WO2018139470A1 - Method for synthesizing sodium 2,2,6,6-tetramethylpiperidide compound - Google Patents
Method for synthesizing sodium 2,2,6,6-tetramethylpiperidide compound Download PDFInfo
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- WO2018139470A1 WO2018139470A1 PCT/JP2018/002054 JP2018002054W WO2018139470A1 WO 2018139470 A1 WO2018139470 A1 WO 2018139470A1 JP 2018002054 W JP2018002054 W JP 2018002054W WO 2018139470 A1 WO2018139470 A1 WO 2018139470A1
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- WO
- WIPO (PCT)
- Prior art keywords
- reaction
- tmp
- tmps
- sodium
- yield
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 54
- 239000011734 sodium Substances 0.000 title claims abstract description 44
- 229910052708 sodium Inorganic materials 0.000 title claims abstract description 42
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 title claims abstract description 40
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 36
- 150000001875 compounds Chemical class 0.000 title abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 120
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-Tetramethylpiperidine Substances CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 claims abstract description 50
- 239000006185 dispersion Substances 0.000 claims abstract description 29
- 125000003118 aryl group Chemical group 0.000 claims abstract description 21
- 239000002904 solvent Substances 0.000 claims description 53
- 239000007810 chemical reaction solvent Substances 0.000 claims description 37
- 150000003388 sodium compounds Chemical class 0.000 claims description 34
- 150000001412 amines Chemical class 0.000 claims description 17
- -1 Li-TMP Chemical class 0.000 abstract description 10
- 150000002642 lithium compounds Chemical class 0.000 abstract description 6
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 abstract description 5
- 229910052744 lithium Inorganic materials 0.000 abstract description 5
- 239000002612 dispersion medium Substances 0.000 abstract 2
- 239000012429 reaction media Substances 0.000 abstract 1
- 238000002474 experimental method Methods 0.000 description 87
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 84
- 101710112672 Probable tape measure protein Proteins 0.000 description 60
- 101710204224 Tape measure protein Proteins 0.000 description 60
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 41
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 description 34
- 239000000047 product Substances 0.000 description 34
- 238000003786 synthesis reaction Methods 0.000 description 24
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- CRSBERNSMYQZNG-UHFFFAOYSA-N 1-dodecene Chemical compound CCCCCCCCCCC=C CRSBERNSMYQZNG-UHFFFAOYSA-N 0.000 description 20
- 239000012039 electrophile Substances 0.000 description 18
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 16
- 239000002585 base Substances 0.000 description 16
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 14
- TXCDCPKCNAJMEE-UHFFFAOYSA-N dibenzofuran Chemical compound C1=CC=C2C3=CC=CC=C3OC2=C1 TXCDCPKCNAJMEE-UHFFFAOYSA-N 0.000 description 14
- 238000002955 isolation Methods 0.000 description 14
- 238000004519 manufacturing process Methods 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- 125000001424 substituent group Chemical group 0.000 description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 11
- ADOQBZAVKYCFOI-HWKANZROSA-N (E)-2-dodecene Chemical compound CCCCCCCCC\C=C\C ADOQBZAVKYCFOI-HWKANZROSA-N 0.000 description 10
- 229940069096 dodecene Drugs 0.000 description 10
- 150000002391 heterocyclic compounds Chemical class 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000000654 additive Substances 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 9
- RMBPEFMHABBEKP-UHFFFAOYSA-N fluorene Chemical compound C1=CC=C2C3=C[CH]C=CC3=CC2=C1 RMBPEFMHABBEKP-UHFFFAOYSA-N 0.000 description 9
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N o-biphenylenemethane Natural products C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 description 9
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 8
- 238000010791 quenching Methods 0.000 description 8
- 230000000171 quenching effect Effects 0.000 description 8
- 230000035484 reaction time Effects 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- 230000005595 deprotonation Effects 0.000 description 7
- 238000010537 deprotonation reaction Methods 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 6
- JWUXJYZVKZKLTJ-UHFFFAOYSA-N Triacetonamine Chemical compound CC1(C)CC(=O)CC(C)(C)N1 JWUXJYZVKZKLTJ-UHFFFAOYSA-N 0.000 description 6
- 230000000996 additive effect Effects 0.000 description 6
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 150000001336 alkenes Chemical class 0.000 description 5
- 239000003849 aromatic solvent Substances 0.000 description 5
- 150000002220 fluorenes Chemical class 0.000 description 5
- 150000002390 heteroarenes Chemical class 0.000 description 5
- 239000012188 paraffin wax Substances 0.000 description 5
- UKODFQOELJFMII-UHFFFAOYSA-N pentamethyldiethylenetriamine Chemical compound CN(C)CCN(C)CCN(C)C UKODFQOELJFMII-UHFFFAOYSA-N 0.000 description 5
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 239000003905 agrochemical Substances 0.000 description 4
- 150000001450 anions Chemical class 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000010419 fine particle Substances 0.000 description 4
- 238000007306 functionalization reaction Methods 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 4
- KSMWLICLECSXMI-UHFFFAOYSA-N sodium;benzene Chemical compound [Na+].C1=CC=[C-]C=C1 KSMWLICLECSXMI-UHFFFAOYSA-N 0.000 description 4
- 238000001308 synthesis method Methods 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000007239 Wittig reaction Methods 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 150000001340 alkali metals Chemical class 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 125000000746 allylic group Chemical group 0.000 description 3
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 150000001721 carbon Chemical class 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 239000012454 non-polar solvent Substances 0.000 description 3
- 150000002894 organic compounds Chemical class 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 238000007086 side reaction Methods 0.000 description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- BLZKSRBAQDZAIX-UHFFFAOYSA-N 2-methyl-1-benzothiophene Chemical compound C1=CC=C2SC(C)=CC2=C1 BLZKSRBAQDZAIX-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- KAKZBPTYRLMSJV-UHFFFAOYSA-N Butadiene Chemical compound C=CC=C KAKZBPTYRLMSJV-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-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
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 238000006621 Wurtz reaction Methods 0.000 description 2
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 238000004458 analytical method Methods 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
- 230000008901 benefit Effects 0.000 description 2
- 150000001555 benzenes Chemical class 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- XGRJZXREYAXTGV-UHFFFAOYSA-N chlorodiphenylphosphine Chemical compound C=1C=CC=CC=1P(Cl)C1=CC=CC=C1 XGRJZXREYAXTGV-UHFFFAOYSA-N 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- VHHHONWQHHHLTI-UHFFFAOYSA-N hexachloroethane Chemical compound ClC(Cl)(Cl)C(Cl)(Cl)Cl VHHHONWQHHHLTI-UHFFFAOYSA-N 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 238000006317 isomerization reaction Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- DIHKMUNUGQVFES-UHFFFAOYSA-N n,n,n',n'-tetraethylethane-1,2-diamine Chemical compound CCN(CC)CCN(CC)CC DIHKMUNUGQVFES-UHFFFAOYSA-N 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 125000002524 organometallic group Chemical group 0.000 description 2
- 239000002245 particle Substances 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
- 150000004714 phosphonium salts Chemical class 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 2
- 238000004448 titration Methods 0.000 description 2
- 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 2
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- NNQDMQVWOWCVEM-NSCUHMNNSA-N (e)-1-bromoprop-1-ene Chemical compound C\C=C\Br NNQDMQVWOWCVEM-NSCUHMNNSA-N 0.000 description 1
- RVHSTXJKKZWWDQ-UHFFFAOYSA-N 1,1,1,2-tetrabromoethane Chemical compound BrCC(Br)(Br)Br RVHSTXJKKZWWDQ-UHFFFAOYSA-N 0.000 description 1
- QXSZNDIIPUOQMB-UHFFFAOYSA-N 1,1,2,2-tetrabromoethane Chemical compound BrC(Br)C(Br)Br QXSZNDIIPUOQMB-UHFFFAOYSA-N 0.000 description 1
- VZKDHLDVXMUSSK-UHFFFAOYSA-N 1-benzofuran-2-yl(trimethyl)silane Chemical compound C1=CC=C2OC([Si](C)(C)C)=CC2=C1 VZKDHLDVXMUSSK-UHFFFAOYSA-N 0.000 description 1
- LKRQKUMXSONWBZ-UHFFFAOYSA-N 1-benzothiophen-2-yl(diphenyl)phosphane Chemical compound S1C2=CC=CC=C2C=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 LKRQKUMXSONWBZ-UHFFFAOYSA-N 0.000 description 1
- KXWSLCVIAOCIQA-UHFFFAOYSA-N 1-benzothiophen-2-yl(phenyl)methanone Chemical compound C=1C2=CC=CC=C2SC=1C(=O)C1=CC=CC=C1 KXWSLCVIAOCIQA-UHFFFAOYSA-N 0.000 description 1
- UHJJFKCQUDIIRB-UHFFFAOYSA-N 1-benzothiophen-2-yl(trimethyl)silane Chemical compound C1=CC=C2SC([Si](C)(C)C)=CC2=C1 UHJJFKCQUDIIRB-UHFFFAOYSA-N 0.000 description 1
- DYSJMQABFPKAQM-UHFFFAOYSA-N 1-benzothiophene-2-carboxylic acid Chemical compound C1=CC=C2SC(C(=O)O)=CC2=C1 DYSJMQABFPKAQM-UHFFFAOYSA-N 0.000 description 1
- WUYYVOWEBMOELQ-UHFFFAOYSA-N 1-bromodibenzofuran Chemical compound O1C2=CC=CC=C2C2=C1C=CC=C2Br WUYYVOWEBMOELQ-UHFFFAOYSA-N 0.000 description 1
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 description 1
- PJWLGAIBGBYTFM-UHFFFAOYSA-N 1-prop-2-enyldibenzofuran Chemical compound O1C2=CC=CC=C2C2=C1C=CC=C2CC=C PJWLGAIBGBYTFM-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
- PWOKJVJRVIFKLP-UHFFFAOYSA-N 2,2,3,6-tetramethylpiperidine Chemical compound CC1CCC(C)C(C)(C)N1 PWOKJVJRVIFKLP-UHFFFAOYSA-N 0.000 description 1
- GWQOOADXMVQEFT-UHFFFAOYSA-N 2,5-dimethyl thiophene Natural products CC1=CC=C(C)S1 GWQOOADXMVQEFT-UHFFFAOYSA-N 0.000 description 1
- WIFMYMXKTAVDSQ-UHFFFAOYSA-N 2-bromo-1-benzothiophene Chemical compound C1=CC=C2SC(Br)=CC2=C1 WIFMYMXKTAVDSQ-UHFFFAOYSA-N 0.000 description 1
- CPYLFALFYKCLRI-UHFFFAOYSA-N 2-chloro-1-benzothiophene Chemical compound C1=CC=C2SC(Cl)=CC2=C1 CPYLFALFYKCLRI-UHFFFAOYSA-N 0.000 description 1
- ZVEJRZRAUYJYCO-UHFFFAOYSA-N 9-methyl-9h-fluorene Chemical compound C1=CC=C2C(C)C3=CC=CC=C3C2=C1 ZVEJRZRAUYJYCO-UHFFFAOYSA-N 0.000 description 1
- IRDQNLLVRXMERV-UHFFFAOYSA-N CCCC[Na] Chemical compound CCCC[Na] IRDQNLLVRXMERV-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical group [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- RPNUMPOLZDHAAY-UHFFFAOYSA-N Diethylenetriamine Chemical compound NCCNCCN RPNUMPOLZDHAAY-UHFFFAOYSA-N 0.000 description 1
- 239000002879 Lewis base Substances 0.000 description 1
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 1
- 239000005662 Paraffin oil Substances 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 238000005644 Wolff-Kishner reduction reaction Methods 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 125000005577 anthracene group Chemical group 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- YNCYPMUJDDXIRH-UHFFFAOYSA-N benzo[b]thiophene-2-boronic acid Chemical compound C1=CC=C2SC(B(O)O)=CC2=C1 YNCYPMUJDDXIRH-UHFFFAOYSA-N 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 125000005382 boronyl group Chemical group 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- PMOWTIHVNWZYFI-WAYWQWQTSA-N cis-2-coumaric acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1O PMOWTIHVNWZYFI-WAYWQWQTSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- FQBIYZMGWHXDMX-UHFFFAOYSA-N dibenzofuran-1-yl(phenyl)methanone Chemical compound C(C1=CC=CC=C1)(=O)C1=CC=CC=2OC3=C(C21)C=CC=C3 FQBIYZMGWHXDMX-UHFFFAOYSA-N 0.000 description 1
- XRZAWLIBMQMNHU-UHFFFAOYSA-N dibenzofuran-4-yl(trimethyl)silane Chemical compound O1C2=CC=CC=C2C2=C1C([Si](C)(C)C)=CC=C2 XRZAWLIBMQMNHU-UHFFFAOYSA-N 0.000 description 1
- 150000004826 dibenzofurans Chemical class 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000020169 heat generation Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 238000010191 image analysis Methods 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 150000008040 ionic compounds Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000007527 lewis bases Chemical class 0.000 description 1
- ANYSGBYRTLOUPO-UHFFFAOYSA-N lithium tetramethylpiperidide Chemical compound [Li]N1C(C)(C)CCCC1(C)C ANYSGBYRTLOUPO-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- MJGFBOZCAJSGQW-UHFFFAOYSA-N mercury sodium Chemical compound [Na].[Hg] MJGFBOZCAJSGQW-UHFFFAOYSA-N 0.000 description 1
- 238000005649 metathesis reaction Methods 0.000 description 1
- 238000001000 micrograph Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- DMQSHEKGGUOYJS-UHFFFAOYSA-N n,n,n',n'-tetramethylpropane-1,3-diamine Chemical compound CN(C)CCCN(C)C DMQSHEKGGUOYJS-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 150000004045 organic chlorine compounds Chemical class 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- MTZWHHIREPJPTG-UHFFFAOYSA-N phorone Chemical compound CC(C)=CC(=O)C=C(C)C MTZWHHIREPJPTG-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 125000005575 polycyclic aromatic hydrocarbon group Chemical group 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- JQSBVBURTZTVJQ-UHFFFAOYSA-N pyridine;pyrrolidine Chemical compound C1CCNC1.C1=CC=NC=C1 JQSBVBURTZTVJQ-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 229910001023 sodium amalgam Inorganic materials 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Images
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
-
- 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
- C07F7/0814—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring said ring is substituted at a C ring atom by Si
-
- 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
- C07F9/6553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms
- C07F9/655345—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a five-membered ring
- C07F9/655354—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a five-membered ring condensed with carbocyclic rings or carbocyclic ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
Definitions
- the present invention relates to a method for synthesizing sodium 2,2,6,6-tetramethylpiperidide.
