WO2004024738A1 - Verfahren zur metallorganischen herstellung organischer zwischenprodukte über aryllithium-basen - Google Patents
Verfahren zur metallorganischen herstellung organischer zwischenprodukte über aryllithium-basen Download PDFInfo
- Publication number
- WO2004024738A1 WO2004024738A1 PCT/EP2003/009252 EP0309252W WO2004024738A1 WO 2004024738 A1 WO2004024738 A1 WO 2004024738A1 EP 0309252 W EP0309252 W EP 0309252W WO 2004024738 A1 WO2004024738 A1 WO 2004024738A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- lithium
- substituted
- aromatic
- compounds
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 24
- 125000003118 aryl group Chemical group 0.000 title claims abstract description 19
- 238000004519 manufacturing process Methods 0.000 title abstract description 5
- 239000013067 intermediate product Substances 0.000 title description 2
- 229910052744 lithium Inorganic materials 0.000 claims abstract description 31
- 150000001875 compounds Chemical class 0.000 claims abstract description 27
- 239000012039 electrophile Substances 0.000 claims abstract description 21
- -1 aryl lithium compound Chemical class 0.000 claims abstract description 18
- 239000000758 substrate Substances 0.000 claims abstract description 12
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 10
- 230000005595 deprotonation Effects 0.000 claims abstract description 8
- 238000010537 deprotonation reaction Methods 0.000 claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims description 24
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 19
- 239000000460 chlorine Chemical group 0.000 claims description 15
- 229910052801 chlorine Inorganic materials 0.000 claims description 15
- 229910052731 fluorine Inorganic materials 0.000 claims description 14
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 12
- 239000011737 fluorine Substances 0.000 claims description 11
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 239000011541 reaction mixture Substances 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 7
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 6
- 125000001931 aliphatic group Chemical group 0.000 claims description 5
- 239000004305 biphenyl Chemical group 0.000 claims description 5
- 235000010290 biphenyl Nutrition 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 150000001299 aldehydes Chemical class 0.000 claims description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 150000001502 aryl halides Chemical class 0.000 claims description 4
- 125000004122 cyclic group Chemical group 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 150000002240 furans Chemical class 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 229930192474 thiophene Natural products 0.000 claims description 4
- 150000003577 thiophenes Chemical class 0.000 claims description 4
- JECYNCQXXKQDJN-UHFFFAOYSA-N 2-(2-methylhexan-2-yloxymethyl)oxirane Chemical group CCCCC(C)(C)OCC1CO1 JECYNCQXXKQDJN-UHFFFAOYSA-N 0.000 claims description 3
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical class [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 3
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 3
- 229910052796 boron Chemical class 0.000 claims description 3
- 239000001569 carbon dioxide Substances 0.000 claims description 3
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000000543 intermediate Substances 0.000 claims description 3
- 150000002561 ketenes Chemical class 0.000 claims description 3
- 229910052710 silicon Inorganic materials 0.000 claims description 3
- 239000010703 silicon Substances 0.000 claims description 3
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims description 2
- 241000251730 Chondrichthyes Species 0.000 claims description 2
- 150000001422 N-substituted pyrroles Chemical class 0.000 claims description 2
- 125000002015 acyclic group Chemical group 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 239000002168 alkylating agent Chemical class 0.000 claims description 2
- 229940100198 alkylating agent Drugs 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 125000001769 aryl amino group Chemical group 0.000 claims description 2
