the atmosphere was replaced with nitrogen. Adding redistilled tetrahydrofuran (180mL) under the cooling of an ice water bath, naturally heating to room temperature after the addition, and stirring for reaction, wherein a large amount of white solid is generated in the system. TLC tracing detection until the reaction is complete. The reaction was stopped, and after removing part of the solvent by concentration, silica gel was added, and after concentration, column chromatography (eluent: n-hexane/ethyl acetate 5/1) was performed to obtain 12.8g of a yellow foamy solid, yield: 100 percent.
Example 19 Compound 1 (R)3＝Ph,R2H) preparation
Add Compound 2 (R) to a 500mL two-necked flask3＝Ph,R2H) (7.3g,13.7mmol) and DMAP (61mg,0.5mmol), replaced with a nitrogen atmosphere. Redistilled dichloromethane (240mL) was added, and after stirring and mixing, triethylamine (4.1mL,29.6mmol) and MsCl (2.1mL,27.1mmol) were added in this order while cooling in an ice-water bath. The reaction was stirred for 30 minutes with the temperature maintained and 17.6mL of triethylamine was added. After the addition, the temperature naturally rises to room temperature, the reaction is stirred, and the TLC tracking detection is carried out until the reaction is complete. The reaction was stopped, and after removing part of the solvent by concentration, silica gel was added, and after concentration, column chromatography (eluent: n-hexane/ethyl acetate 10/1) was performed to obtain 5.1g of a white foamy solid, yield: 72 percent.
Example 20 Compound 1 (R)3＝Xyl,R2H) preparation
To a 500mL two-necked flask was added Compound 1 (R)3＝Xyl,R2H) and DMAP (64mg,0.5mmol), replaced with a nitrogen atmosphere. Redistilled dichloromethane (240mL) was added, and after stirring and mixing, triethylamine (4.1mL,29.6mmol) and MsCl (2.1mL,27.1mmol) were added in this order while cooling in an ice-water bath. The reaction was stirred for 30 minutes with the temperature maintained and 17.6mL of triethylamine was added. After the addition, the temperature naturally rises to room temperature, the reaction is stirred, and the TLC tracking detection is carried out until the reaction is complete. The reaction was stopped, and after removing part of the solvent by concentration, silica gel was added, and after concentration, column chromatography (eluent: n-hexane/ethyl acetate 10/1) was performed to obtain 6.3g of a white foamy solid, yield: 77 percent.
Example 21 Compound 1 (R)3＝DTB,R2H) preparation
Into a 500mL two-mouth bottleAdding Compound 2 (R)3＝DTB,R2H) (11.4g,15.0mmol) and DMAP (74mg,0.6mmol), replaced with a nitrogen atmosphere. Redistilled dichloromethane (240mL) was added, and after stirring and mixing, triethylamine (4.1mL,29.6mmol) and MsCl (2.1mL,27.1mmol) were added in this order while cooling in an ice-water bath. The reaction was stirred for 30 minutes with the temperature maintained and 17.6mL of triethylamine was added. After the addition, the temperature naturally rises to room temperature, the reaction is stirred, and the TLC tracking detection is carried out until the reaction is complete. The reaction was stopped, and after removing part of the solvent by concentration, silica gel was added, and after concentration, column chromatography (eluent: n-hexane/ethyl acetate 10/1) was performed to obtain 8.9g of a white foamy solid, yield: 80 percent.
Example 22 Compound 1 (R)3＝DTB,R2Ph) preparation
Add Compound 2 (R) to a 500mL two-necked flask3＝DTB,R2Ph) (12.5g,15.0mmol) and DMAP (74mg,0.6mmol), and replaced with a nitrogen atmosphere. Redistilled dichloromethane (240mL) was added, and after stirring and mixing, triethylamine (4.1mL,29.6mmol) and MsCl (2.1mL,27.1mmol) were added in this order while cooling in an ice-water bath. The reaction was stirred for 30 minutes with the temperature maintained and 17.6mL of triethylamine was added. After the addition, the temperature naturally rises to room temperature, the reaction is stirred, and the TLC tracking detection is carried out until the reaction is complete. The reaction was stopped, and after removing part of the solvent by concentration, silica gel was added, and after concentration, column chromatography (eluent: n-hexane/ethyl acetate 10/1) was performed to obtain 10.4g of a white foamy solid, yield: 85 percent.
