JP4639042B2 - ハロゲン−リチウム交換反応を用いる有機化合物の製造法 - Google Patents
ハロゲン−リチウム交換反応を用いる有機化合物の製造法 Download PDFInfo
- Publication number
- JP4639042B2 JP4639042B2 JP2003337787A JP2003337787A JP4639042B2 JP 4639042 B2 JP4639042 B2 JP 4639042B2 JP 2003337787 A JP2003337787 A JP 2003337787A JP 2003337787 A JP2003337787 A JP 2003337787A JP 4639042 B2 JP4639042 B2 JP 4639042B2
- Authority
- JP
- Japan
- Prior art keywords
- lithium
- reaction
- halogen
- compound
- ring
- 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.)
- Expired - Lifetime
Links
- 238000006243 chemical reaction Methods 0.000 title claims description 81
- 229910052744 lithium Inorganic materials 0.000 title claims description 30
- 238000004519 manufacturing process Methods 0.000 title claims description 28
- 150000002894 organic compounds Chemical class 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims description 32
- 239000003153 chemical reaction reagent Substances 0.000 claims description 22
- 150000002642 lithium compounds Chemical class 0.000 claims description 16
- 125000001979 organolithium group Chemical group 0.000 claims description 16
- 150000002366 halogen compounds Chemical class 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 229920006395 saturated elastomer Polymers 0.000 claims description 8
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 7
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- -1 electrophotography Substances 0.000 description 55
- 239000000243 solution Substances 0.000 description 27
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- 238000002156 mixing Methods 0.000 description 22
- 239000007788 liquid Substances 0.000 description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 17
- 238000000034 method Methods 0.000 description 17
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 16
- 239000000047 product Substances 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- PLDWAJLZAAHOGG-UHFFFAOYSA-N 1-bromo-3-methoxybenzene Chemical compound COC1=CC=CC(Br)=C1 PLDWAJLZAAHOGG-UHFFFAOYSA-N 0.000 description 8
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 230000009257 reactivity Effects 0.000 description 8
- 230000003068 static effect Effects 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 7
- 229910052751 metal Inorganic materials 0.000 description 7
- 239000002184 metal Substances 0.000 description 7
- 125000002950 monocyclic group Chemical group 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- 239000000758 substrate Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 6
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical class [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- 239000003905 agrochemical Substances 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000000975 dye Substances 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 4