- 125000005228 aryl sulfonate group Chemical group 0.000 claims description 2
- 150000001555 benzenes Chemical class 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 2
- 150000001735 carboxylic acids Chemical class 0.000 claims description 2
- 150000001907 coumarones Chemical class 0.000 claims description 2
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 2
- 125000004986 diarylamino group Chemical group 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 150000002475 indoles Chemical class 0.000 claims description 2
- 150000002642 lithium compounds Chemical class 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 150000002790 naphthalenes Chemical class 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 150000003216 pyrazines Chemical class 0.000 claims description 2
- 150000004892 pyridazines Chemical class 0.000 claims description 2
- 150000003222 pyridines Chemical class 0.000 claims description 2
- 150000003230 pyrimidines Chemical class 0.000 claims description 2
- 150000003233 pyrroles Chemical class 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 150000001491 aromatic compounds Chemical class 0.000 abstract description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 24
- 239000000203 mixture Substances 0.000 description 15
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 239000000047 product Substances 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 8
- 239000000725 suspension Substances 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical class ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 6
- NPDACUSDTOMAMK-UHFFFAOYSA-N 4-Chlorotoluene Chemical compound CC1=CC=C(Cl)C=C1 NPDACUSDTOMAMK-UHFFFAOYSA-N 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 150000002170 ethers Chemical class 0.000 description 5
- 229930195733 hydrocarbon Natural products 0.000 description 5
- 150000002430 hydrocarbons Chemical class 0.000 description 5
- 229910052751 metal Inorganic materials 0.000 description 5
- 239000002184 metal Substances 0.000 description 5
- DPZNOMCNRMUKPS-UHFFFAOYSA-N 1,3-Dimethoxybenzene Chemical compound COC1=CC=CC(OC)=C1 DPZNOMCNRMUKPS-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 4
- OHWGZCNPFKBCDJ-UHFFFAOYSA-N 2-chloro-6-(trifluoromethyl)benzoic acid Chemical compound OC(=O)C1=C(Cl)C=CC=C1C(F)(F)F OHWGZCNPFKBCDJ-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 0 CC(C(N)=*(*)*(*=C)=*(**)NC)=C Chemical compound CC(C(N)=*(*)*(*=C)=*(**)NC)=C 0.000 description 3
- 235000013844 butane Nutrition 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 3
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical class CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 150000002900 organolithium compounds Chemical class 0.000 description 3
- 125000002524 organometallic group Chemical group 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 3
- BKWVXPCYDRURMK-UHFFFAOYSA-N (2,6-dimethoxyphenyl)boronic acid Chemical compound COC1=CC=CC(OC)=C1B(O)O BKWVXPCYDRURMK-UHFFFAOYSA-N 0.000 description 2
- JUWYQISLQJRRNT-UHFFFAOYSA-N (5-formylfuran-2-yl)boronic acid Chemical compound OB(O)C1=CC=C(C=O)O1 JUWYQISLQJRRNT-UHFFFAOYSA-N 0.000 description 2
- UEMGWPRHOOEKTA-UHFFFAOYSA-N 1,3-difluorobenzene Chemical compound FC1=CC=CC(F)=C1 UEMGWPRHOOEKTA-UHFFFAOYSA-N 0.000 description 2
- VGIIILXIQLXVLC-UHFFFAOYSA-N 1-(2,6-difluorophenyl)ethanone Chemical compound CC(=O)C1=C(F)C=CC=C1F VGIIILXIQLXVLC-UHFFFAOYSA-N 0.000 description 2
- YTCGOUNVIAWCMG-UHFFFAOYSA-N 1-chloro-3-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC(Cl)=C1 YTCGOUNVIAWCMG-UHFFFAOYSA-N 0.000 description 2
- ISAHRYXMBYDJEV-UHFFFAOYSA-N 2-chloro-6-(trifluoromethyl)benzaldehyde Chemical compound FC(F)(F)C1=CC=CC(Cl)=C1C=O ISAHRYXMBYDJEV-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- SEILDMUKBMYIEZ-UHFFFAOYSA-N Furfural diethyl acetal Chemical compound CCOC(OCC)C1=CC=CO1 SEILDMUKBMYIEZ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000003905 agrochemical Substances 0.000 description 2
- 150000001350 alkyl halides Chemical class 0.000 description 2