Example 23 Compound 1 (R)3＝DTB,R2Preparation of ═ Bn)
Add Compound 2 (R) to a 500mL two-necked flask3＝DTB,R2Bn) (12.8g,15.0mmol) and DMAP (74mg,0.6mmol), replaced with a nitrogen atmosphere. Adding redistilled dichloromethane (240mL), stirring and mixing uniformly, and sequentially adding three under the cooling of ice-water bathEthylamine (4.1mL,29.6mmol) and MsCl (2.1mL,27.1 mmol). The reaction was stirred for 30 minutes with the temperature maintained and 17.6mL of triethylamine was added. After the addition, the temperature naturally rises to room temperature, the reaction is stirred, and the TLC tracking detection is carried out until the reaction is complete. The reaction was stopped, and after removing part of the solvent by concentration, silica gel was added, and after concentration, column chromatography (eluent: n-hexane/ethyl acetate 10/1) was performed to obtain 9.2g of a white foamy solid, yield: 74 percent.
Example 24 chiral Spirocyclic monophosphine-oxazoline ligand 1 (R)3＝DTB,R2H) applications
The compound of formula 7 (32.3g,75mmol) and the catalyst (1/6000 in molar amount corresponding to the substrate compound of formula 7) were weighed into a reaction tube equipped with a stirrer and sealed for use in a glove box. After being taken out, triethylamine (22.8g, 225mmol) and absolute methanol (150mL) are added, an inner tube is placed in a hydrogenation reaction kettle, the system is replaced into a hydrogen atmosphere through three times of hydrogenation-deflation operation, finally, the pressure is increased to 12atm, and the mixture is stirred at 70 ℃ until the hydrogen pressure is not reduced. Then stopping the reaction, discharging hydrogen, carrying out rotary evaporation and concentration on the reaction system, adding 100mL of diethyl ether for dilution, adjusting the system to be acidic by using 3N hydrochloric acid, separating liquid, extracting the water phase twice by using diethyl ether (100mL), combining organic phases, washing once by using saturated saline solution, and drying by using anhydrous sodium sulfate. Filtering out the drying agent, removing the solvent by rotary evaporation to obtain a crude product,1the conversion was greater than 99% by H NMR analysis. The ee value was 97% by chiral HPLC analysis. The product yield is 95% by column chromatography.
Claims (13)
1. A chiral spiro monophosphine-oxazoline ligand 1 has the following structural formula:
including racemates and optical isomers thereof, wherein,
m, n are each independently an integer of 0, 1,2 or 3;
x is CR1’R2’、NR1’O or S; r1’And R2’Each independently is hydrogen, C1-C8Alkyl, phenyl, 1-naphthyl, 2-naphthyl, C1-C8Alkoxy of (5), by 1-3C2-C9Ester group substituted C of1-C8Alkyl groups of (a);
r is hydrogen, C1-C8Alkyl of (C)1-C8Alkoxy, phenyl, or a substituted or unsubstituted alkoxy group of 1 to 5C1-C8Phenyl substituted by 1 to 5C1-C8Phenyl substituted by alkoxy, phenyl substituted by 1 to 5 phenyl, 1-naphthyl, 2-naphthyl, fluoro, chloro, bromo, iodo, cyano, carboxy, hydroxy, C substituted by 1 to 3 fluoro1-C8Alkyl of (2), C substituted by 1-3 chlorine1-C8Alkyl of (2), C substituted by 1-3 bromine1-C8Alkyl of (2), C substituted by 1-3 iodine1-C8Alkyl of (2), C substituted by 1-3 hydroxy groups1-C8Alkyl of (2), C substituted by 1-3 carboxyl groups1-C8Alkyl of (5) by 1-3C2-C9Ester group substituted C of1-C8Alkyl groups of (a);
R2is hydrogen, C1-C8Alkyl, phenyl, 1-naphthyl, 2-naphthyl, substituted by 1-5C1-C8Alkyl-substituted phenyl of (a);
R3is C1-C8Alkyl, phenyl, 1-naphthyl, 2-naphthyl, substituted by 1-5C1-C8Phenyl substituted by alkoxy, phenyl substituted by 1 to 5 halogen groups, phenyl substituted by 1 to 5 amino, (C)1-C8Acyl) -amino substituted phenyl, di (C)1-C8Alkyl) amino-substituted phenyl, phenyl substituted with 1-5 hydroxy groups, phenyl substituted with 1-5 sulfonic acid groups, phenyl substituted with 1-5C1-C8Phenyl substituted by acyl, by 1-5C1-C8Phenyl substituted by 1 to 5C2-C9Phenyl and furyl substituted by ester groupsAnd thienyl.