- the metal amide compound is an organic base having a metal-nitrogen bond in the molecule, and is widely used in organic synthetic chemistry of agricultural chemicals and pharmaceuticals. Of these, those obtained by substituting hydrogen atoms of secondary amines with metal atoms such as alkali metals are preferably used.
- metal atoms such as alkali metals
- Li-TMP lithium 2,2,6,6-tetramethylpiperidide in which the ⁇ -position is tetrasubstituted carbon
- Na-TMP sodium 2,2,6,6-tetramethylpiperidide
- Na-TMP has been produced in 2,5,6,6-tetramethylpiperidine (44 mmol) (hereinafter sometimes abbreviated as “TMP”) and 0.95 in a pentane solvent (50 ml).
- TMP 2,5,6,6-tetramethylpiperidine
- n BuNa n-butyl sodium
- Non-Patent Document 1 Li-TMP (38 mmol) and 1 equivalent of sodium t-butoxide (38 mmol) (hereinafter sometimes abbreviated as “NaO t Bu”) in a hexane solvent (50 ml). It has also been reported that Na-TMP was obtained in a yield of 87% by reacting at room temperature (25 ° C).
- Non-Patent Document 1 using TMP and n BuNa is because n BuNa is prepared by a metathesis reaction between n -butyllithium (hereinafter “ n BuLi”) and NaO t Bu.
- n BuLi n -butyllithium
- the resulting n BuNa contains lithium and lithium compounds. Therefore, the resulting Na-TMP has a problem that lithium compounds such as lithium and Li-TMP are mixed as impurities.
- the synthetic process from including the step preparation of n Buna is multistage, the production cost from using an expensive reagent n BuLi etc. In the preparation of n Buna there is a problem such as increasing.
- n BuLi is designated as a Class 3 dangerous material by the Fire Service Act, so equipment that is suitable for handling is required.
- Non-Patent Document 1 using Li-TMP and NaO t Bu synthesizes Na-TMP in one step.
- Li-TMP needs to be obtained by reacting n BuLi and TMP, which is essentially a multistage reaction.
- n BuLi and TMP which is essentially a multistage reaction.
- Li-TMP since Li-TMP is used, it is difficult to obtain good-quality Na-TMP by mixing lithium or a lithium compound such as Li-TMP as impurities as in the above-described method. Therefore, there is a problem that a synthetic reaction system using Na-TMP alone as an organic base or the like cannot be constructed, such as undesirable side reactions due to the difference in reactivity between Na-TMP and Li-TMP.
- the present inventors obtained TMPs by a reaction with a dispersion in which sodium is dispersed in a dispersion solvent or a dispersion in which sodium is dispersed in a dispersion solvent. It was found that Na-TMPs can be synthesized stably and efficiently by reacting with an organic sodium compound having an aromatic ring. This method of synthesizing Na-TMPs is economically advantageous without requiring expensive reagents and equipment, and is simple and quick in a short time with a small number of steps without requiring complicated chemical methods. Can be synthesized. In addition, since a lithium compound required in the conventional method is not used in the synthesis process, high-quality Na-TMPs can be obtained. Based on these findings, the present inventors have completed the present invention.
- the present invention relates to a method for synthesizing sodium 2,2,6,6-tetramethylpiperidide (Na-TMP), and its characteristic constitution is 2,2,6,6-tetramethylpiperidine.
- An organic sodium compound having an aromatic ring obtained by reacting (TMP) s with a dispersion (SD) in which sodium is dispersed in a dispersion solvent, or a dispersion (SD) in which sodium is dispersed in a dispersion solvent. It has the process of making it react in a reaction solvent and obtaining sodium 2,2,6,6-tetramethylpiperidide (Na-TMP).
- Na-TMPs can be stably and efficiently synthesized by adding SD or an organic sodium compound using TMPs as a starting material.
- SD used in the method for synthesizing Na-TMPs is uniformly dispersed throughout the reaction system, so that Na-TMP can be synthesized stably with a uniform temperature distribution.
- Na-TMPs can be easily and quickly used with a small number of steps without requiring complicated chemical methods under mild conditions. It can be manufactured and is very advantageous economically and industrially.
- TMPs are bulky and abundant in electrons, anions formed by extracting protons on nitrogen of TMPs are unstable. Therefore, in TMPs, it is difficult to produce sodium amide itself.
- by using SD such a synthetic reaction system can proceed stably, and sodium can be stably and efficiently produced.
- -TMPs can be synthesized.
- Another characteristic configuration is that the above process is performed in the presence of amines.
- the synthesis reaction system of Na-TMPs can be stabilized and the progress of the reaction can be promoted, and Na-TMPs can be synthesized more stably and efficiently.
- Stabilization of the synthesis reaction system increases the collision frequency between TMPs and SD or organic sodium compounds, and the reaction energy stabilizes the driving force of the synthesis reaction system for Na-TMPs, thus promoting the progress of the synthesis reaction. As a result, the yield is improved.
- TMPs are bulky and abundant in electrons, so that the anion formed by the extraction of protons on nitrogen of TMPs is unstable.
- Example 3 Examination conditions of Example 3 in which the stability of the product synthesized by the method for synthesizing Na-TMPs using the organic sodium compound having an aromatic ring obtained by the reaction with SD according to the present embodiment was examined It is a figure which summarizes examination results. It is a figure which summarizes the examination conditions and examination result of Example 4 which examined the time-dependent stability of SD used in the synthesis
- Example 6 Examination conditions and examination of Example 6 in which the reaction using the Na-TMP synthesized in the method for synthesizing Na-TMP according to the present embodiment (the isomerization reaction through deprotonation of allylic hydrogen) was examined It is a figure which summarizes a result. Examination conditions and results of Example 7 in which the reaction (deprotonation and functionalization reaction of heteroarene) using Na-TMP synthesized in the method for synthesizing Na-TMPs according to the present embodiment was examined It is a figure which summarizes. The figure which summarizes the examination conditions and examination result of Example 8 which examined the reaction (functionalization of a heterocyclic compound) using Na-TMP synthesized in the synthesis method of Na-TMPs concerning this embodiment It is.
- an aromatic ring obtained by reacting TMPs with a dispersion in which sodium is dispersed in a dispersion solvent or a dispersion in which sodium is dispersed in a dispersion solvent is used.
- Na-TMPs are sodium 2,2,6,6-tetramethylpiperidide (Na-TMP) which may or may not have a substituent.
- Na-TMP sodium 2,2,6,6-tetramethylpiperidide
- it may be introduced into some or all of the carbon atoms at the 3, 4, and 5 positions of the piperidine ring, and when it has a plurality of substituents, All may be the same or all may be different.
- substituent include alkyl groups such as a methyl group, an ethyl group, and a propyl group, but are not limited thereto.
- the TMPs that are starting materials in the method for synthesizing Na-TMPs according to the present embodiment are 2,2,6,6-tetramethylpiperidines that may or may not have a substituent. Depending on the desired Na-TMP, it is set as appropriate. Therefore, when it has a substituent, it may be introduced into some or all of the carbon atoms at the 3, 4, and 5 positions of the piperidine ring, depending on the desired Na-TMPs. Or a part thereof may be the same or different from each other.
- the substituent include alkyl groups such as a methyl group, an ethyl group, and a propyl group, but are not limited thereto.
- TMPs can be synthesized by methods known in the art, and can be obtained by, for example, 1,4-addition reaction of ammonia to 2,6-dimethyl-2,5-heptadien-4-one (holon).
- TMP can be obtained from 2,2,6,6-tetramethyl-4-piperidone (triacetoneamine) obtained by reduction with tin, zinc and sodium amalgam, or by catalytic hydrogenation.
- TMP can also be obtained by the Wolff-Kishner reduction of triacetoneamine, but is not limited thereto.
- commercially available products can be suitably used for TMPs.
- a dispersion in which sodium is dispersed in a dispersion solvent is a dispersion in which sodium is dispersed in an insoluble solvent as fine particles, or sodium is dispersed in an insoluble solvent in a liquid state.
- the average particle diameter of the fine particles is preferably less than 10 ⁇ m, and particularly preferably less than 5 ⁇ m.
- the average particle diameter was represented by the diameter of a sphere having a projected area equivalent to the projected area obtained by image analysis of micrographs.
- sodium can be dispersed as fine particles, or sodium can be dispersed in an insoluble solvent in a liquid state, and the reaction between TMPs and sodium contained in the dispersion in which sodium is dispersed in the dispersion solvent is not inhibited.
- solvents known in the art can be used. Examples thereof include aromatic solvents such as xylene and toluene, normal paraffin solvents such as decane, heterocyclic compound solvents such as tetrahydrothiophene, and mixed solvents thereof.
- SD is an abbreviation for Sodium Dispersion.
- a solvent known in the technical field can be used as long as the reaction between TMPs and SD is not inhibited.
- an ether solvent a normal paraffin solvent, a cycloparaffin solvent, an aromatic solvent, an amine solvent, or a heterocyclic compound solvent can be used.
- a cyclic ether solvent is preferable, and tetrahydrofuran is particularly preferable.
- the normal paraffin solvent and cycloparaffin solvent hexane, normal decane, cyclohexane and the like are particularly preferable.
- the aromatic solvent xylene, toluene, benzene and the like are preferable.
- the amine solvent ethylenediamine or the like is preferable.
- tetrahydrothiophene etc. can be preferably utilized as the heterocyclic compound solvent. These may be used alone or in combination of two or more as a mixed solvent.
- the dispersion solvent and the reaction solvent described above may be the same type or different types.
- an organic sodium compound having an aromatic ring obtained by reaction with SD can be used instead of SD.
- the organic sodium compound having an aromatic ring is a compound having one or several aromatic rings and one or several carbon atom-sodium bonds in the molecule, and preferably the carbon atom on the aromatic ring is sodium and It is a bonded compound.
- the aromatic ring may be any of a hydrocarbon aromatic ring composed only of hydrocarbons and a heteroaromatic ring containing atoms other than carbon atoms in the ring structure, preferably a hydrocarbon aromatic ring. Further, it may be a single ring or may have a plurality of rings such as an aggregate ring or a condensed polycycle.
- aromatic ring examples include, but are not limited to, a benzene ring, a naphthalene ring, an anthracene ring, a pyridine ring, and an imidazole ring.
- the aromatic ring may or may not have one or several substituents, and examples of the substituent include alkyl groups such as a methyl group, an ethyl group, and a propyl group. It is not limited to.
- organic sodium compound having an aromatic ring obtained by the reaction with SD examples include phenyl sodium and naphthyl sodium. It is not limited to these.
- the organic sodium compound is obtained by reacting SD and an organic compound having an aromatic ring, preferably in a reaction solvent.
- a reaction solvent a solvent known in the art can be used as long as the reaction between SD and the organic compound having an aromatic ring is not inhibited.
- an ether solvent, a normal paraffin solvent, a cycloparaffin solvent, an aromatic solvent, an amine solvent, or a heterocyclic compound solvent can be used, and details of these solvents have been described above.
- the organic sodium compound can be prepared by dropping an organic compound having an aromatic ring in a reaction solvent to which SD is added, and then Na-TMPs can be synthesized by adding TMPs.
- an electron acceptor is added to the reaction system as necessary when the TMPs are reacted with SD or an organic sodium compound.
- the electron acceptor any substance can be used as long as it can receive electrons from SD or an organic sodium compound.
- the electron acceptor include branched unsaturated hydrocarbons such as isoprene, linear unsaturated hydrocarbons such as 1,3-butadiene, aromatic hydrocarbons such as biphenyl, 4,4′-ditertbutylbiphenyl, styrene, and naphthalene. Examples thereof include, but are not limited to, polycyclic aromatic hydrocarbons such as phenanthrene and anthracene.
- the addition timing of the electron acceptor is not particularly limited as long as the electron acceptor can receive electrons from SD or an organic sodium compound.
- the electron acceptor may be reacted simultaneously with the reaction of TMPs with SD or an organic sodium compound, or the TMPs may be reacted after the electron acceptor is reacted with SD or an organic sodium compound. Can be made to react.
- Na-TMPs can be efficiently obtained without adding an electron acceptor.
- the reaction temperature is not particularly limited, and can be appropriately set according to the type and amount of TMPs, SD or organic sodium compound, and reaction solvent, reaction pressure, and the like. Specifically, the reaction temperature is preferably set to a temperature that does not exceed the boiling point of the reaction solvent. Since the boiling point under atmospheric pressure is higher than the boiling point, the reaction temperature can be set at a high temperature.