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- PZJSZBJLOWMDRG-UHFFFAOYSA-N furan-2-ylboronic acid Chemical compound OB(O)C1=CC=CO1 PZJSZBJLOWMDRG-UHFFFAOYSA-N 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 2
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 2
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- VXNZUUAINFGPBY-UHFFFAOYSA-N 1-Butene Chemical compound CCC=C VXNZUUAINFGPBY-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- CDKCEZNPAYWORX-UHFFFAOYSA-N 1-tert-butyl-4-(4-tert-butylphenyl)benzene Chemical group C1=CC(C(C)(C)C)=CC=C1C1=CC=C(C(C)(C)C)C=C1 CDKCEZNPAYWORX-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- HBBGRARXTFLTSG-UHFFFAOYSA-N Lithium ion Chemical compound [Li+] HBBGRARXTFLTSG-UHFFFAOYSA-N 0.000 description 1
- LFGWEGCCZHIJLM-UHFFFAOYSA-N [Li]C1=C(F)C=CC=C1F Chemical compound [Li]C1=C(F)C=CC=C1F LFGWEGCCZHIJLM-UHFFFAOYSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 150000001500 aryl chlorides Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 150000008359 benzonitriles Chemical class 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 150000001639 boron compounds Chemical class 0.000 description 1
- 125000005620 boronic acid group Chemical class 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- IAQRGUVFOMOMEM-UHFFFAOYSA-N butene Natural products CC=CC IAQRGUVFOMOMEM-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002485 combustion reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 150000002222 fluorine compounds Chemical class 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002497 iodine compounds Chemical class 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical class [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- 229910001416 lithium ion Inorganic materials 0.000 description 1
- CETVQRFGPOGIQJ-UHFFFAOYSA-N lithium;hexane Chemical compound [Li+].CCCCC[CH2-] CETVQRFGPOGIQJ-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 150000001282 organosilanes Chemical class 0.000 description 1
- 125000001190 organyl group Chemical group 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 150000002924 oxiranes Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- FDNAPBUWERUEDA-UHFFFAOYSA-N silicon tetrachloride Chemical class Cl[Si](Cl)(Cl)Cl FDNAPBUWERUEDA-UHFFFAOYSA-N 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 235000013547 stew Nutrition 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 238000005406 washing Methods 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
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Definitions
- the invention relates to a process for the preparation of substituted aromatic compounds by producing lithium arylene and their reaction with suitable electrophiles, an aryllithium compound (“auxiliary base”) being generated first (step 1) by reacting a halogen aromatic with lithium metal, which is then (step 2) to deprotonate the aromatic substrate to form the corresponding lithium aromatic, which is then reacted (step 3) with an appropriate electrophile to form the desired substituted aromatic compound (equation I).
- auxiliary base aryllithium compound
- Step 1 creating the base
- Step 2 deprotonation of the substrate
- Step 3 reaction of the aryllithium compound with an electrophile
- organometallic chemistry especially that of the element lithium
- the upswing in organometallic chemistry, especially that of the element lithium, in the production of compounds for the pharmaceutical and agrochemical industry and for numerous other applications has been almost exponential in recent years if the number of applications or the amount of correspondingly manufactured products is compared plots a timeline.
- the main reasons for this are the increasingly complex structures of the fine chemicals required for the pharmaceuticals sector and agro on the one hand, and the almost unlimited synthetic potential of lithium organyls for building complex organic structures on the other.
- organolithium compound can be easily generated via the modern arsenal of organometallic chemistry and implemented with almost any electrophile to the desired product.