2. The chiral spirocyclic monophosphine-oxazoline ligand of claim 1, wherein C is1-C8Alkyl of (a) is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, sec-pentyl, tert-pentyl, n-hexyl, isohexyl, neohexyl, sec-hexyl, tert-hexyl, n-heptyl, isoheptyl, neoheptyl, sec-heptyl, tert-heptyl, n-octyl, isooctyl, neooctyl, sec-octyl, tert-octyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane; said C is1-C8The alkoxy group of (A) is methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, cyclobutoxy, n-pentoxy, isopentoxy, neopentoxy, sec-pentoxy, tert-pentoxy, cyclopentoxy, n-hexoxy, isohexoxy, neohexoxy, sec-hexoxy, tert-hexoxy, cyclohexoxy, n-heptoxy, isoheptoxy, neoheptoxy, sec-heptoxy, tert-heptoxy, cycloheptoxy, n-octoxy, isooctoxy, neooctoxy, sec-octoxy, tert-octoxy, cyclooctoxy; said C is2-C9The ester group of (a) is methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, cyclopropyloxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, cyclobutyloxycarbonyl, n-pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, sec-pentyloxycarbonyl, tert-pentyloxycarbonyl, cyclopentyloxycarbonyl, n-hexyloxycarbonyl, isohexyloxycarbonyl, neohexyloxycarbonyl, sec-hexyloxycarbonyl, tert-hexyloxycarbonyl, cyclohexyloxycarbonyl, n-heptyloxycarbonyl, isoheptyloxycarbonyl, neoheptyloxycarbonyl, sec-heptyloxycarbonyl, tert-heptyloxycarbonyl, cycloheptyloxycarbonyl, n-octyloxycarbonyl, isooctyloxycarbonyl, neooctyloxycarbonyl, sec-octyloxycarbonyl, tert-octyloxycarbonyl, cyclooctyloxycarbonyl; said C is1-C8The acyl group is formyl, acetyl, propionyl, n-butyryl, isobutyryl, n-valeryl, isovaleryl, sec-valeryl, pivaloyl, n-hexanoyl, isohexanoyl, neohexanoylSecondary hexanoyl, n-heptanoyl, isoheptanoyl, neoheptanoyl, sec-heptanoyl, n-octanoyl, isooctanoyl, neooctanoyl, sec-octanoyl, 1-cyclopropylformyl, 1-cyclobutylformyl, 1-cyclopentylcarbonyl, 1-cyclohexylformyl, 1-cycloheptylcarbonyl.
3. The chiral spirocyclic monophosphine-oxazoline ligand of claim 1, wherein the optically active chiral spirocyclic monophosphine-oxazoline ligand is:
4. the chiral spirocyclic monophosphine-oxazoline ligand of claim 1, wherein the optically active chiral spirocyclic monophosphine-oxazoline ligand has the structural formula:
5. an intermediate 2 for preparing a chiral spiro monophosphine-oxazoline ligand 1, which has the following structural formula:
comprises a racemate and optical isomers thereof, wherein m, n, X, R and R3、R2The definition of (A) is as above.