- 239000004973 liquid crystal related substance Substances 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 125000003367 polycyclic group Chemical group 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 238000004445 quantitative analysis Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- PBKONEOXTCPAFI-UHFFFAOYSA-N 1,2,4-trichlorobenzene Chemical compound ClC1=CC=C(Cl)C(Cl)=C1 PBKONEOXTCPAFI-UHFFFAOYSA-N 0.000 description 3
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 3
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Natural products CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 3
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 238000010923 batch production Methods 0.000 description 3
- 229910052802 copper Inorganic materials 0.000 description 3
- 239000010949 copper Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 150000002900 organolithium compounds Chemical class 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 229930192474 thiophene Natural products 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 2
- KVNYFPKFSJIPBJ-UHFFFAOYSA-N 1,2-diethylbenzene Chemical compound CCC1=CC=CC=C1CC KVNYFPKFSJIPBJ-UHFFFAOYSA-N 0.000 description 2
- FLBAYUMRQUHISI-UHFFFAOYSA-N 1,8-naphthyridine Chemical compound N1=CC=CC2=CC=CN=C21 FLBAYUMRQUHISI-UHFFFAOYSA-N 0.000 description 2
- RMHQDKYZXJVCME-UHFFFAOYSA-N 2-pyridin-4-ylpyridine Chemical class N1=CC=CC=C1C1=CC=NC=C1 RMHQDKYZXJVCME-UHFFFAOYSA-N 0.000 description 2
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 description 2
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N Butyraldehyde Chemical compound CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- ATOMTHYGEJDUAK-UHFFFAOYSA-N [Li]COC Chemical compound [Li]COC ATOMTHYGEJDUAK-UHFFFAOYSA-N 0.000 description 2
- UAASQOAINZDWHR-UHFFFAOYSA-N [Mg].C(CCC)[Li] Chemical compound [Mg].C(CCC)[Li] UAASQOAINZDWHR-UHFFFAOYSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 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
- 125000004429 atom Chemical group 0.000 description 2
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 2
- XXRGLCKZBCIEKO-DLMDZQPMSA-N azocine Chemical compound C/1=C/C=C\N=C/C=C\1 XXRGLCKZBCIEKO-DLMDZQPMSA-N 0.000 description 2
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- QZHPTGXQGDFGEN-UHFFFAOYSA-N chromene Chemical compound C1=CC=C2C=C[CH]OC2=C1 QZHPTGXQGDFGEN-UHFFFAOYSA-N 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 239000000498 cooling water Substances 0.000 description 2
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- DMEGYFMYUHOHGS-UHFFFAOYSA-N cycloheptane Chemical compound C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 2
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 2
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- WQOXQRCZOLPYPM-UHFFFAOYSA-N dimethyl disulfide Chemical compound CSSC WQOXQRCZOLPYPM-UHFFFAOYSA-N 0.000 description 2
- SQNZJJAZBFDUTD-UHFFFAOYSA-N durene Chemical compound CC1=CC(C)=C(C)C=C1C SQNZJJAZBFDUTD-UHFFFAOYSA-N 0.000 description 2
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- BLHLJVCOVBYQQS-UHFFFAOYSA-N ethyllithium Chemical compound [Li]CC BLHLJVCOVBYQQS-UHFFFAOYSA-N 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-M hexanoate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 2