- Most of the lithium organyls are generated in one of the following ways:
- Li organyls can be prepared by reacting bromoaromatics with lithium metal, provided that the molecule does not contain any interfering groups that react with Li metal
- n-, s- and tert-butyllithium Due to the extreme sensitivity and pyrophoric nature of such lithium aliphates in concentrated solutions, very complex logistic systems for transport, feeding into the dosing template and dosing have to be set up in the order of magnitude desired in large industrial production (annual production quantities between 5 and 500 tons). Furthermore, the reactions of n-, s- and tert-butyllithium produce either butanes (deprotonation), butyl halides (halogen-metal exchange, 1 equivalent of BuLi) or butene and butane (halogen-metal exchange), which are gaseous at room temperature and escape the reaction mixtures during the required hydrolytic work-ups. As a result, complex exhaust gas purification or corresponding combustion devices are also required to meet the strict legal immission regulations. As a way out, the specialized companies offer alternatives such as n-hexyllithium, which do not produce butanes, but are significantly more expensive than butyllithium.
- the present invention solves these problems and relates to a process for the preparation of aryllithium compounds of the formulas (V) and (VI) and their reaction with suitable electrophiles to give compounds of the formulas (VII) and (VIII), first ("two-stage variant") or if appropriate, a lithium compound (II) is generated in the presence of the electrophilic compound (substrate) (“in situ variant”) by reacting aryl halides of the formula (I) with lithium metal, this compound for deprotonating the aromatic substrate (III) or (IV ) is used, and finally the target compound of the formula (VII) or (VIII) is reacted by adding the electrophilic component (equation I),
- Step 1 creating the base
- Step 2 deprotonation of the substrate
- Step 3 reaction of the aryllithium compound with an electrophile
- XjRj 1-4
- W two neighboring and one each formal double bond connected W can together stand for O (furans), S (thiophenes), NH or NRj (pyrroles),
- Z has, either in the case of benzoid aromatics, the meaning of a group which activates the ortho position, such as CF 3 , OCF 3 , Cl, F, Oalkyl, OAryl, SAkkyl, SAryl, CH 2 OH, CH 2 OR, CH (OR) 2 , CONR 2) NHR, NR 2 or in the case of heterocycles the same meaning as R ⁇ -,
- R 1-4 are substituents from the group hydrogen, methyl, primary, secondary or tertiary, cyclic or acyclic alkyl radicals having 2 to 12 carbon atoms, substituted cyclic or acyclic alkyl groups, alkoxy, dialkylamino, alkylamino, arylamino, diarylamino, Phenyl, substituted phenyl, alkylthio, diarylphosphino, dialkylphosphino, dialkyl- or diarylaminocarbonyl, monoalkyl- or monoarylaminocarbonyl, C0 2 alkyl, CO 2 " , 1-hydroxyalkyl, 1-alkoxyalkyl, fluorine or chlorine, CN or heteroaryl, each with two adjacent radicals R ⁇ - together can correspond to a fused aromatic or aliphatic ring,
- electrophilic components that can be reacted with aryllithium compounds.
- Preferred compounds of the formula (III) or (IV) which can be reacted by the process according to the invention are e.g. Benzenes, furans, thiophenes, pyridines, pyridazines, pyrimidines, pyrazines, N-substituted pyrroles, benzofurans, indoles or naphthalenes, to name but a few.
- the lithium organyls prepared in this way can be reacted with any electrophilic compounds by methods of the prior art.
- C, C linkages can be carried out by reaction with carbon electrophiles
- boronic acids can be produced by reaction with boron compounds
- an efficient route to organosilanes is opened up by reaction with halogen or alkoxysilanes.
- All available fluorine, chlorine, bromine or iodine aromatics can be used as halogen aromatics, since lithium metal in ethereal solvents reacts easily with all halogen aromatics and in almost all cases with quantitative yields.
- Aromatic chlorine or bromine aromatics are preferably used here, since iodine compounds are often expensive, fluorine compounds lead to the formation of LiF, which can lead to material problems in later aqueous work-ups as HF. In special cases, however, such halides can also be used advantageously.
- aryl chlorides such as chlorobenzene, but especially the isomeric chlorotoluenes. It is even possible to use the technical mixtures of isomers, which in many cases are even cheaper.