6. An intermediate 3 for preparing a chiral spirocyclic monophosphine-oxazoline ligand 1, which has the following structural formula:
comprises racemate and optical isomer thereof, wherein M, n, R and X are defined as above, M is OTf, COOH or COOR5M' is P (O) (R)3)2Or P (R)3)2；R5Is C1-C8Alkyl of R3The definition of (A) is as above, OTf represents a trifluoromethanesulfonic group; said C is1-C8The alkyl group of (a) is as defined above.
7. A preparation method of chiral spiro monophosphine-oxazoline ligand 1 is characterized in that the chiral spiro monophosphine-oxazoline ligand 1 is prepared by cyclization reaction of an intermediate with a structure shown in formula 2:
comprises a racemate and optical isomers thereof, wherein m, n, X, R and R3、R2The definition of (A) is as above.
8. The preparation method of claim 7, wherein the structural intermediate of formula 2 is prepared by performing acid-amine condensation reaction between the structural intermediate of formula 3-4 and aminoethanol compound:
comprises racemate and optical isomers thereof, wherein m, n, R, X and R2，R3The definition of (A) is as above.
9. The method according to claim 8, wherein the structural intermediate of formula 3-4 is prepared from the structural intermediate of formula 3-3 by hydrolysis reaction under alkaline conditions:
comprises racemate and optical isomers thereof, wherein m, n, R, X and R5，R3The definition of (A) is as above.
10. The method of claim 9, wherein the structural intermediate of formula 3-3 is prepared from the structural intermediate of formula 3-2 by esterification reaction under catalysis of palladium reagent:
comprises racemate and optical isomers thereof, wherein m, n, R, X, OTf and R3，R5The definition of (A) is as above.
11. The method according to claim 10, wherein the structural intermediate of formula 3-2 is prepared from the structural intermediate of formula 3-1 by reduction reaction with trichlorosilane:
comprises racemate and optical isomers thereof, wherein m, n, R, X, OTf and R3The definition of (A) is as above.
12. A preparation method of chiral spiro monophosphine-oxazoline ligand 1 is characterized in that chiral spiro diphenol with a structure shown in formula 6 is used as an initial raw material, and is prepared by esterification reaction with trifluoromethanesulfonic anhydride, coupling reaction under catalysis of a palladium reagent, reduction reaction under action of trichlorosilane, esterification reaction under catalysis of a palladium reagent, hydrolysis reaction under alkaline condition, acid-amine condensation reaction with aminoethanol compound to obtain amidol with a structure shown in formula 2, and cyclization reaction:
wherein OTf is trifluoromethanesulfonic group; r3Is selected from
R2Is selected from
Connection R2With amide alcohols or linkages R2With oxazoline rings
The key is
Key or
A key.
13. The preparation method according to claim 12, wherein the chiral spirocyclic monophosphine-oxazoline ligand 1 is prepared by:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910631270.5A CN112209967A (en) | 2019-07-12 | 2019-07-12 | Chiral spiro monophosphine-oxazoline ligand and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910631270.5A CN112209967A (en) | 2019-07-12 | 2019-07-12 | Chiral spiro monophosphine-oxazoline ligand and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN112209967A true CN112209967A (en) | 2021-01-12 |
Family
ID=74047211
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910631270.5A Pending CN112209967A (en) | 2019-07-12 | 2019-07-12 | Chiral spiro monophosphine-oxazoline ligand and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112209967A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1884290A (en) * | 2006-07-11 | 2006-12-27 | 南开大学 | Phosphorus-oxazoline ligand with spiro backbone and its uses in asymmetrical catalytic hydrogenation |
| CN101565434A (en) * | 2008-04-25 | 2009-10-28 | 南开大学 | Spiro phosphine-oxazoline and preparation method and application thereof |