- the reaction can be carried out at room temperature when a normal paraffin or cycloparaffin solvent is used, preferably 10 to 100 ° C., particularly preferably 20 to 80 ° C., more preferably room temperature to 50 ° C. It is not necessary to provide a temperature control means for special heating or cooling, but a temperature control means may be provided if necessary.
- the Na-TMP generated in the synthesis reacts with the solvent at room temperature.
- the reaction time is not particularly limited, and may be appropriately set according to the starting material, SD or organic sodium compound, the type and amount of the reaction solvent, the reaction pressure, the reaction temperature, and the like.
- the reaction time is usually 30 minutes or more, preferably 30 minutes to 24 hours, particularly preferably 1 to 12 hours.
- THF or toluene is used as a reaction solvent, it must be used as soon as possible after preparation.
- the reaction is normally performed in the atmosphere. It can be performed under pressure conditions.
- each reagent has high reactivity and generates heat, it is preferable to perform in an inert gas atmosphere filled with argon gas or nitrogen gas.
- an organic sodium compound is unstable in air
- the yield decreases if SD that has been prepared for a long period of time is used or if air is mixed in, it is desirable that each reagent and solvent should remove as much water as possible.
- the amount of SD or organic sodium compound used can be appropriately set according to the type and amount of TMPs and reaction solvent.
- the reaction between TMPs and SD or an organic sodium compound is carried out in a 1.0 to 2.0 molar equivalent of a reaction solvent with respect to 1 mmol of the TMP substances in a TMPs and 2.1 to It is preferable to react 2.5 molar equivalents of SD with 0.8 to 1.0 molar equivalents of an organic chlorine compound or 1.0 to 1.2 molar equivalents of an organic sodium compound.
- the amount of substance of SD means the amount of substance in terms of alkali metal contained in SD.
- the Na-TMPs obtained by the method for synthesizing Na-TMPs according to the present embodiment may be purified by purification means known in the art such as column chromatography, distillation, recrystallization and the like. Further, the TMPs remaining unreacted may be recovered and used again for the method of synthesizing Na-TMPs.
- FIG. 1 shows an example of a reaction mechanism in the method for synthesizing Na-TMPs according to this embodiment, but the present invention is not limited to this.
- the reaction mechanism shown in FIG. 1 schematically shows a reaction of synthesizing Na-TMP by reacting TMP with SD in the presence of isoprene as an electron acceptor.
- the reaction of isoprene and SD releases electrons from metallic sodium in SD.
- the electrons from which the metallic sodium is released move to isoprene to form an isoprene radical anion / sodium salt.
- isoprene radical anion / sodium salt extracts Na-TMP by extracting a proton on the nitrogen atom of TMP and replacing it with sodium.
- the method for synthesizing Na-TMPs according to the present embodiment proceeds by adding SD or an organic sodium compound, and, if necessary, an electron acceptor using TMPs as a starting material.
- Na-TMPs can be synthesized efficiently.
- metallic sodium alone is added to the reaction system, the temperature distribution in the reaction system becomes uneven due to local heat generation, etc., and it is difficult to stabilize the reaction conditions, causing undesirable side reactions. Inconvenience such as doing may occur.
- SD used in the method for synthesizing Na-TMPs according to the present embodiment is uniformly dispersed throughout the reaction system, Na-TMP can be stably synthesized with a uniform temperature distribution.
- the method for synthesizing Na-TMPs according to the present embodiment uses SD that is easy to handle, it does not require a complicated chemical method under mild conditions, and it is simple and quick with a small number of steps. Na-TMPs can be produced, which is very advantageous economically and industrially.
- TMPs are bulky and rich in electrons, the anions formed by extracting protons on the nitrogen of TMPs are unstable. Therefore, although it is difficult to produce sodium amide per se in TMPs, the use of SD in the method for synthesizing Na-TMPs according to the present embodiment may cause the synthesis reaction system to proceed stably. It is possible to synthesize Na-TMPs stably and efficiently. Further, when using an organic sodium compound, an isoprene-derived by-product is produced without using expensive N, N, N ′, N′-tetramethylethylenediamine (hereinafter sometimes abbreviated as “TMEDA”). There is an advantage that it does not occur.
- TMEDA N, N, N ′, N′-tetramethylethylenediamine
- the obtained Na-TMPs can be used for synthesizing pharmaceuticals, veterinary drugs, agricultural chemicals, etc. as they are or by applying functional group modification.
- amines can be added as an additive to the reaction system of TMPs and SD or an organic sodium compound.
- any of aliphatic amine, aromatic amine, and heterocyclic amine can be used, and the amino group in the molecule may be any of primary, secondary, and tertiary.
- the amino group may be singular or several.
- examples of amines include N, N, N ′, N′-tetramethylethylenediamine, N, N, N ′, N ′′, N ′′ -pentamethyldiethylenetriamine, ethylamine, ethylenediamine, diethylamine, triethylamine, diethylenetriamine, Diisopropylethylamine, N, N, N ', N'-tetraethylethylenediamine (hereinafter sometimes abbreviated as "TEEDA”), N, N, N', N'-tetramethyl-1,3-propanediamine, pyridine Pyrrolidine, N-methylpiperidine, N-methylpyrrolidine and the like can be used, and TMEDA is particularly preferable.
- the addition timing of amines is not particularly limited, and may be simultaneous with the start of the reaction between TMPs and SD or an organic sodium compound, or before or after the start of the reaction.
- Na-TMPs By adding amines, the synthesis reaction system of Na-TMPs can be stabilized and the progress of the reaction can be promoted, and Na-TMPs can be synthesized more stably and efficiently.
- the product Na-TMPs are ionic compounds and are unstable in nonpolar solvents such as hexane which can be suitably used as a reaction solvent. Therefore, in non-polar solvents, Na-TMPs exist with most of Na + exposed.
- Lewis base which is a donor of lone pairs such as amines
- Na-TMPs form a complex with amines, and the solubility of Na-TMPs in nonpolar solvents increases.
- the production system of Na-TMPs is stabilized. By stabilizing the production system, the collision frequency between TMPs and SD or organic sodium compounds is improved, and the transition state is stabilized, which increases the driving force for the synthesis reaction of Na-TMPs and It is thought that the progress is promoted and the yield is improved.
- TMPs are bulky and abundant in electrons, the anions formed when protons on nitrogen of TMPs are extracted are unstable. Therefore, it is difficult to generate sodium amide itself in TMPs, but by using amines in addition to SD, such a synthetic reaction system can proceed stably, and more stably and efficiently Na. -TMPs can be synthesized.
- Na-TMPs synthesized by the method for synthesizing Na-TMPs of the present embodiment can be used as bases in various reactions, and can be used for organic synthesis of drugs, animal drugs, agricultural chemicals and the like. it can.
- Evaluation of the production of Na-TMPs synthesized by the method for synthesizing Na-TMPs of the above-described embodiment was performed by reacting the product with fluorene, quenching with heavy water, and using 1H-NMR for the quenched product. This can be done by measuring.
- Na-TMPs one of the two hydrogen atoms on the 9th carbon atom of fluorene is extracted and replaced with sodium from Na-TMP.
- fluorene is deuterated by quenching with heavy water.
- the yield of product Na-TMPs can be analyzed from the amount of deuterated fluorene.
- Na-TMPs have a dark brown color
- a colorimetric titration method using 9-methylfluorene or the like known as an indicator in titration of group IA and IIA organometallic reagents could not evaluate Na-TMPs with high accuracy.
- fluorene is deprotonated and quenched with heavy water, so that the production of Na-TMPs can be accurately evaluated.
- Example 1 In this example, the reaction conditions such as reaction solvent, additives, and reaction time were examined for the synthesis of Na-TMP using SD. (See FIG. 2).
- an equivalent means the molar equivalent with respect to TMP thrown into the reaction system.
- the yield is obtained by dividing the actually obtained amount of Na-TMP by the amount of added SD, and showing the percentage as a percentage.
- Example number 1 1.1 equivalents of TMP was dissolved in 1M cyclohexane (reaction solvent), 1 equivalent of SD and 1.1 equivalents of isoprene were added, and the mixture was reacted at 25 ° C. for 12 hours. After the reaction, 1.1 equivalents of fluorene was added to the product and reacted at 25 ° C. for 30 minutes, and then the product was evaluated by analyzing the deuterated fluorene obtained by quenching with heavy water by 1H-NMR. Was calculated. The yield of Na-TMP was 45%.
- Example number 2 The reaction was carried out in the same manner as in Experiment No. 1 except that 2M cyclohexane was used instead of 1M cyclohexane as the reaction solvent and the reaction was performed for 30 hours, and the yield was calculated. Specifically, TMP was dissolved in 2M cyclohexane (reaction solvent), 1 equivalent of SD and 1.1 equivalent of isoprene were added and reacted at 25 ° C. for 30 hours. The yield of Na-TMP was 77%.
- Example No. 3 The reaction was carried out in the same manner as in Experiment No. 1 except that hexane was used instead of cyclohexane as the reaction solvent, and the yield was calculated. Specifically, TMP was dissolved in 1M hexane (reaction solvent), 1 equivalent of SD and 1.1 equivalent of isoprene were added, and the mixture was reacted at 25 ° C. for 12 hours. The yield of Na-TMP was 62%.
- Example No. 4 Except that 1 equivalent of N, N, N ′, N′-tetramethylethylenediamine (hereinafter referred to as “TMEDA”) was added as an additive and reacted for 0.5 hour, the reaction was conducted in the same manner as in Experiment No. 3, Yield was calculated. Specifically, TMP was dissolved in 1M hexane (reaction solvent), 1 equivalent of SD, 1.1 equivalent of isoprene, and 1 equivalent of TMEDA were added and reacted at 25 ° C. for 0.5 hour. The yield of Na-TMP was 79%.
- Example No. 5 The reaction was conducted in the same manner as in Experiment No. 4 except that the reaction time was 1 hour, and the yield was calculated. Specifically, TMP was dissolved in 1M hexane (reaction solvent), 1 equivalent of SD, 1.1 equivalent of isoprene, and 1 equivalent of TMEDA were added and reacted at 25 ° C. for 1 hour. The yield of Na-TMP was 88%.
- Example No. 6 The reaction was conducted in the same manner as in Experiment No. 4 except that the reaction time was 12 hours, and the yield was calculated. Specifically, TMP was dissolved in 1M hexane (reaction solvent), 1 equivalent of SD, 1.1 equivalent of isoprene, and 1 equivalent of TMEDA were added and reacted at 25 ° C. for 12 hours. The yield of Na-TMP was 89%.
- Example 7 The reaction was performed in the same manner as in Experiment No. 3 except that 1 equivalent of N, N, N ′, N ′′, N ′′ -pentamethyldiethylenetriamine was added and allowed to react for 1 hour, and the yield was calculated. . Specifically, TMP is dissolved in 1M hexane (reaction solvent), 1 equivalent of SD, 1.1 equivalents of isoprene, and 1 equivalent of N, N, N ', N'',N''-pentamethyldiethylenetriamine And reacted at 25 ° C. for 1 hour. The yield of Na-TMP was 60%.
- Example 8 The reaction was carried out in the same manner as in Experiment No. 3 except that 1 equivalent of 1,2-dimethoxyethane (hereinafter referred to as “DME”) was added as an additive, and the yield was calculated. Specifically, TMP was dissolved in 1M hexane (reaction solvent), 1 equivalent of SD, 1.1 equivalent of isoprene, and 1 equivalent of DME were added and reacted at 25 ° C. for 12 hours. Only trace amounts of Na-TMP were obtained.
- DME 1,2-dimethoxyethane
- Figure 2 summarizes the reaction scheme, reaction conditions and yield.
- Na-TMP is synthesized under mild conditions. It was confirmed that it was possible.
- TMEDA which is an amine
- TMEDA which is an amine
- the acceleration effect of the synthesis reaction can be confirmed, and Na-TMP can be obtained in a high yield (about 90%) even in a short reaction time. It has been found that it can be synthesized.
- N, N, N ′, N ′′, N ′′ -pentamethyldiethylenetriamine was added, it was found that Na-TMP could be synthesized with a high yield in a short reaction of 1 hour.
- Example 2 Examination of synthesis conditions in the synthesis method of Na-TMP using organic sodium compounds with aromatic rings obtained by reaction with SD-1
- the reaction conditions such as reaction solvent, additives, and reaction time were examined (Fig. 3).
- the ratio (%) of actually obtained Na-TMP to Na-TMP that can theoretically be generated from halogenated benzene added to the reaction system was calculated.
- the production of the coupling product (Ph-Ph) was measured by 1H-NMR and the Ph-Ph production rate (%) was calculated.
- FIG. 3 summarizes the reaction scheme, reaction conditions, base type, and yield.
- bromobenzene when used as a starting compound, it can be understood that Na-TMP can be synthesized with a high yield of 99% or more by reacting SD with 2.2 molar equivalents or more.
- chlorobenzene when used as a starting compound, it can be understood that Na-TMP can be synthesized with a high yield of 99% or more by reacting SD with 2.1 molar equivalents or more.
- the SD was less than 2.0 molar equivalents, it was found that the wurtz reaction, which is a side reaction, was induced and the yield of Na-TMP decreased.
- Example 3 Examination of stability of Na-TMP
- the stability of Na-TMP synthesized using SD was examined (see FIG. 4).