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 150000002497 iodine compounds Chemical class 0.000 description 2
- SNHOZPMHMQQMNI-UHFFFAOYSA-N lithium;2h-thiophen-2-ide Chemical compound [Li+].C=1C=[C-]SC=1 SNHOZPMHMQQMNI-UHFFFAOYSA-N 0.000 description 2
- CETVQRFGPOGIQJ-UHFFFAOYSA-N lithium;hexane Chemical compound [Li+].CCCCC[CH2-] CETVQRFGPOGIQJ-UHFFFAOYSA-N 0.000 description 2
- YNXURHRFIMQACJ-UHFFFAOYSA-N lithium;methanidylbenzene Chemical compound [Li+].[CH2-]C1=CC=CC=C1 YNXURHRFIMQACJ-UHFFFAOYSA-N 0.000 description 2
- VCPPTNDHEILJHD-UHFFFAOYSA-N lithium;prop-1-ene Chemical compound [Li+].[CH2-]C=C VCPPTNDHEILJHD-UHFFFAOYSA-N 0.000 description 2
- XBEREOHJDYAKDA-UHFFFAOYSA-N lithium;propane Chemical compound [Li+].CC[CH2-] XBEREOHJDYAKDA-UHFFFAOYSA-N 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- YLYBTZIQSIBWLI-UHFFFAOYSA-N octyl acetate Chemical compound CCCCCCCCOC(C)=O YLYBTZIQSIBWLI-UHFFFAOYSA-N 0.000 description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 2
- YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical compound C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 2
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 2
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
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- MPQXHAGKBWFSNV-UHFFFAOYSA-N oxidophosphanium Chemical class [PH3]=O MPQXHAGKBWFSNV-UHFFFAOYSA-N 0.000 description 1
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- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 125000002958 pentadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
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- 125000005981 pentynyl group Chemical group 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000006678 phenoxycarbonyl group Chemical group 0.000 description 1
- FCJSHPDYVMKCHI-UHFFFAOYSA-N phenyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OC1=CC=CC=C1 FCJSHPDYVMKCHI-UHFFFAOYSA-N 0.000 description 1
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-M phenylacetate Chemical compound [O-]C(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-M 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 150000003003 phosphines Chemical class 0.000 description 1
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
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- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- PSAYJRPASWETSH-UHFFFAOYSA-N pyridine-2-carbonyl chloride Chemical compound ClC(=O)C1=CC=CC=N1 PSAYJRPASWETSH-UHFFFAOYSA-N 0.000 description 1
- QJZUKDFHGGYHMC-UHFFFAOYSA-N pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CN=C1 QJZUKDFHGGYHMC-UHFFFAOYSA-N 0.000 description 1
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- 230000002829 reductive effect Effects 0.000 description 1
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- 239000003727 serotonin 1A antagonist Substances 0.000 description 1