| CN111848673A (en) * | 2019-04-24 | 2020-10-30 | 浙江瑞博制药有限公司 | Cyclohexyl fused ring spiroindane diphosphine ligand |
-
2019
- 2019-07-12 CN CN201910631270.5A patent/CN112209967A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1884290A (en) * | 2006-07-11 | 2006-12-27 | 南开大学 | Phosphorus-oxazoline ligand with spiro backbone and its uses in asymmetrical catalytic hydrogenation |
| CN101565434A (en) * | 2008-04-25 | 2009-10-28 | 南开大学 | Spiro phosphine-oxazoline and preparation method and application thereof |
| CN111848673A (en) * | 2019-04-24 | 2020-10-30 | 浙江瑞博制药有限公司 | Cyclohexyl fused ring spiroindane diphosphine ligand |
Non-Patent Citations (1)
| Title |
|---|
| ZHIYAO ZHENG等: ""ChiralCyclohexyl-FusedSpirobiindanes:PracticalSynthesis, LigandDevelopment, andAsymmetricCatalysis"", 《J.AM.CHEM.SOC.》, vol. 140, pages 10374 - 10381 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4691037A (en) | Ruthenium-phosphine complex | |
| JP4488739B2 (en) | P-chiral phosphoranes and phosphocyclic compounds and their use in asymmetric catalysis | |
| JP4837857B2 (en) | Chiral ligands, their transition metal complexes and their use in asymmetric reactions | |
| US5012002A (en) | 2,2'-bis(di-(m-tolyl)phosphino)-1,1'-binaphthyl | |
| JPH04139140A (en) | 2,2'-bis(diphenylphosphino)-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthyl and transition metallic complex containing the same as ligand | |
| US4239914A (en) | Process for preparing 2-(6'-methoxy-2'-naphthyl)-propionic acid | |
| AU2007292167B2 (en) | Process for production of optically active aminophosphinylbutanoic acid | |
| EP1899358A2 (en) | Novel p-chiral functionalised arylphosphines and derivatives, the preparation and use thereof for asymmetrical catalysis | |
| CN112209967A (en) | Chiral spiro monophosphine-oxazoline ligand and preparation method thereof | |
| US5648548A (en) | Optically active asymmetric diphosphine and process for producing optically active substance in its presence | |
| CN107445999B (en) | Metal complex, preparation method and application and intermediate thereof | |
| CN1775789A (en) | Method for synthesizing di-ferrocene phosphine diimine structure connected with aliphatic series and benzene ring | |
| JP2001261689A (en) | Method for producing optically active ruthenium phosphine complex, and method for producing optically active alcohol by using the complex | |
| EP2621893A1 (en) | Process for the preparation of amino acid derivatives | |
| JPH02183A (en) | Optically active phosphine compound | |
| US5886182A (en) | Chiral pyridylphosphines and their application in asymmetric catalytic hydrogenation of 2-arylpropenoic acids | |
| Šebesta et al. | Influence of structural changes in ferrocene phosphane aminophosphane ligands on their catalytic activity | |
| CN109627161B (en) | Method for synthesizing alpha-hydroxy-beta-dicarbonyl compound by using water as solvent | |
| CN111909206A (en) | Chiral spiro monophosphine ligand and preparation method thereof | |
| US5919981A (en) | Chiral aminophosphines | |
| CN112675920A (en) | Mono-chiral center catalyst, preparation thereof and method for catalytically synthesizing chiral alcohol compound and chiral alpha-allyl alcohol | |
| US4906773A (en) | Process for preparing optically active threonine | |
| Kanai et al. | Asymmetric cyclopropanation of chiral fumarates with gem-dihalides catalyzed by Co (0) or Ni (0) complexes and zinc | |
| Stankevič et al. | An efficient resolution of phosphinous acid-boranes | |
| CN113816855B (en) | Method for synthesizing chiral allyl carboxylic ester |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20221010 Address after: Jiaojiang District of Taizhou City, Zhejiang province 318000 road outside No. 99 Applicant after: ZHEJIANG JIUZHOU PHARMACEUTICAL Co.,Ltd. Address before: 310018 Building 9, Hangzhou east medical port town, Xiasha street, economic and Technological Development Zone, Jianggan District, Hangzhou City, Zhejiang Province Applicant before: Ruibo (Hangzhou) Pharmaceutical Technology Co.,Ltd. |
|
| TA01 | Transfer of patent application right |