- reaction is carried out in a suitable organic solvent, preference is given to ethereal solvents, for example tetrahydrofuran (THF), dioxane, diethyl ether, di-n-butyl ether, glymes or diisopropyl ether, and THF is preferably used.
- ethereal solvents for example tetrahydrofuran (THF), dioxane, diethyl ether, di-n-butyl ether, glymes or diisopropyl ether, and THF is preferably used.
- the preferred reaction temperatures are in the range from -100 to + 35 ° C, temperatures from -70 to + 25 ° C are particularly preferred.
- organolithium compounds at very high concentrations. This results primarily from the fact that when using, for example, butyllithium in commercial concentrations, five to six times the volume of solvent is also introduced. Concentrations of the aliphatic or aromatic intermediates of the formula (II) or (IV) of 5 to 30% by weight, in particular 12 to 25% by weight, are preferred. Furthermore, higher selectivities are also frequently observed, which is due to the fact that it is possible to work in pure ethers instead of ether / hydrocarbon mixtures.
- halogen aromatic and aromatic substrate are added simultaneously or as a mixture to lithium metal in the ether.
- the lithium aromatic forms first, which then immediately deprotonates the actual substrate.
- a second preferred embodiment which is used especially when the aromatic can undergo side reactions with metallic lithium, it is possible first to generate the aryllithium compound in an ether by reaction of the halogen aromatic and lithium and only then to meter in the aromatic substrate, before finally the target molecule is generated by reaction with an electrophile.
- the lithium can be used as a dispersion, powder, chips, sand, granules, pieces, bars or in some other form, the size of the lithium particles not being quality-relevant but merely influencing the reaction times. Smaller particle sizes are therefore preferred, for example granules, powders or dispersions.
- the amount of lithium added is 1.95 to 2.5 mol, preferably 1.98 to 2.15 mol, per mole of halogen to be reacted.
- Aromatics which can be used for deprotonation are all compounds which are sufficiently acidic to be able to be deprotonated under the conditions according to the invention.
- aromatics which have strong “ortho-directing substituents” Z are to be mentioned here, that is to say in particular aromatics which carry alkoxy, CF 3 , F, Cl, substituted amino, CN, heteroaryl, aminoalkyl, hydroxyalkyl or similar radicals
- the mode of action of such radicals is based on the fact that these substituents enable the coordination of the lithium ion of the aliphatic base, as a result of which the counter ion Ar "can then very easily deprotonate in the ortho position.
- the lithium aromatics generated according to the invention can be reacted with electrophilic compounds by the methods familiar to the person skilled in the art, carbon, boron and silicon electrophiles in particular being of interest to the pharmaceutical and agrochemical industry with regard to the intermediate products required.
- the carbon electrophiles come in particular from one of the following
- Aryl or alkyl cyanates (benzonitriles) nitroenolates (oximes)
- Aromatic nitriles (ArCOCH 3 for acetonitrile, ArR 1 CO for R 1 CN) Aromatic nitriles (ArCOAr ' )
- Alkylating agents such as Alkyl halides or alkyl sulfonates (Ar-alkyl).
- Trialkoxyboranes BF 3 * OR 2 , BF 3 * THF, BCI 3 or BBr 3 , particularly preferably trialkoxyboranes.
- SiW 4 Compounds of the formula SiW 4 are used as silicon electrophiles, in which W represents the same or different (C 1 -C 6 alkoxy), fluorine, chlorine, bromine, iodine, N (C 1 -C 6 alkyl) 2 or S (-C-C 5 alkyl) is used, preferred are tetraalkoxysilanes, tetrachlorosilanes or substituted alkyl or aryl halosilanes or substituted alkyl or aryl alkoxysilanes.
- the workups are generally aqueous, with either water or aqueous mineral acids being metered in or the reaction mixture being metered into water or aqueous mineral acids.