- an equivalent is a molar equivalent.
- the yield is obtained by dividing the actually obtained amount of Na-TMP by the amount of added SD, and showing the percentage as a percentage.
- Figure 4 summarizes the reaction scheme, reaction conditions and yield. It was confirmed that the yield of Na-TMP synthesized using SD was almost constant even when the reaction time was long. As a result, it has been found that Na-TMP can remain stable and maintain activity in a hexane solvent.
- the yield of Na-TMP was 98% (0 hours), 91% (1 hour), 75% (3 hours), 63% (6 hours) in the experimental system (experiment numbers 1-7) stored at 0 ° C. ), 63% (12 hours), 44% (18 hours), 38% (24 hours), and 98% (0 hours), 89 in the experimental system (Experiment Nos. 8 to 14) stored at ⁇ 20 ° C. % (1 hour), 90% (3 hours), 84% (6 hours), 73% (12 hours), 56% (18 hours), 51% (24 hours). From the experimental results, it was found that Na-TMP was stably present at 0 ° C. for up to 1 hour and at ⁇ 20 ° C. for up to 3 hours in the presence of THF.
- Example 4 Examination of Stability of SD over Time
- the change in quality of SD over time was evaluated (see FIG. 6).
- an equivalent is a molar equivalent.
- the yield is obtained by dividing the actually obtained amount of Na-TMP by the amount of added SD, and showing the percentage as a percentage.
- Example number 1 1.1 equivalents of TMP was dissolved in 1M hexane (reaction solvent), 1 equivalent of SD, 1.1 equivalents of isoprene, and 1 equivalent of TMEDA were added and reacted at 25 ° C. for 0.5 hour. SD used 4 days after opening the packaging. After the reaction, 1.1 equivalents of fluorene was added to the product and reacted at 25 ° C for 1 hour, and then the product was evaluated by analyzing the deuterated fluorene obtained by quenching with heavy water by 1H-NMR. Was calculated. The yield of Na-TMP was 90%.
- Example numbers 2--7 TMPs were reacted with SD, isoprene, and TMEDA in hexane for 1 hour in the same manner as in Experiment No. 1, and the yield of Na-TMP was calculated.
- SD is 6 days (experiment number 2), 8 days (experiment number 3), 10 days (experiment number 4), 13 days (experiment number 5), 30 days (experiment number 6), 32 days (experiment number). 7) The past ones were used.
- the yields of Na-TMP are 89% (experiment number 2), 88% (experiment number 3), 87% (experiment number 4), 82% (experiment number 5), 77% (experiment number 6), 72%. (Experiment No. 7).
- FIG. 6 summarizes the reaction scheme, reaction conditions, elapsed time after opening the SD (age), and yield.
- the SD activity decreased with time, and the reproducibility decreased. However, no significant decrease was observed within the study period. In particular, within 10 days after opening, it was found that SD retains its activity and exhibits good reproducibility.
- Embodiment 5 FIG. Reaction with Na-TMP-1
- the Wittig reaction is a reaction in which a Wittig reagent (phosphorus ylide) and an aldehyde (or ketone) react to produce an alkene.
- the Wittig reagent treats the phosphonium salt produced by reacting triphenylphosphine with an alkyl halide with a base. Can be synthesized.
- the production rate of the cis-trans isomer of the produced alkene was evaluated by GC.
- the yields using Li-TMP, Li-TMP / NaO t Bu, and Na-TMP as a base were 89%, 96%, and 92%, respectively.
- the cis-trans selectivity (E / Z) was 18/82, 12/88, and 8/92, respectively.
- FIG. 7 summarizes the reaction scheme, reaction conditions, base type, yield, and cis-trans selectivity.
- Example 6 Reaction with Na-TMP-2
- an isomerization reaction through deprotonation of allylic hydrogen using Na-TMP was examined (see FIG. 8).
- the study was conducted using 1-dodecene having one double bond in the molecular chain.
- Example No. 4 The reaction was carried out in the same manner as in Experiment No. 1 except that the addition amount of Na-TMP was 10 mol%, the reaction temperature was 25 ° C. and the reaction was performed for 5 hours, and the yield and cis-trans selectivity were calculated.
- Example No. 5 The reaction was carried out in the same manner as in Experiment No. 1 except that Li-TMP was added instead of Na-TMP and the reaction was conducted in THF at a reaction temperature of 25 ° C., and the yield and cis-trans selectivity were calculated.
- FIG. 8 summarizes the reaction scheme, reaction conditions, base type, yield, and cis-trans selectivity.
- Example 7 Reaction with Na-TMP-3
- the deprotonation and functionalization reaction of heteroarene using Na-TMP was examined (see FIG. 9).
- examination was performed using dibenzofuran which is a heterocyclic compound as a heteroarene.
- Example number 1 The dibenzofuran was deprotonated by reacting n BuLi as a base in a hexane solvent for a predetermined time. Specifically, 1.1 mole equivalent of Na-TMP was reacted with 0.45 mole of benzofuran in hexane solvent at 25 ° C. for 30 minutes, and then deuterated dibenzofuran obtained by quenching with heavy water was analyzed by 1H-NMR. By analyzing the product, the yield was calculated. The yield was 79%.
- FIG. 9 summarizes the reaction scheme, reaction conditions, base type, and yield. It was confirmed that the deprotonation of the heteroarene can be efficiently performed by using Na-TMP as a base. n It was also confirmed that the deprotonation efficiency is high in comparison with the case of using BuLi and Li-TMP.
- heteroarene substitution reaction proceeds efficiently when reacted with an electrophile.
- 1-bromodibenzofuran was produced in a yield of 84% by reaction with tetrabromoethane, an electrophile.
- 1-benzoyldibenzofuran was produced in a yield of 72% by reaction with benzoyl chloride, which is an electrophile.
- dibenzofuran substituted with an allyl group is produced by reaction with allyl bromide, which is an electrophile.
- 1- (2-propenyl) -dibenzofuran is obtained by reaction with 1-bromopropene. Produced at 37%. The yield is expected to be further improved by optimizing the reaction conditions, and it has been found that Na-TMP can be used for various substitution reactions.
- Example 8 FIG. Reaction with Na-TMP-4
- the functionalization reaction of a heterocyclic compound using Na-TMP was examined (see FIG. 10).
- the product was evaluated by analysis with 1H-NMR, and the benzo [b] thiophene-2-boronic acid of thiophene with a boronyl group (-B (OH) 2) attached to the 2-position of benzo [b] thiophene
- the isolation yield was calculated.
- the isolated yield is a value obtained by dividing the amount of the product by the difference in the amount of raw material recovered after the reaction (net amount used) from the amount of the starting raw material.
- the isolation yield was 64%.
- Example 11 After reacting in the same manner as in Experiment No. 2 using benzo [b] furan as arene and chlorotrimethylsilane (Me3SiCl) as the electrophile, the product was evaluated, and a trimethylsilyl group at the 2-position of benzo [b] furan The isolated yield of 2-trimethylsilyl-benzo [b] furan provided with (-SiMe3) was calculated. The isolation yield was 82%.
- Example 12 After reacting in the same manner as in Experiment No. 2 using dibenzofuran as arene and chlorotrimethylsilane (Me3SiCl) as the electrophile, the product was evaluated and a trimethylsilyl group (-SiMe3) was added to the 4-position of dibenzofuran. The isolated yield of 4-trimethylsilyl-dibenzofuran was calculated. The isolation yield was 83%.
- Example 13 After reacting in the same manner as in Experiment No. 2 using dibenzofuran as arene and benzoyl chloride (PhC (O) Cl) as the electrophile, the product was evaluated and a benzoyl group was added to the 4-position of dibenzofuran 4 The isolated yield of -benzoyl-dibenzofuran was calculated. The isolation yield was 73%.
- FIG. 10 summarizes the reaction scheme, reaction conditions, and isolated yield. It was confirmed that by using Na-TMP as a base, it was possible to give a substituent to the heterocyclic compound, such as synthesis of boronic acid from benzothiophene. Thus, by using Na-TMP, it is possible to give a substituent to a heterocyclic compound in a short time under mild conditions, and there is an advantage that various compounds such as boronic acid can be synthesized.
- the present invention is a method for synthesizing Na-TMPs, and all technical fields using Na-TMPs obtained by such a synthesis method, in particular, for organic synthesis of drugs, animal drugs, agricultural chemicals and the like. Can do.
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Abstract
There is a desire for a technique wherein a sodium 2,2,6,6-tetramethylpiperidide (Na-TMP) compound can be economically and efficiently synthesized in a short time under mild conditions by a simple procedure including a small number of steps. There also is a desire for a technique wherein an Na-TMP compound of good quality with no inclusion of lithium or lithium compounds, e.g., Li-TMP, can be synthesized. The method for synthesizing a sodium 2,2,6,6-tetramethylpiperidide compound according to the present invention includes a step in which a 2,2,6,6-tetramethylpiperidine compound is reacted, in a reaction medium, with a dispersion obtained by dispersing sodium in a dispersion medium or with an aromatic-ring-containing organosodium compound obtained by reaction with a dispersion obtained by dispersing sodium in a dispersion medium, thereby obtaining the sodium 2,2,6,6-tetramethylpiperidide compound.
Description
本発明は、ナトリウム2,2,6,6-テトラメチルピペリジド類の合成方法に関する。
The present invention relates to a method for synthesizing sodium 2,2,6,6-tetramethylpiperidide.
金属アミド化合物は、その分子内に金属-窒素結合を有する有機塩基であり、農薬や医薬の有機合成化学において汎用されている。なかでも第２級アミンの水素原子をアルカリ金属等の金属原子に置換したものが好適に利用され、例えば、α位が四置換炭素であるリチウム2,2,6,6-テトラメチルピペリジド（以下、「Li-TMP」と略する場合がある）、ナトリウム2,2,6,6-テトラメチルピペリジド（以下、「Na-TMP」と略する場合がある）等が挙げられる。
The metal amide compound is an organic base having a metal-nitrogen bond in the molecule, and is widely used in organic synthetic chemistry of agricultural chemicals and pharmaceuticals. Of these, those obtained by substituting hydrogen atoms of secondary amines with metal atoms such as alkali metals are preferably used. For example, lithium 2,2,6,6-tetramethylpiperidide in which the α-position is tetrasubstituted carbon (Hereinafter sometimes abbreviated as “Li-TMP”), sodium 2,2,6,6-tetramethylpiperidide (hereinafter sometimes abbreviated as “Na-TMP”), and the like.
従来において、Na-TMPの製造方法として、ペンタン溶媒（50 ml）中で、2,2,6,6-テトラメチルピペリジン（44 mmol）（以下、「TMP」と略する場合がある）と0.95当量のn-ブチルナトリウム（42 mmol）（以下、「nBuNa」と略する場合がある）を外気温度（25℃）で反応させることで、収率82％でNa-TMPが得られたことが報告されている（非特許文献１）。
Conventionally, Na-TMP has been produced in 2,5,6,6-tetramethylpiperidine (44 mmol) (hereinafter sometimes abbreviated as “TMP”) and 0.95 in a pentane solvent (50 ml). Na-TMP was obtained in a yield of 82% by reacting an equivalent amount of n-butyl sodium (42 mmol) (hereinafter may be abbreviated as “ n BuNa”) at an ambient temperature (25 ° C.). Has been reported (Non-patent Document 1).
非特許文献１には、ヘキサン溶媒（50 ml）中で、Li-TMP（38 mmol）と1当量のナトリウムt-ブトキシド（38 mmol）（以下、「NaOtBu」と略する場合がある）を外気温度（25℃）で反応させることで、収率87％でNa-TMPが得られたことも報告されている。
In Non-Patent Document 1, Li-TMP (38 mmol) and 1 equivalent of sodium t-butoxide (38 mmol) (hereinafter sometimes abbreviated as “NaO t Bu”) in a hexane solvent (50 ml). It has also been reported that Na-TMP was obtained in a yield of 87% by reacting at room temperature (25 ° C).
しかしながら、TMPとnBuNaを利用する非特許文献１の方法は、nBuNaの調製を、n-ブチルリチウム（以下、「nBuLi」）とNaOtBuとのメタセシス反応により行うものであるため、得られるnBuNaにはリチウムやリチウム化合物が混入する。そのため、結果として得られるNa-TMPには、不純物としてリチウムやLi-TMP等のリチウム化合物が混入するとの問題がある。また、nBuNaの調製工程を含むことから合成工程が多段階となると共に、nBuNaの調製に際してnBuLi等の高価な試薬を用いることから生産コストが増加する等の問題もある。更に、nBuLiは消防法で第３類危険物に指定されていることから、取り扱いに適した装置等が必要となる。
However, the method of Non-Patent Document 1 using TMP and n BuNa is because n BuNa is prepared by a metathesis reaction between n -butyllithium (hereinafter “ n BuLi”) and NaO t Bu. The resulting n BuNa contains lithium and lithium compounds. Therefore, the resulting Na-TMP has a problem that lithium compounds such as lithium and Li-TMP are mixed as impurities. Further, the synthetic process from including the step preparation of n Buna is multistage, the production cost from using an expensive reagent n BuLi etc. In the preparation of n Buna there is a problem such as increasing. In addition, n BuLi is designated as a Class 3 dangerous material by the Fire Service Act, so equipment that is suitable for handling is required.