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- 229940014800 succinic anhydride Drugs 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960005333 tetrabenazine Drugs 0.000 description 1
- 125000005063 tetradecenyl group Chemical group C(=CCCCCCCCCCCCC)* 0.000 description 1
- 150000003606 tin compounds Chemical class 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 125000005040 tridecenyl group Chemical group C(=CCCCCCCCCCCC)* 0.000 description 1
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005065 undecenyl group Chemical group C(=CCCCCCCCCC)* 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- HGBOYTHUEUWSSQ-UHFFFAOYSA-N valeric aldehyde Natural products CCCCC=O HGBOYTHUEUWSSQ-UHFFFAOYSA-N 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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Landscapes
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Description
これらの中で、グリニヤール試薬は一般に反応性が低く、反応の基質としてアリールクロリドまたはアリールブロミドを用いる反応では反応可能な基質が限定され、また反応を完結させるためには過剰量の使用や、長い反応時間を必要とするなどの問題がある(非特許文献3参照)。また、反応の基質としてアリールヨージドに対しては反応性が高いが、原料へのヨード基の導入は高価であり、工業的には好ましくない。
しかしながら、上記のハロゲン−金属交換反応で得られる化合物は、医薬品、農薬、液晶、電子写真や染料等の分野で合成中間体として有用性が高い。一例を挙げると、2−ブロモピリジンを原料として合成される2−リチオピリジンは、ファルマコアとして有用である2,4−ビピリジン誘導体の合成中間体である。この2,4−ビピリジン誘導体は、例えばtetrabenazine antagonist(非特許文献6参照)、α1A receptor antagonist(特許文献2参照)、5−HT1A receptor antagonist(特許文献3参照)、α1A receptor antagonist(特許文献4参照)等の合成中間体に用いられている。
尚、本発明は特許請求の範囲に記載の構成を有するものであるが、以下、その他についても参考のため記載した。
本発明の製造プロセスを簡潔に説明すると、ハロゲン化合物と有機リチウム試薬を、少なくとも1個の連続式反応器で混合し、前記一般式(I)で表されるリチウム化合物を得る。次いで、このリチウム化合物と求電子化合物とを反応させて目的物を得る。
以下に有機リチウム試薬としてn−ブチルリチウムを、求電子化合物にクロロトリメチルシランを用いた本発明の一例を挙げるが、本発明はこれに限定されるものではない。
定常マイクロ反応器とは、小型流動反応器、または静的マイクロミキサー(スタティックマイクロミキサー)を使用して定常状態で反応を実施するための反応装置である。静的マイクロミキサーとは、例えばWO96/30113号に記載されているような、混合のための微細な流路を有しているミキサーに代表される装置である。市販されている定常マイクロ反応器としては、例えばインスティチュート・フュール・マイクロテクニック・マインツ(IMM)社製シングルミキサーおよびキャタピラーミキサー;ミクログラス社製ミクログラスリアクター;CPCシステムス社製サイトス;山武社製YM−1型ミキサー;島津GLC社製ミキシングティーおよびティー;マイクロ化学技研社製IMTチップリアクター、等が挙げられ、いずれも本発明で使用することができる。
インラインミキサーは、ラインミキサーやパイプラインミキサーとも呼ばれており、連続した流れの中で複数の液体を攪拌混合する装置であり、複数の液体の混合比率を正確に制御することができるという特長を有し、スタティックミキサーやプロペラ式ミキサー、タービン式ミキサー、ローター/ステーター式ミキサー、コロイドミル、高圧ホモジナイザーのようなものが含まれる。市販されているインラインミキサーとしては、例えば、東レ製Hi−Mixer;ケニックス社製スタティックミキサー;特殊機化工業製パイプラインホモミキサー;西華産業製OHRラインミキサー等が挙げられ、いずれも本発明で使用することができる。
本発明において、好ましくは定常マイクロ反応器である。定常マイクロ反応器を用いることにより、原料溶液の迅速な混合や流れの制御、および反応熱の部分蓄熱の防止や反応温度の精密な制御が可能となる。合成反応を定常状態で安定して実施できるため、安定化した合成プロセスが実現される。
連続式反応器に送液される際の流速は、反応する基質、連続式反応器の種類、および連続式反応器の流路断面積によって最適値は異なるが、例えば定常マイクロ反応器の場合は、好ましくは0.1μl/分〜1000ml/分、より好ましくは1μl/分〜100ml/分、特に好ましくは10μl/分〜10ml/分である。
尚、本発明の変換法は公知のハロゲン−金属交換反応の改良方法であることから、本発明の該工程に用いられる製造条件は、有機リチウム試薬などのハロゲン−金属交換反応および求電子試薬との反応に使用されている反応生成物の精製法を含め、反応温度以外の製造条件を全て採用することができる。
本発明で用いるハロゲン化合物は、塩素化合物、臭素化合物、ヨウ素化合物等が挙げられるが、その中でも臭素化合物、ヨウ素化合物が反応性が高く好ましい。
n−ブチルリチウムを用いた3−ブロモアニソールのハロゲン−リチウム交換反応をインスティチュート・フュール・マイクロテクニック・マインツ(IMM)社製シングルミキサー(流路断面積12,000μm2、ニッケル オン カッパー インレイ)を用いた定常マイクロ反応器内で行った。このシングルミキサーは分割された流路から得られる多数の副流を接触させることにより混合を行う方式のものであり、定常マイクロ反応器の出口には外径Φ1.58mm、内径Φ0.8mmのSUS316製キャピラリーをHPLCコネクターを用いて接続し、キャピラリーの出口は一方にドレン流路の付いた三方バルブを介し、クロロトリメチルシランのテトラヒドロフラン溶液を入れてあるアルゴンガス置換済みの100ml二口フラスコに導いた。また定常反応器とSUSキャピラリー、二口フラスコの温度は恒温冷却水槽の冷媒中で0℃に温度設定した。