- the pH of the product to be isolated is set here, ie usually a slightly acidic, in the case of heterocycles also slightly alkaline pH.
- the reaction products are, for example, by extraction and
- the organic solvents can also be distilled off from the hydrolysis mixture and the product which then precipitates can be obtained by filtration.
- the purities of the products from the processes according to the invention are generally high, but a further purification step, for example by recrystallization with the addition of small amounts of activated carbon, may be required for special applications (pharmaceutical precursors).
- the yields of the reaction products are between 70 and 99%, typical yields are in particular 85 to 95%.
- the method according to the invention opens up a very economical method to accomplish the transformation of aromatic hydrogen into any residues in a very economical way.
- 18.3 g of trimethyl borate (0.176 mol) are added dropwise in 30 minutes at the same temperature.
- the reaction mixture is added to 120 g of water, the pH is adjusted to 6.3 with 37% HCl and THF and toluene at max. 35 ° C distilled off in vacuo. The pH is then adjusted to 1.5, and the mixture is stirred until the product has completely precipitated and filtered off. After washing with a little cold water and a little cold acetone, 18.2 g of 5-formyl-2-furanboronic acid (0.130 mol, 81.5%) are obtained after drying in the form of a beige, fine powder, HPLC purity> 99.8% a / a.
- the reaction mixture is added to 120 g of water, the pH is adjusted to 6.3 with 37% HCl and the THF and toluene are distilled off at 35 ° C. in vacuo.
- 25 ml of methylcyclohexane are added to the product suspension, the colorless product is filtered off with suction and washed once with 25 ml cold methylcyclohexane and once with 25 ml of cold water.
- 27.5 g of 2,6-dimethoxyphenylboronic acid (0.151 mol, 94%, melting point 107 ° C.) are obtained in the form of colorless crystals, HPLC purity> 99% a / a.
- the reaction mixture is then poured into 100 g of water, the pH is adjusted to 3.4 with 37% HCl and the solvents at max. 55 ° C distilled off in vacuo.
- the colorless product is filtered off with suction and, after drying, 2-trifluoromethyl-6-chlorobenzoic acid (yield 69%) is obtained in the form of colorless crystals, HPLC purity> 99% a / a.
- 2-trifluoromethyl-6-chlorobenzoic acid By extraction of the mother liquor with dichloromethane, drying with sodium sulfate and evaporation, a further 2-trifluoromethyl-6-chlorobenzoic acid can be obtained, overall yield 89%.
- a solution of phenyllithium in THF is first produced by reacting 65.2 g of chlorobenzene with 7.0 g of lithium granules in 400 g of THF at -25 ° C. After a conversion of> 98% (GC a / a) is cooled to -65 ° C and then 1,3-difluorobenzene (55 g) is added in 30 min. After stirring for 30 minutes, the solution of 2,6-difluoro-1-lithiobenzene obtained is dropped into a solution of 88 g of acetic anhydride in 250 g of THF, cooled to -5 ° C. After the usual aqueous work-up, 2,6-difluoroacetophenone is obtained in a yield of 88%.