Li-TMPとNaOtBuを利用する非特許文献１の方法は、一段階でNa-TMPを合成するものである。しかしながら、Li-TMPは、nBuLiとTMPを反応させて得る必要があり、実質的には多段階の反応となる。また、Li-TMPを利用することから、上述の方法と同様に不純物としてリチウムやLi-TMP等のリチウム化合物が混入し良質なNa-TMPを得ることは困難である。そのため、Na-TMPとLi-TMPの反応性の相違等から好ましくない副反応が併発される等、有機塩基等としてNa-TMPを単独で用いる合成反応系を構築できないとの問題がある。
The method of Non-Patent Document 1 using Li-TMP and NaO t Bu synthesizes Na-TMP in one step. However, Li-TMP needs to be obtained by reacting n BuLi and TMP, which is essentially a multistage reaction. In addition, since Li-TMP is used, it is difficult to obtain good-quality Na-TMP by mixing lithium or a lithium compound such as Li-TMP as impurities as in the above-described method. Therefore, there is a problem that a synthetic reaction system using Na-TMP alone as an organic base or the like cannot be constructed, such as undesirable side reactions due to the difference in reactivity between Na-TMP and Li-TMP.
そこで、温和な条件の下、少ない工程数の簡便な操作で短時間に、経済的かつ効率的にNa-TMP類を合成できる技術の構築が望まれている。更にはリチウムやLi-TMP等のリチウム化合物の混入のない良質なNa-TMP類を合成できる技術の構築が望まれている。
Therefore, it is desired to construct a technology that can synthesize Na-TMPs economically and efficiently in a short time with a simple operation with a small number of steps under mild conditions. Furthermore, it is desired to establish a technology that can synthesize high-quality Na-TMPs that are free from lithium compounds such as lithium and Li-TMP.
本発明者らは、上述課題を解決すべく鋭意検討した結果、TMP類を、ナトリウムを分散溶媒に分散させた分散体、又はナトリウムを分散溶媒に分散させた分散体との反応により得られた芳香環を有する有機ナトリウム化合物と反応させることにより、安定的かつ効率的にNa-TMP類を合成できることを見出した。かかるNa-TMP類の合成方法は、高価な試薬類や装置等を必要とせず経済的に有利であると共に、煩雑な化学的手法を必要とせず少ない工程数で簡便かつ短時間にNa-TMP類を合成できる。また、合成過程において、従来法においては必要とされたリチウム化合物を用いないことから、良質なNa-TMP類を得ることができる。本発明者らは、これらの知見に基づき本発明を完成するに至った。
As a result of intensive studies to solve the above-mentioned problems, the present inventors obtained TMPs by a reaction with a dispersion in which sodium is dispersed in a dispersion solvent or a dispersion in which sodium is dispersed in a dispersion solvent. It was found that Na-TMPs can be synthesized stably and efficiently by reacting with an organic sodium compound having an aromatic ring. This method of synthesizing Na-TMPs is economically advantageous without requiring expensive reagents and equipment, and is simple and quick in a short time with a small number of steps without requiring complicated chemical methods. Can be synthesized. In addition, since a lithium compound required in the conventional method is not used in the synthesis process, high-quality Na-TMPs can be obtained. Based on these findings, the present inventors have completed the present invention.
即ち、本発明は、ナトリウム2,2,6,6-テトラメチルピペリジド（Na-TMP）類の合成方法に関するものであり、その特徴構成は、2,2,6,6-テトラメチルピペリジン（TMP）類と、ナトリウムを分散溶媒に分散させた分散体（SD）、又はナトリウムを分散溶媒に分散させた分散体（SD）との反応により得られた芳香環を有する有機ナトリウム化合物とを反応溶媒中で反応させて、ナトリウム2,2,6,6-テトラメチルピペリジド（Na-TMP）類を得る工程を有する点にある。
That is, the present invention relates to a method for synthesizing sodium 2,2,6,6-tetramethylpiperidide (Na-TMP), and its characteristic constitution is 2,2,6,6-tetramethylpiperidine. An organic sodium compound having an aromatic ring obtained by reacting (TMP) s with a dispersion (SD) in which sodium is dispersed in a dispersion solvent, or a dispersion (SD) in which sodium is dispersed in a dispersion solvent. It has the process of making it react in a reaction solvent and obtaining sodium 2,2,6,6-tetramethylpiperidide (Na-TMP).
本構成によれば、TMP類を出発物質として、SD又は有機ナトリウム化合物を添加することで、安定的かつ効率的にNa-TMP類を合成することができる。本構成において、Na-TMP類の合成方法で用いるSDは反応系全体に均一に分散することから、均一な温度分布で安定してNa-TMPを合成することができる。また、本構成によれば、取り扱いが容易なSDを用いているので、温和な条件下で、煩雑な化学的手法を必要とせず、少ない工程数で簡便かつ短時間に、Na-TMP類を製造することができ、経済的かつ工業的にも非常に有利である。また、TMP類は嵩高く電子豊富であるため、TMP類の窒素上のプロトンを引き抜かれることによって形成するアニオンが不安定である。そのため、TMP類においてはナトリウムアミド自体を生成することが困難であるが、本構成よれば、SDを用いることにより、かかる合成反応系が安定に進行することができ、安定的かつ効率的にNa-TMP類を合成することができる。
According to this configuration, Na-TMPs can be stably and efficiently synthesized by adding SD or an organic sodium compound using TMPs as a starting material. In this configuration, SD used in the method for synthesizing Na-TMPs is uniformly dispersed throughout the reaction system, so that Na-TMP can be synthesized stably with a uniform temperature distribution. In addition, according to this configuration, since SD that is easy to handle is used, Na-TMPs can be easily and quickly used with a small number of steps without requiring complicated chemical methods under mild conditions. It can be manufactured and is very advantageous economically and industrially. In addition, since TMPs are bulky and abundant in electrons, anions formed by extracting protons on nitrogen of TMPs are unstable. Therefore, in TMPs, it is difficult to produce sodium amide itself. However, according to this configuration, by using SD, such a synthetic reaction system can proceed stably, and sodium can be stably and efficiently produced. -TMPs can be synthesized.
他の特徴構成は、前記工程が、アミン類の存在下で行われる点にある。
Another characteristic configuration is that the above process is performed in the presence of amines.
本構成によれば、アミン類の添加により、Na-TMP類の合成反応系が安定化し反応の進行を促進することができ、より安定的かつ効率的にNa-TMP類を合成することができる。合成反応系の安定化により、TMP類とSD又は有機ナトリウム化合物との衝突頻度の向上、反応エネルギーの安定化等によりNa-TMP類の合成反応系の駆動力が増し、合成反応の進行が促進され収率が向上するとの効果が得られる。また、上述した通りTMP類は嵩高く電子豊富であるため、TMP類の窒素上のプロトンが引き抜かれることによって形成するアニオンが不安定である。そのため、TMP類においてはナトリウムアミド自体を生成することが困難であるが、本構成のようにSDに加えアミン類を用いることにより、かかる合成反応系が安定に進行することができ、更に安定的かつ効率的にNa-TMP類を合成することができる。
According to this configuration, by adding amines, the synthesis reaction system of Na-TMPs can be stabilized and the progress of the reaction can be promoted, and Na-TMPs can be synthesized more stably and efficiently. . Stabilization of the synthesis reaction system increases the collision frequency between TMPs and SD or organic sodium compounds, and the reaction energy stabilizes the driving force of the synthesis reaction system for Na-TMPs, thus promoting the progress of the synthesis reaction. As a result, the yield is improved. Further, as described above, TMPs are bulky and abundant in electrons, so that the anion formed by the extraction of protons on nitrogen of TMPs is unstable. For this reason, it is difficult to produce sodium amide itself in TMPs, but by using amines in addition to SD as in this configuration, such a synthesis reaction system can proceed stably, and more stable. In addition, Na-TMPs can be synthesized efficiently.
（本発明の実施形態に係るNa-TMP類の合成方法）
以下、本発明のNa-TMP類の合成方法の実施形態について詳細に説明する。ただし、本発明は、後述する実施形態に限定されるものではない。 (Method for synthesizing Na-TMPs according to an embodiment of the present invention)
Hereinafter, embodiments of the method for synthesizing Na-TMP of the present invention will be described in detail. However, the present invention is not limited to the embodiments described below.
以下、本発明のNa-TMP類の合成方法の実施形態について詳細に説明する。ただし、本発明は、後述する実施形態に限定されるものではない。 (Method for synthesizing Na-TMPs according to an embodiment of the present invention)
Hereinafter, embodiments of the method for synthesizing Na-TMP of the present invention will be described in detail. However, the present invention is not limited to the embodiments described below.
本実施形態に係るNa-TMP類の合成方法は、TMP類と、ナトリウムを分散溶媒に分散させた分散体、又はナトリウムを分散溶媒に分散させた分散体との反応により得られた芳香環を有する有機ナトリウム化合物とを反応溶媒中で反応させて、Na-TMP類を得る工程を有する。
In the method for synthesizing Na-TMPs according to the present embodiment, an aromatic ring obtained by reacting TMPs with a dispersion in which sodium is dispersed in a dispersion solvent or a dispersion in which sodium is dispersed in a dispersion solvent is used. A step of obtaining Na-TMPs by reacting with an organic sodium compound in a reaction solvent.
ここで、Na-TMP類とは、置換基を有していても、有していなくてもよいナトリウム2,2,6,6-テトラメチルピペリジド（Na-TMP）である。置換基を有する場合には、例えば、ピペリジン環の3、4、及び5位の炭素原子の一部又は全部に導入されていてよく、複数の置換基を有する場合には、それらの一部又は全部が同じであっても、又は、全部が異なっていてもよい。置換基としては、メチル基やエチル基、プロピル基等のアルキル基が例示されるが、これらに限定するものではない。
Here, Na-TMPs are sodium 2,2,6,6-tetramethylpiperidide (Na-TMP) which may or may not have a substituent. When it has a substituent, for example, it may be introduced into some or all of the carbon atoms at the 3, 4, and 5 positions of the piperidine ring, and when it has a plurality of substituents, All may be the same or all may be different. Examples of the substituent include alkyl groups such as a methyl group, an ethyl group, and a propyl group, but are not limited thereto.
本実施形態に係るNa-TMP類の合成方法における出発物質であるTMP類は、置換基を有していても、有していなくてもよい2,2,6,6-テトラメチルピペリジンであり、所望のNa-TMP類に応じて適宜設定される。したがって、置換基を有する場合には、所望のNa-TMP類に応じて、例えばピペリジン環の3、4、及び5位の炭素原子の一部又は全部に導入されていてよく、複数の置換基を有する場合には、それらの一部又は全部が同じであっても、又は、全部が異なっていてもよい。置換基としては、メチル基やエチル基、プロピル基等のアルキル基が例示されるが、これらに限定するものではない。
The TMPs that are starting materials in the method for synthesizing Na-TMPs according to the present embodiment are 2,2,6,6-tetramethylpiperidines that may or may not have a substituent. Depending on the desired Na-TMP, it is set as appropriate. Therefore, when it has a substituent, it may be introduced into some or all of the carbon atoms at the 3, 4, and 5 positions of the piperidine ring, depending on the desired Na-TMPs. Or a part thereof may be the same or different from each other. Examples of the substituent include alkyl groups such as a methyl group, an ethyl group, and a propyl group, but are not limited thereto.
TMP類は、当該技術分野で公知の方法で合成することができ、例えば、2,6-ジメチル-2,5-ヘプタジエン-4-オン（ホロン）へのアンモニアの1,4付加反応等によって得られる2,2,6,6-テトラメチル-4-ピペリドン（トリアセトンアミン）から、スズ、亜鉛及びナトリウムアマルガムとの還元によって、又は、接触水素化等によってTMPを得ることができる。
また、トリアセトンアミンのウォルフ-キシュナー(Wolff-Kishner)還元によってもTMPを得ることができるが、これらに限定するものではない。更に、TMP類は、市販品をも好適に利用することができる。 TMPs can be synthesized by methods known in the art, and can be obtained by, for example, 1,4-addition reaction of ammonia to 2,6-dimethyl-2,5-heptadien-4-one (holon). TMP can be obtained from 2,2,6,6-tetramethyl-4-piperidone (triacetoneamine) obtained by reduction with tin, zinc and sodium amalgam, or by catalytic hydrogenation.
TMP can also be obtained by the Wolff-Kishner reduction of triacetoneamine, but is not limited thereto. Furthermore, commercially available products can be suitably used for TMPs.
また、トリアセトンアミンのウォルフ-キシュナー(Wolff-Kishner)還元によってもTMPを得ることができるが、これらに限定するものではない。更に、TMP類は、市販品をも好適に利用することができる。 TMPs can be synthesized by methods known in the art, and can be obtained by, for example, 1,4-addition reaction of ammonia to 2,6-dimethyl-2,5-heptadien-4-one (holon). TMP can be obtained from 2,2,6,6-tetramethyl-4-piperidone (triacetoneamine) obtained by reduction with tin, zinc and sodium amalgam, or by catalytic hydrogenation.
TMP can also be obtained by the Wolff-Kishner reduction of triacetoneamine, but is not limited thereto. Furthermore, commercially available products can be suitably used for TMPs.