Measured MS(180.0987)、Calcurated MS(180.0970)。
1H−NMR(400MHz,CDCl3,δppm):0.29(9H,s),3.84(3H,s),6.91(1H,dd,J=2.8,7.2Hz),7.07(1H,d,J=2.8Hz),7.10(1H,d,J=7.2Hz),7.31(1H,t,J=7.6Hz)
定常マイクロ反応器に、T字型に流体を衝突させる方式のT字型ミキサー(SUS316製、流路内径0.8mm、流路断面積0.5mm2)を用いて、実施例1と同様の条件で合成を行った。結果を表1に示す。
アルゴンガスで置換した100ml二口フラスコにn−ブチルリチウム7mlとテトラヒドロフラン35mlを仕込み、ドライアイスーアセトン浴に浸して−78℃に冷却した。、攪拌下、3−ブロモアニソール1.72gを滴下して−78℃で30分間攪拌した。次に、この中にクロロトリメチルシラン1.5gとテトラヒドロフラン9mlの混合溶液を滴下して−78℃で20分間攪拌した後、徐々に室温まで30分間かけて昇温した。得られた反応液を定量分析した結果、目的物の収率は90%だった。
アルゴンガスで置換した100ml二口フラスコに3−ブロモアニソール1.72gとテトラヒドロフラン35mlを仕込み、ドライアイスーアセトン浴に浸して−78℃に冷却した。この中に攪拌下、n−ブチルリチウム7mlを滴下して−78℃で30分間攪拌した。次に、この中にクロロトリメチルシラン1.5gとテトラヒドロフラン9mlの混合溶液を滴下して−78℃で20分間攪拌した後、徐々に室温まで30分間かけて昇温した。得られた反応液を定量分析した結果、目的物の収率は88%だった。
反応温度を0℃とした他は、それぞれ比較例1及び2と同様の条件で実施した。
アルゴンガスで置換した100ml二口フラスコを恒温冷却水槽の冷媒中で0℃に温度設定した。実施例1と同様に、3−ブロモアニソール溶液とn−ブチルリチウム溶液はガラスシリンジに吸い上げた後、それぞれHARVARD APPARATUS INC.社製PHD2000型計量ポンプ、Kd Scientific社製Model100型計量ポンプを用い、100ml二口フラスコの中に、攪拌下同時に7分間送液した。この時の3−ブロモアニソール溶液とn−ブチルリチウム溶液の送液速度は、それぞれ5.0ml/minと1.0ml/minに設定した。次に、この反応液に、クロロトリメチルシラン1.5gとテトラヒドロフラン9mlの混合溶液を滴下して0℃で20分間攪拌した後、徐々に室温まで30分間かけて昇温した。得られた反応液を定量分析した結果、目的物の収率は80%だった。
反応温度を20℃とした他は、それぞれ比較例5と同様の条件で実施した。
これらの結果を表1に示す。
定常マイクロ反応器に、実施例2で用いたT字型ミキサー(SUS316製、流路内径0.8mm、流路断面積0.5mm2)を用い、表2に記載したハロゲン化合物および求電子化合物に変えた以外は実施例1と同様の条件で合成を行った。その結果を表2に示す。
すなわち、バッチプロセスでは−78℃もの超低温冷却が必要な反応が、本発明の製造方法である、マイクロ流路を用いた定常反応器を反応に使用してフロー系で実施する方法を使用することで、超低温冷却を必要とせず、0℃という温和な冷却条件で有機リチウム試薬を用いたハロゲン−リチウム交換反応を実施できる。本製造方法はベンゼン誘導体のみならず、ナフタレン誘導体や、ピリジン誘導体の様な複素環化合物にも適用可能であり、有用性が高い。
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MX2014003064A (es) * | 2011-09-14 | 2014-05-07 | Dow Agrosciences Llc | Metodos y sistemas para formar acidos boronicos y sus intermedios. |
JP2015120642A (ja) * | 2013-12-20 | 2015-07-02 | 株式会社堀場エステック | 連続反応装置及びこれを用いる連続合成方法 |
KR102159608B1 (ko) * | 2016-12-22 | 2020-09-25 | 주식회사 엘지화학 | 변성 개시제 제조방법 및 제조장치 |
JP2021008436A (ja) * | 2019-07-01 | 2021-01-28 | Jnc株式会社 | リチウム化合物の製造方法 |
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JPH03101643A (ja) * | 1989-08-16 | 1991-04-26 | Sandoz Ag | ハロゲノアルキルフェニルアルコール、ケトンおよびそれらの水和物 |
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JP2002292274A (ja) * | 2001-04-02 | 2002-10-08 | Mitsubishi Chemicals Corp | 流通型微小反応流路,反応装置及び反応方法 |
JP2003523960A (ja) * | 2000-01-14 | 2003-08-12 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング | カルボニル化合物と有機金属試薬の反応 |
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JPS62142187A (ja) * | 1983-09-06 | 1987-06-25 | ザ・ダウ・ケミカル・カンパニ− | 2,3−ジクロロ−5−リチオピリジン及びその製造方法 |
JPH03101643A (ja) * | 1989-08-16 | 1991-04-26 | Sandoz Ag | ハロゲノアルキルフェニルアルコール、ケトンおよびそれらの水和物 |
JP2000229981A (ja) * | 1998-12-19 | 2000-08-22 | Merck Patent Gmbh | アリールメタル化合物の製造方法および親電子試薬とのそれらの反応のための方法 |
JP2003523960A (ja) * | 2000-01-14 | 2003-08-12 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング | カルボニル化合物と有機金属試薬の反応 |
JP2002292274A (ja) * | 2001-04-02 | 2002-10-08 | Mitsubishi Chemicals Corp | 流通型微小反応流路,反応装置及び反応方法 |
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