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EP03794907A EP1537126A1 (de) | 2002-08-31 | 2003-08-21 | Verfahren zur metallorganischen herstellung organischer zwischenprodukte ber aryllithium-basen |
US10/526,237 US20060131762A1 (en) | 2002-08-31 | 2003-08-21 | Method for metal-organic production of organic intermediate products by means of aryl lithium-bases |
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DE10240262.0 | 2002-08-31 | ||
DE10240262A DE10240262A1 (de) | 2002-08-31 | 2002-08-31 | Verfahren zur metallorganischen Herstellung organischer Zwischenprodukte über Aryllithium-Basen |
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US7858644B2 (en) | 2003-01-29 | 2010-12-28 | Asterand Uk Limited | EP4 receptor antagonists |
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US20050282814A1 (en) * | 2002-10-03 | 2005-12-22 | Targegen, Inc. | Vasculostatic agents and methods of use thereof |
NZ551027A (en) | 2004-04-08 | 2011-01-28 | Targegen Inc | Benzotriazine inhibitors of kinases |
MX2007002208A (es) | 2004-08-25 | 2007-05-08 | Targegen Inc | Compuestos hetrociclicos y metodos de uso. |
US20060247250A1 (en) * | 2005-03-16 | 2006-11-02 | Targegen, Inc. | Pyrimidine inhibitors of kinases |
NZ563984A (en) * | 2005-06-08 | 2011-11-25 | Targegen Inc | Methods and compositions for the treatment of ocular disorders |
US20070067217A1 (en) * | 2005-09-20 | 2007-03-22 | Joshua Schachter | System and method for selecting advertising |
HUE028987T2 (en) * | 2005-11-01 | 2017-01-30 | Targegen Inc | BI-aryl-meta-pyrimidine inhibitors of kinases |
US8133900B2 (en) * | 2005-11-01 | 2012-03-13 | Targegen, Inc. | Use of bi-aryl meta-pyrimidine inhibitors of kinases |
US8604042B2 (en) * | 2005-11-01 | 2013-12-10 | Targegen, Inc. | Bi-aryl meta-pyrimidine inhibitors of kinases |
WO2007056075A2 (en) * | 2005-11-02 | 2007-05-18 | Targegen, Inc. | Six membered heteroaromatic inhibitors targeting resistant kinase mutations |
WO2009089310A1 (en) * | 2008-01-11 | 2009-07-16 | Dow Agrosciences Llc | Process for the selective deprotonation and functionalization of 1-fluoro-2-substituted-3-chlorobenzenes |
US8190473B2 (en) * | 2009-03-10 | 2012-05-29 | Google Inc. | Category similarities |
DK2451796T3 (da) | 2009-07-08 | 2013-07-29 | Dermira Canada Inc | Tofaanaloger til behandling af dermatologiske lidelser eller tilstande |
CA2816957A1 (en) | 2010-11-07 | 2012-05-10 | Targegen, Inc. | Compositions and methods for treating myelofibrosis |
TW201323392A (zh) * | 2011-12-05 | 2013-06-16 | Du Pont | 用於製備2,6-二氟苯乙酮之方法 |
CZ2012712A3 (cs) | 2012-10-17 | 2014-04-30 | Zentiva, K.S. | Nový způsob výroby klíčového intermediátu výroby lapatinibu |
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WO2000064905A2 (fr) * | 1999-04-23 | 2000-11-02 | Rhodia Chimie | Procede d'alpha-metallation d'un derive heterocyclique, monocyclique ou polycyclique et possedant au moins un heterocycle a 5 atomes, insature ou aromatique |
WO2003033503A2 (de) * | 2001-10-12 | 2003-04-24 | Clariant Gmbh | Verfahren zur metallierung von aromaten durch lithiumorganische verbindungen |
-
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- 2002-08-31 DE DE10240262A patent/DE10240262A1/de not_active Withdrawn
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- 2003-08-21 EP EP03794907A patent/EP1537126A1/de not_active Withdrawn
- 2003-08-21 WO PCT/EP2003/009252 patent/WO2004024738A1/de not_active Application Discontinuation
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WO2000064905A2 (fr) * | 1999-04-23 | 2000-11-02 | Rhodia Chimie | Procede d'alpha-metallation d'un derive heterocyclique, monocyclique ou polycyclique et possedant au moins un heterocycle a 5 atomes, insature ou aromatique |
WO2003033503A2 (de) * | 2001-10-12 | 2003-04-24 | Clariant Gmbh | Verfahren zur metallierung von aromaten durch lithiumorganische verbindungen |
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US7858644B2 (en) | 2003-01-29 | 2010-12-28 | Asterand Uk Limited | EP4 receptor antagonists |
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