本実施形態に係るNa-TMP類の合成方法におけるナトリウムを分散溶媒に分散させた分散体は、ナトリウムを微粒子として不溶性溶媒に分散させたもの、又はナトリウムを液体の状態で不溶性溶媒に分散させたものである。微粒子の平均粒子径として、好ましくは、10μm未満であり、特に好ましくは、5μm未満のものを用いることができる。平均粒子径は、顕微鏡写真の画像解析によって得られた投影面積と同等の投影面積を有する球の径で表した。
In the method for synthesizing Na-TMPs according to this embodiment, a dispersion in which sodium is dispersed in a dispersion solvent is a dispersion in which sodium is dispersed in an insoluble solvent as fine particles, or sodium is dispersed in an insoluble solvent in a liquid state. Is. The average particle diameter of the fine particles is preferably less than 10 μm, and particularly preferably less than 5 μm. The average particle diameter was represented by the diameter of a sphere having a projected area equivalent to the projected area obtained by image analysis of micrographs.
分散溶媒としては、ナトリウムを微粒子として分散、又はナトリウムを液体の状態で不溶性溶媒に分散でき、かつ、TMP類とナトリウムを分散溶媒に分散させた分散体中に含まれるナトリウムとの反応を阻害しない限り、当該技術分野で公知の溶媒を用いることができる。例えば、キシレン、トルエン等の芳香族系溶媒や、デカン等のノルマルパラフィン系溶媒、又は、テトラヒドロチオフェン等の複素環化合物溶媒、それらの混合溶媒などが挙げられる。
As a dispersion solvent, sodium can be dispersed as fine particles, or sodium can be dispersed in an insoluble solvent in a liquid state, and the reaction between TMPs and sodium contained in the dispersion in which sodium is dispersed in the dispersion solvent is not inhibited. As long as it is known, solvents known in the art can be used. Examples thereof include aromatic solvents such as xylene and toluene, normal paraffin solvents such as decane, heterocyclic compound solvents such as tetrahydrothiophene, and mixed solvents thereof.
以下、アルカリ金属を分散溶媒に分散させた分散体につき、「SD」と略する場合がある。SDは、Sodium Dispersionの略号である。
Hereinafter, a dispersion in which an alkali metal is dispersed in a dispersion solvent may be abbreviated as “SD”. SD is an abbreviation for Sodium Dispersion.
本実施形態に係るNa-TMP類の合成方法における反応溶媒としては、TMP類とSDとの反応を阻害しない限り、当該技術分野で公知の溶媒を用いることができる。例えば、エーテル系溶媒、ノルマルパラフィン系やシクロパラフィン系溶媒、芳香族系溶媒、アミン系溶媒、複素環化合物溶媒を用いることができる。エーテル系溶媒としては、環状エーテル溶媒が好ましく、テトラヒドロフランが特に好ましい。ノルマルパラフィン系溶媒やシクロパラフィン系溶媒としては、ヘキサン、ノルマルデカン、シクロヘキサン等が特に好ましい。芳香族系溶媒としては、キシレン、トルエン及びベンゼン等が好ましい。アミン系溶媒としては、エチレンジアミン等が好ましい。また、複素環化合物溶媒としては、テトラヒドロチオフェン等を好ましく利用することができる。これらは1種類のみを用いてもよいし、2種以上を併用し混合溶媒として用いることもできる。ここで、前述の分散溶媒と反応溶媒とは同一の種類のものを用いてもよいし、異なる種類のものを用いてもよい。
As a reaction solvent in the method for synthesizing Na-TMPs according to this embodiment, a solvent known in the technical field can be used as long as the reaction between TMPs and SD is not inhibited. For example, an ether solvent, a normal paraffin solvent, a cycloparaffin solvent, an aromatic solvent, an amine solvent, or a heterocyclic compound solvent can be used. As the ether solvent, a cyclic ether solvent is preferable, and tetrahydrofuran is particularly preferable. As the normal paraffin solvent and cycloparaffin solvent, hexane, normal decane, cyclohexane and the like are particularly preferable. As the aromatic solvent, xylene, toluene, benzene and the like are preferable. As the amine solvent, ethylenediamine or the like is preferable. Moreover, tetrahydrothiophene etc. can be preferably utilized as the heterocyclic compound solvent. These may be used alone or in combination of two or more as a mixed solvent. Here, the dispersion solvent and the reaction solvent described above may be the same type or different types.
本実施形態に係るNa-TMP類の合成方法は、SDに代えて、SDとの反応により得られた芳香環を有する有機ナトリウム化合物を用いることができる。芳香環を有する有機ナトリウム化合物とは、分子内に1又は数個の芳香環、及び１又は数個の炭素原子－ナトリウム結合を有する化合物であり、好ましくは、芳香環上の炭素原子がナトリウムと結合している化合物である。芳香環は、炭化水素のみから構成される炭化水素芳香環、及び環構造に炭素原子以外の原子を含む複素芳香族環の何れであってよく、好ましくは炭化水素芳香環である。また、単環であっても、集合環や縮合多環等の複数の環をもつものであってもよい。芳香環としては、ベンゼン環、ナフタレン環、アントラセン環、ピリジン環、イミダゾール環等が例示されるが、これらに限定されるものではない。芳香環は、１又は数個の置換基を有していても、有していなくてもよく、置換基としては、メチル基、エチル基、プロピル基等のアルキル基が例示されるが、これらに限定されるものではない。
In the method for synthesizing Na-TMPs according to the present embodiment, an organic sodium compound having an aromatic ring obtained by reaction with SD can be used instead of SD. The organic sodium compound having an aromatic ring is a compound having one or several aromatic rings and one or several carbon atom-sodium bonds in the molecule, and preferably the carbon atom on the aromatic ring is sodium and It is a bonded compound. The aromatic ring may be any of a hydrocarbon aromatic ring composed only of hydrocarbons and a heteroaromatic ring containing atoms other than carbon atoms in the ring structure, preferably a hydrocarbon aromatic ring. Further, it may be a single ring or may have a plurality of rings such as an aggregate ring or a condensed polycycle. Examples of the aromatic ring include, but are not limited to, a benzene ring, a naphthalene ring, an anthracene ring, a pyridine ring, and an imidazole ring. The aromatic ring may or may not have one or several substituents, and examples of the substituent include alkyl groups such as a methyl group, an ethyl group, and a propyl group. It is not limited to.
SDとの反応により得られた芳香環を有する有機ナトリウム化合物（以下、「有機ナトリウム化合物」と略する場合がある）としては、具体的には、フェニルナトリウム、ナフチルナトリウム等が例示されるが、これらに限定されるものではない。
Specific examples of the organic sodium compound having an aromatic ring obtained by the reaction with SD (hereinafter sometimes abbreviated as “organic sodium compound”) include phenyl sodium and naphthyl sodium. It is not limited to these.
有機ナトリウム化合物は、SDと芳香環を有する有機化合物とを、好ましくは反応溶媒中で反応させることによって得られたものである。反応溶媒としては、SDと芳香環を有する有機化合物との反応を阻害しない限り、当該技術分野で公知の溶媒を用いることができる。例えば、エーテル系溶媒、ノルマルパラフィン系溶媒やシクロパラフィン系溶媒、芳香族系溶媒、アミン系溶媒、複素環化合物溶媒を用いることができ、これらの溶媒の詳細については上述した。好ましくは、有機ナトリウム化合物は、SDを加えた反応溶媒に芳香環を有する有機化合物を滴下することにより調製でき、続いて、TMP類を加えることによりNa-TMP類を合成することができる。
The organic sodium compound is obtained by reacting SD and an organic compound having an aromatic ring, preferably in a reaction solvent. As the reaction solvent, a solvent known in the art can be used as long as the reaction between SD and the organic compound having an aromatic ring is not inhibited. For example, an ether solvent, a normal paraffin solvent, a cycloparaffin solvent, an aromatic solvent, an amine solvent, or a heterocyclic compound solvent can be used, and details of these solvents have been described above. Preferably, the organic sodium compound can be prepared by dropping an organic compound having an aromatic ring in a reaction solvent to which SD is added, and then Na-TMPs can be synthesized by adding TMPs.
本実施形態に係るNa-TMP類の合成方法は、TMP類と、SD又は有機ナトリウム化合物との反応に際して、必要に応じて電子受容体が反応系に添加される。電子受容体は、SD又は有機ナトリウム化合物から電子を受け取ることができる限り、何れの物質をも利用することができる。電子受容体としては、イソプレン等の分岐不飽和炭化水素、1,3-ブタジエン等の直鎖不飽和炭化水素、ビフェニル、4,4'-ジtertブチルビフェニル、スチレン等の芳香族炭化水素、ナフタレン、フェナントレン、アントラセン等の多環芳香族炭化水素等が例示されるが、これらに限定されるものではない。電子受容体の添加時期は、電子受容体がSD又は有機ナトリウム化合物から電子を受け取ることができる限り特に制限はない。好ましくは、TMP類とSD又は有機ナトリウム化合物との反応と同時に電子受容体を反応させるように構成してもよいし、若しくは、電子受容体をSD又は有機ナトリウム化合物とを反応させた後にTMP類を反応させるように構成することができる。なお、TMP類と有機ナトリウム化合物との反応に際しては、電子受容体を添加せずともNa-TMP類を効率的に得ることができる。
In the method for synthesizing Na-TMPs according to the present embodiment, an electron acceptor is added to the reaction system as necessary when the TMPs are reacted with SD or an organic sodium compound. As the electron acceptor, any substance can be used as long as it can receive electrons from SD or an organic sodium compound. Examples of the electron acceptor include branched unsaturated hydrocarbons such as isoprene, linear unsaturated hydrocarbons such as 1,3-butadiene, aromatic hydrocarbons such as biphenyl, 4,4′-ditertbutylbiphenyl, styrene, and naphthalene. Examples thereof include, but are not limited to, polycyclic aromatic hydrocarbons such as phenanthrene and anthracene. The addition timing of the electron acceptor is not particularly limited as long as the electron acceptor can receive electrons from SD or an organic sodium compound. Preferably, the electron acceptor may be reacted simultaneously with the reaction of TMPs with SD or an organic sodium compound, or the TMPs may be reacted after the electron acceptor is reacted with SD or an organic sodium compound. Can be made to react. In the reaction of TMPs with organic sodium compounds, Na-TMPs can be efficiently obtained without adding an electron acceptor.
以下、本実施形態に係るNa-TMP類の合成方法の反応条件及び反応機構を詳細に説明する。
Hereinafter, the reaction conditions and reaction mechanism of the method for synthesizing Na-TMPs according to this embodiment will be described in detail.
反応温度は特に限定されず、TMP類、SD又は有機ナトリウム化合物、及び反応溶媒の種類や量、並びに反応圧力等により適宜設定することができる。具体的には、反応温度は、反応溶媒の沸点を越えない温度に設定することが好ましい。加圧下では大気圧下での沸点よりも高くなるため反応温度を高い温度で設定することができる。反応は、ノルマルパラフィン系やシクロパラフィン系溶媒を用いる場合、室温で行うこともでき、好ましくは10～100℃であり、特に好ましくは20～80℃、更に好ましくは室温～50℃である。特段の加熱や冷却などのための温度制御手段を設ける必要はないが、必要に応じて、温度制御手段を設けても良い。エーテル系溶媒、芳香族系溶媒、アミン系溶媒、複素環化合物系溶媒を反応に用いる場合、室温では合成で生じたNa-TMPと溶媒が反応するため、0℃以下に設定する必要がある。
The reaction temperature is not particularly limited, and can be appropriately set according to the type and amount of TMPs, SD or organic sodium compound, and reaction solvent, reaction pressure, and the like. Specifically, the reaction temperature is preferably set to a temperature that does not exceed the boiling point of the reaction solvent. Since the boiling point under atmospheric pressure is higher than the boiling point, the reaction temperature can be set at a high temperature. The reaction can be carried out at room temperature when a normal paraffin or cycloparaffin solvent is used, preferably 10 to 100 ° C., particularly preferably 20 to 80 ° C., more preferably room temperature to 50 ° C. It is not necessary to provide a temperature control means for special heating or cooling, but a temperature control means may be provided if necessary. When an ether solvent, an aromatic solvent, an amine solvent, or a heterocyclic compound solvent is used for the reaction, the Na-TMP generated in the synthesis reacts with the solvent at room temperature.
反応時間についても、特に限定されず、出発物質、SD又は有機ナトリウム化合物、及び反応溶媒の種類や量、並びに反応圧力や反応温度等に応じて適宜設定すればよい。通常は、30分間以上であればよく、好ましくは30分～24時間、特に好ましくは1～12時間で行われる。THFやトルエンを反応溶媒として用いる場合、調製後できるだけ早く用いる必要がある。
The reaction time is not particularly limited, and may be appropriately set according to the starting material, SD or organic sodium compound, the type and amount of the reaction solvent, the reaction pressure, the reaction temperature, and the like. The reaction time is usually 30 minutes or more, preferably 30 minutes to 24 hours, particularly preferably 1 to 12 hours. When THF or toluene is used as a reaction solvent, it must be used as soon as possible after preparation.
また、本実施形態に係るNa-TMP類の合成方法で必要とされるTMP類、SD、及び反応溶媒等の試薬類は大気下で安定して扱うことができることから、反応は大気下の常圧条件下で行うことができる。しかしながら、それぞれの試薬は反応性が高く発熱を伴うのでアルゴンガスや窒素ガスなどを充填した不活性ガス雰囲気下で行う方が望ましい。また、有機ナトリウム化合物は大気下では不安定であるため、不活性ガス雰囲気下とすることが必須である。更に、調製して長期間経過したSDを用いたり、空気が混入していると収率が低下するため、各試薬類や溶媒は、できるだけ水分を除去しているほうが望ましい。
In addition, since the reagents such as TMPs, SD, and reaction solvents required in the method for synthesizing Na-TMPs according to this embodiment can be handled stably in the atmosphere, the reaction is normally performed in the atmosphere. It can be performed under pressure conditions. However, since each reagent has high reactivity and generates heat, it is preferable to perform in an inert gas atmosphere filled with argon gas or nitrogen gas. Moreover, since an organic sodium compound is unstable in air | atmosphere, it is essential to set it as inert gas atmosphere. Furthermore, since the yield decreases if SD that has been prepared for a long period of time is used or if air is mixed in, it is desirable that each reagent and solvent should remove as much water as possible.
SD又は有機ナトリウム化合物の使用量は、TMP類、及び反応溶媒の種類や量に応じて適宜設定することができるものである。好ましくは、TMP類と、SD又は有機ナトリウム化合物との反応は、TMP類の物質量1mmolに対して、1.0～2.0モル当量の反応溶媒中で、TMP類に、当該TMP類に対して2.1～2.5モル当量のSDと0.8～1.0モル当量の有機塩素化合物又は1.0～1.2モル当量の有機ナトリウム化合物を反応させることが好ましい。ここで、SDの物質量は、SD中に含まれるアルカリ金属換算での物質量を意味する。また、電子受容体を添加する場合には、反応系に当該TMP類に対して1.0～1.5モル当量の電子受容体と1.0～1.5モル当量のSDと0.8～1.5モル当量のTMEDAを添加することが好ましい。
The amount of SD or organic sodium compound used can be appropriately set according to the type and amount of TMPs and reaction solvent. Preferably, the reaction between TMPs and SD or an organic sodium compound is carried out in a 1.0 to 2.0 molar equivalent of a reaction solvent with respect to 1 mmol of the TMP substances in a TMPs and 2.1 to It is preferable to react 2.5 molar equivalents of SD with 0.8 to 1.0 molar equivalents of an organic chlorine compound or 1.0 to 1.2 molar equivalents of an organic sodium compound. Here, the amount of substance of SD means the amount of substance in terms of alkali metal contained in SD. When adding an electron acceptor, 1.0 to 1.5 molar equivalents of electron acceptor, 1.0 to 1.5 molar equivalents of SD and 0.8 to 1.5 molar equivalents of TMEDA are added to the reaction system. Is preferred.
本実施形態に係るNa-TMP類の合成方法によって得られたNa-TMP類は、カラムクロマトグラフィー、蒸留、再結晶等、当該技術分野で公知の精製手段により精製してもよい。また、未反応で残存したTMP類等を回収し、再度Na-TMP類の合成方法に利用するように構成してもよい。
The Na-TMPs obtained by the method for synthesizing Na-TMPs according to the present embodiment may be purified by purification means known in the art such as column chromatography, distillation, recrystallization and the like. Further, the TMPs remaining unreacted may be recovered and used again for the method of synthesizing Na-TMPs.
図１に、本実施形態に係るNa-TMP類の合成方法における反応機構の一例を示すが、これに限定するものではない。図１に示す反応機構は、TMPを、電子受容体であるイソプレンの存在下でSDと反応させてNa-TMPを合成する反応を模式的に示したものである。イソプレンとSDとの反応により、SD中の金属ナトリウムから電子が放出される。かかる金属ナトリウムが放出された電子がイソプレンに移動し、イソプレンラジカルアニオン・ナトリウム塩を形成する。続いて、かかるイソプレンラジカルアニオン・ナトリウム塩が、TMPの窒素原子上のプロトンを引き抜き、ナトリウムと置換することで、Na-TMPが得られると考えられる。
FIG. 1 shows an example of a reaction mechanism in the method for synthesizing Na-TMPs according to this embodiment, but the present invention is not limited to this. The reaction mechanism shown in FIG. 1 schematically shows a reaction of synthesizing Na-TMP by reacting TMP with SD in the presence of isoprene as an electron acceptor. The reaction of isoprene and SD releases electrons from metallic sodium in SD. The electrons from which the metallic sodium is released move to isoprene to form an isoprene radical anion / sodium salt. Subsequently, it is considered that such isoprene radical anion / sodium salt extracts Na-TMP by extracting a proton on the nitrogen atom of TMP and replacing it with sodium.
このように、本実施形態に係るNa-TMP類の合成方法は、TMP類を出発物質として、SD又は有機ナトリウム化合物、及び必要に応じて電子受容体を添加することで進行し、安定的かつ効率的にNa-TMP類を合成することができる。一般的に金属ナトリウム単体等を反応系に投入した場合等には、局所的な発熱等によって反応系内における温度分布にムラが生じ、反応条件を安定化させることが難しく望ましくない副反応を併発する等の不都合が生じることがある。一方、本実施形態に係るNa-TMP類の合成方法で用いるSDは反応系全体に均一に分散することから、均一な温度分布で安定してNa-TMPを合成することができる。
As described above, the method for synthesizing Na-TMPs according to the present embodiment proceeds by adding SD or an organic sodium compound, and, if necessary, an electron acceptor using TMPs as a starting material. Na-TMPs can be synthesized efficiently. In general, when metallic sodium alone is added to the reaction system, the temperature distribution in the reaction system becomes uneven due to local heat generation, etc., and it is difficult to stabilize the reaction conditions, causing undesirable side reactions. Inconvenience such as doing may occur. On the other hand, since SD used in the method for synthesizing Na-TMPs according to the present embodiment is uniformly dispersed throughout the reaction system, Na-TMP can be stably synthesized with a uniform temperature distribution.
本実施形態に係るNa-TMP類の合成方法は、取り扱いが容易なSDを用いているので、温和な条件下で、煩雑な化学的手法を必要とせず、少ない工程数で簡便かつ短時間に、Na-TMP類を製造することができ、経済的かつ工業的にも非常に有利である。
Since the method for synthesizing Na-TMPs according to the present embodiment uses SD that is easy to handle, it does not require a complicated chemical method under mild conditions, and it is simple and quick with a small number of steps. Na-TMPs can be produced, which is very advantageous economically and industrially.
TMP類は嵩高く電子豊富であるため、TMP類の窒素上のプロトンを引き抜かれることによって形成するアニオンが不安定である。そのため、TMP類においてはナトリウムアミド自体を生成することが困難であるが、本実施形態に係るNa-TMP類の合成方法においてはSDを用いることにより、かかる合成反応系が安定に進行することができ、安定的かつ効率的にNa-TMP類を合成することができる。また、有機ナトリウム化合物を用いる場合、高価なN,N,N',N'-テトラメチルエチレンジアミン（以下、「TMEDA」と略する場合がある）を用いることなく、かつイソプレン由来の副生成物が生じないという利点がある。
Since TMPs are bulky and rich in electrons, the anions formed by extracting protons on the nitrogen of TMPs are unstable. Therefore, although it is difficult to produce sodium amide per se in TMPs, the use of SD in the method for synthesizing Na-TMPs according to the present embodiment may cause the synthesis reaction system to proceed stably. It is possible to synthesize Na-TMPs stably and efficiently. Further, when using an organic sodium compound, an isoprene-derived by-product is produced without using expensive N, N, N ′, N′-tetramethylethylenediamine (hereinafter sometimes abbreviated as “TMEDA”). There is an advantage that it does not occur.
得られたNa-TMP類は、そのまま、若しくは官能基修飾等を施すことにより医薬、動物薬及び農薬等の合成に利用することができる。
The obtained Na-TMPs can be used for synthesizing pharmaceuticals, veterinary drugs, agricultural chemicals, etc. as they are or by applying functional group modification.
（本発明の別実施形態に係るNa-TMP類の合成方法）
別実施形態に係るNa-TMP類の合成方法において、TMP類とSD又は有機ナトリウム化合物との反応系に添加物としてアミン類を添加することができる。 (Method for synthesizing Na-TMPs according to another embodiment of the present invention)
In the method for synthesizing Na-TMPs according to another embodiment, amines can be added as an additive to the reaction system of TMPs and SD or an organic sodium compound.
別実施形態に係るNa-TMP類の合成方法において、TMP類とSD又は有機ナトリウム化合物との反応系に添加物としてアミン類を添加することができる。 (Method for synthesizing Na-TMPs according to another embodiment of the present invention)
In the method for synthesizing Na-TMPs according to another embodiment, amines can be added as an additive to the reaction system of TMPs and SD or an organic sodium compound.
アミン類は、脂肪族アミン、芳香族アミン、複素環アミンの何れをも用いることができ、分子内に有するアミノ基は、第１級、第２級、及び第３級の何れであってもよく、またアミノ基は単数であっても数個であってもよい。アミン類としては、例えば、N,N,N',N'-テトラメチルエチレンジアミン、N,N,N',N'',N''-ペンタメチルジエチレントリアミン、エチルアミン、エチレンジアミン、ジエチルアミン、トリエチルアミン、ジエチレントリアミン、ジイソプロピルエチルアミン、N,N,N',N'-テトラエチルエチレンジアミン（以下、「TEEDA」と略する場合がある）、N,N,N',N'-テトラメチル-1,3-プロパンジアミン、ピリジン、ピロリジン、N-メチルピペリジン、N-メチルピロリジン等を用いることができ、特に好ましくはTMEDAである。これらは1種類のみを用いてもよいし、2種以上を併用することもできる。
As the amine, any of aliphatic amine, aromatic amine, and heterocyclic amine can be used, and the amino group in the molecule may be any of primary, secondary, and tertiary. The amino group may be singular or several. Examples of amines include N, N, N ′, N′-tetramethylethylenediamine, N, N, N ′, N ″, N ″ -pentamethyldiethylenetriamine, ethylamine, ethylenediamine, diethylamine, triethylamine, diethylenetriamine, Diisopropylethylamine, N, N, N ', N'-tetraethylethylenediamine (hereinafter sometimes abbreviated as "TEEDA"), N, N, N', N'-tetramethyl-1,3-propanediamine, pyridine Pyrrolidine, N-methylpiperidine, N-methylpyrrolidine and the like can be used, and TMEDA is particularly preferable. These may be used alone or in combination of two or more.
アミン類の添加時期は、特に制限はなく、TMP類とSD又は有機ナトリウム化合物との反応開始と同時、若しくは、反応開始の前又は後であってもよい。
The addition timing of amines is not particularly limited, and may be simultaneous with the start of the reaction between TMPs and SD or an organic sodium compound, or before or after the start of the reaction.
アミン類の添加により、Na-TMP類の合成反応系が安定化し反応の進行を促進することができ、より安定的かつ効率的にNa-TMP類を合成することができる。理由としては、生成物であるNa-TMP類はイオン性化合物であるため、反応溶媒として好適に利用できるヘキサン等の非極性溶媒中では不安定である。したがって、非極性溶媒中ではNa-TMP類はNa+の大部分がむき出しになった状態で存在する。ここに、アミン類等の孤立電子対の供与体であるLewis塩基を配位させると、Na-TMP類はアミン類と錯体を形成し、Na-TMP類の非極性溶媒への溶解性が高まりNa-TMP類の生成系が安定化する。生成系の安定化により、TMP類とSD又は有機ナトリウム化合物との衝突頻度が向上し、また、遷移状態が安定化されることでNa-TMP類の合成反応の駆動力が増し、合成反応の進行が促進され収率が向上すると考えられる。
By adding amines, the synthesis reaction system of Na-TMPs can be stabilized and the progress of the reaction can be promoted, and Na-TMPs can be synthesized more stably and efficiently. The reason is that the product Na-TMPs are ionic compounds and are unstable in nonpolar solvents such as hexane which can be suitably used as a reaction solvent. Therefore, in non-polar solvents, Na-TMPs exist with most of Na + exposed. When Lewis base, which is a donor of lone pairs such as amines, is coordinated here, Na-TMPs form a complex with amines, and the solubility of Na-TMPs in nonpolar solvents increases. The production system of Na-TMPs is stabilized. By stabilizing the production system, the collision frequency between TMPs and SD or organic sodium compounds is improved, and the transition state is stabilized, which increases the driving force for the synthesis reaction of Na-TMPs and It is thought that the progress is promoted and the yield is improved.
また、上述した通りTMP類は嵩高く電子豊富であるため、TMP類の窒素上のプロトンが引き抜かれることによって形成するアニオンが不安定である。そのため、TMP類においてはナトリウムアミド自体を生成することが困難であるが、SDに加えアミン類を用いることにより、かかる合成反応系が安定に進行することができ、更に安定的かつ効率的にNa-TMP類を合成することができる。
Also, as described above, since TMPs are bulky and abundant in electrons, the anions formed when protons on nitrogen of TMPs are extracted are unstable. Therefore, it is difficult to generate sodium amide itself in TMPs, but by using amines in addition to SD, such a synthetic reaction system can proceed stably, and more stably and efficiently Na. -TMPs can be synthesized.
本実施形態のNa-TMP類の合成方法によって合成されたNa-TMP類は、様々な反応において塩基等として用いることができ、医薬、動物薬や農薬等の有機合成のために利用することができる。
Na-TMPs synthesized by the method for synthesizing Na-TMPs of the present embodiment can be used as bases in various reactions, and can be used for organic synthesis of drugs, animal drugs, agricultural chemicals and the like. it can.
（本発明のNa-TMP類生成の評価方法）
上述した実施形態のNa-TMP類の合成方法により合成されたNa-TMP類生成の評価は、生成物をフルオレンと反応させ、重水でクエンチし、クエンチ後の生成物を1H-NMRを用いて測定することにより行うことができる。Na-TMP類が存在すると、フルオレンの9位の炭素原子上の2つの水素原子のうちの1つの水素原子が引き抜かれ、Na-TMPからのナトリウムと置換する。続いて、重水でクエンチすることにより、フルオレンは重水素化する。重水素化したフルオレン量から生成物であるNa-TMP類の収率を解析することができる。 (Evaluation method for Na-TMP production of the present invention)
Evaluation of the production of Na-TMPs synthesized by the method for synthesizing Na-TMPs of the above-described embodiment was performed by reacting the product with fluorene, quenching with heavy water, and using 1H-NMR for the quenched product. This can be done by measuring. When Na-TMPs are present, one of the two hydrogen atoms on the 9th carbon atom of fluorene is extracted and replaced with sodium from Na-TMP. Subsequently, fluorene is deuterated by quenching with heavy water. The yield of product Na-TMPs can be analyzed from the amount of deuterated fluorene.
上述した実施形態のNa-TMP類の合成方法により合成されたNa-TMP類生成の評価は、生成物をフルオレンと反応させ、重水でクエンチし、クエンチ後の生成物を1H-NMRを用いて測定することにより行うことができる。Na-TMP類が存在すると、フルオレンの9位の炭素原子上の2つの水素原子のうちの1つの水素原子が引き抜かれ、Na-TMPからのナトリウムと置換する。続いて、重水でクエンチすることにより、フルオレンは重水素化する。重水素化したフルオレン量から生成物であるNa-TMP類の収率を解析することができる。 (Evaluation method for Na-TMP production of the present invention)
Evaluation of the production of Na-TMPs synthesized by the method for synthesizing Na-TMPs of the above-described embodiment was performed by reacting the product with fluorene, quenching with heavy water, and using 1H-NMR for the quenched product. This can be done by measuring. When Na-TMPs are present, one of the two hydrogen atoms on the 9th carbon atom of fluorene is extracted and replaced with sodium from Na-TMP. Subsequently, fluorene is deuterated by quenching with heavy water. The yield of product Na-TMPs can be analyzed from the amount of deuterated fluorene.
Na-TMP類は焦げ茶色を呈するため、IA族及びIIA族有機金属試薬の滴定における指示薬として知られている9‐メチルフルオレン等を用いた比色滴定法（例えば、M.E. Brown 他著、J. Org. Chem., 2002, 67(25), p9087-9088を参照のこと）では、精度よくNa-TMP類生成の評価を行うことができなかった。本実施形態のNa-TMP類生成の評価方法では、フルオレンを脱プロトン化し重水でクエンチするものであるので精度よくNa-TMP類生成の評価を行うことできる。
Since Na-TMPs have a dark brown color, a colorimetric titration method using 9-methylfluorene or the like known as an indicator in titration of group IA and IIA organometallic reagents (for example, ME Brown et al., J. Org. Chem., 2002, 67 (25), p9087-9088) could not evaluate Na-TMPs with high accuracy. In the method for evaluating the production of Na-TMPs according to this embodiment, fluorene is deprotonated and quenched with heavy water, so that the production of Na-TMPs can be accurately evaluated.
以下、実施例により具体的に説明するが、本発明は、これらの実施例に限定されるものではない。本実施例では、置換基を有しないNa-TMPの合成について検討した。SDとしては、金属ナトリウムを微粒子としてノルマルパラフィン油に分散させた分散体を用い、SD量は、SDに含まれる金属ナトリウム換算での数値である。
Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited to these examples. In this example, synthesis of Na-TMP having no substituent was studied. As SD, a dispersion in which metallic sodium is dispersed as fine particles in normal paraffin oil is used, and the SD amount is a numerical value in terms of metallic sodium contained in SD.
実施例１．SDを用いたNa-TMPの合成方法における合成条件の検討
本実施例では、SDを用いたNa-TMPの合成について、反応溶媒、添加物、及び反応時間等の反応条件について検討を行った（図２参照）。なお、当量は、反応系に投入したTMPに対するモル当量を意味する。また、ここで収率とは、実際に取得できたNa-TMP量を、添加したSD量で除し、その割合を百分率で示したものである。 Example 1. In this example, the reaction conditions such as reaction solvent, additives, and reaction time were examined for the synthesis of Na-TMP using SD. (See FIG. 2). In addition, an equivalent means the molar equivalent with respect to TMP thrown into the reaction system. Here, the yield is obtained by dividing the actually obtained amount of Na-TMP by the amount of added SD, and showing the percentage as a percentage.
本実施例では、SDを用いたNa-TMPの合成について、反応溶媒、添加物、及び反応時間等の反応条件について検討を行った（図２参照）。なお、当量は、反応系に投入したTMPに対するモル当量を意味する。また、ここで収率とは、実際に取得できたNa-TMP量を、添加したSD量で除し、その割合を百分率で示したものである。 Example 1. In this example, the reaction conditions such as reaction solvent, additives, and reaction time were examined for the synthesis of Na-TMP using SD. (See FIG. 2). In addition, an equivalent means the molar equivalent with respect to TMP thrown into the reaction system. Here, the yield is obtained by dividing the actually obtained amount of Na-TMP by the amount of added SD, and showing the percentage as a percentage.
（実験番号１）
1Mのシクロヘキサン（反応溶媒）中に1.1当量のTMPを溶解させ、1当量のSD、1.1当量のイソプレンを加え、25℃で12時間反応させた。反応後、生成物に1.1当量のフルオレンを添加し25℃で30分間反応させた後、重水でクエンチし得られた重水素化フルオレンを1H-NMRで解析することで生成物を評価し収率を算出した。Na-TMPの収率は45％であった。 (Experiment number 1)
1.1 equivalents of TMP was dissolved in 1M cyclohexane (reaction solvent), 1 equivalent of SD and 1.1 equivalents of isoprene were added, and the mixture was reacted at 25 ° C. for 12 hours. After the reaction, 1.1 equivalents of fluorene was added to the product and reacted at 25 ° C. for 30 minutes, and then the product was evaluated by analyzing the deuterated fluorene obtained by quenching with heavy water by 1H-NMR. Was calculated. The yield of Na-TMP was 45%.
1Mのシクロヘキサン（反応溶媒）中に1.1当量のTMPを溶解させ、1当量のSD、1.1当量のイソプレンを加え、25℃で12時間反応させた。反応後、生成物に1.1当量のフルオレンを添加し25℃で30分間反応させた後、重水でクエンチし得られた重水素化フルオレンを1H-NMRで解析することで生成物を評価し収率を算出した。Na-TMPの収率は45％であった。 (Experiment number 1)
1.1 equivalents of TMP was dissolved in 1M cyclohexane (reaction solvent), 1 equivalent of SD and 1.1 equivalents of isoprene were added, and the mixture was reacted at 25 ° C. for 12 hours. After the reaction, 1.1 equivalents of fluorene was added to the product and reacted at 25 ° C. for 30 minutes, and then the product was evaluated by analyzing the deuterated fluorene obtained by quenching with heavy water by 1H-NMR. Was calculated. The yield of Na-TMP was 45%.
（実験番号２）
反応溶媒として1Mのシクロヘキサンに代えて、2Mのシクロヘキサンを用い、30時間反応させた以外は実験番号１と同様に反応を行い、収率を算出した。詳細には、2Mのシクロヘキサン（反応溶媒）中にTMPを溶解させ、1当量のSD、及び1.1当量のイソプレンを加え、25℃で30時間反応させた。Na-TMPの収率は77％であった。 (Experiment number 2)
The reaction was carried out in the same manner as in Experiment No. 1 except that 2M cyclohexane was used instead of 1M cyclohexane as the reaction solvent and the reaction was performed for 30 hours, and the yield was calculated. Specifically, TMP was dissolved in 2M cyclohexane (reaction solvent), 1 equivalent of SD and 1.1 equivalent of isoprene were added and reacted at 25 ° C. for 30 hours. The yield of Na-TMP was 77%.
反応溶媒として1Mのシクロヘキサンに代えて、2Mのシクロヘキサンを用い、30時間反応させた以外は実験番号１と同様に反応を行い、収率を算出した。詳細には、2Mのシクロヘキサン（反応溶媒）中にTMPを溶解させ、1当量のSD、及び1.1当量のイソプレンを加え、25℃で30時間反応させた。Na-TMPの収率は77％であった。 (Experiment number 2)
The reaction was carried out in the same manner as in Experiment No. 1 except that 2M cyclohexane was used instead of 1M cyclohexane as the reaction solvent and the reaction was performed for 30 hours, and the yield was calculated. Specifically, TMP was dissolved in 2M cyclohexane (reaction solvent), 1 equivalent of SD and 1.1 equivalent of isoprene were added and reacted at 25 ° C. for 30 hours. The yield of Na-TMP was 77%.
（実験番号３）
反応溶媒としてシクロヘキサンに代え、ヘキサンを用いた以外は実験番号１と同様に反応を行い、収率を算出した。詳細には、1Mのヘキサン（反応溶媒）中にTMPを溶解させ、1当量のSD、及び1.1当量のイソプレンを加え、25℃で12時間反応させた。Na-TMPの収率は62％であった。 (Experiment No. 3)
The reaction was carried out in the same manner as in Experiment No. 1 except that hexane was used instead of cyclohexane as the reaction solvent, and the yield was calculated. Specifically, TMP was dissolved in 1M hexane (reaction solvent), 1 equivalent of SD and 1.1 equivalent of isoprene were added, and the mixture was reacted at 25 ° C. for 12 hours. The yield of Na-TMP was 62%.
反応溶媒としてシクロヘキサンに代え、ヘキサンを用いた以外は実験番号１と同様に反応を行い、収率を算出した。詳細には、1Mのヘキサン（反応溶媒）中にTMPを溶解させ、1当量のSD、及び1.1当量のイソプレンを加え、25℃で12時間反応させた。Na-TMPの収率は62％であった。 (Experiment No. 3)
The reaction was carried out in the same manner as in Experiment No. 1 except that hexane was used instead of cyclohexane as the reaction solvent, and the yield was calculated. Specifically, TMP was dissolved in 1M hexane (reaction solvent), 1 equivalent of SD and 1.1 equivalent of isoprene were added, and the mixture was reacted at 25 ° C. for 12 hours. The yield of Na-TMP was 62%.
（実験番号４）
添加剤として1当量のN,N,N',N'-テトラメチルエチレンジアミン（以下、「TMEDA」と称する）を添加し、0.5時間反応させた以外は、実験番号３と同様に反応を行い、収率を算出した。詳細には、1Mのヘキサン（反応溶媒）中にTMPを溶解させ、1当量のSD、1.1当量のイソプレン、及び1当量のTMEDAを加え、25℃で0.5時間反応させた。Na-TMPの収率は79％であった。 (Experiment No. 4)
Except that 1 equivalent of N, N, N ′, N′-tetramethylethylenediamine (hereinafter referred to as “TMEDA”) was added as an additive and reacted for 0.5 hour, the reaction was conducted in the same manner as in Experiment No. 3, Yield was calculated. Specifically, TMP was dissolved in 1M hexane (reaction solvent), 1 equivalent of SD, 1.1 equivalent of isoprene, and 1 equivalent of TMEDA were added and reacted at 25 ° C. for 0.5 hour. The yield of Na-TMP was 79%.
添加剤として1当量のN,N,N',N'-テトラメチルエチレンジアミン（以下、「TMEDA」と称する）を添加し、0.5時間反応させた以外は、実験番号３と同様に反応を行い、収率を算出した。詳細には、1Mのヘキサン（反応溶媒）中にTMPを溶解させ、1当量のSD、1.1当量のイソプレン、及び1当量のTMEDAを加え、25℃で0.5時間反応させた。Na-TMPの収率は79％であった。 (Experiment No. 4)
Except that 1 equivalent of N, N, N ′, N′-tetramethylethylenediamine (hereinafter referred to as “TMEDA”) was added as an additive and reacted for 0.5 hour, the reaction was conducted in the same manner as in Experiment No. 3, Yield was calculated. Specifically, TMP was dissolved in 1M hexane (reaction solvent), 1 equivalent of SD, 1.1 equivalent of isoprene, and 1 equivalent of TMEDA were added and reacted at 25 ° C. for 0.5 hour. The yield of Na-TMP was 79%.
（実験番号５）
反応時間を1時間とした以外は、実験番号４と同様に反応を行い、収率を算出した。詳細には、1Mのヘキサン（反応溶媒）中にTMPを溶解させ、1当量のSD、1.1当量のイソプレン、及び1当量のTMEDAを加え、25℃で1時間反応させた。Na-TMPの収率は88％であった。 (Experiment No. 5)
The reaction was conducted in the same manner as in Experiment No. 4 except that the reaction time was 1 hour, and the yield was calculated. Specifically, TMP was dissolved in 1M hexane (reaction solvent), 1 equivalent of SD, 1.1 equivalent of isoprene, and 1 equivalent of TMEDA were added and reacted at 25 ° C. for 1 hour. The yield of Na-TMP was 88%.
反応時間を1時間とした以外は、実験番号４と同様に反応を行い、収率を算出した。詳細には、1Mのヘキサン（反応溶媒）中にTMPを溶解させ、1当量のSD、1.1当量のイソプレン、及び1当量のTMEDAを加え、25℃で1時間反応させた。Na-TMPの収率は88％であった。 (Experiment No. 5)
The reaction was conducted in the same manner as in Experiment No. 4 except that the reaction time was 1 hour, and the yield was calculated. Specifically, TMP was dissolved in 1M hexane (reaction solvent), 1 equivalent of SD, 1.1 equivalent of isoprene, and 1 equivalent of TMEDA were added and reacted at 25 ° C. for 1 hour. The yield of Na-TMP was 88%.
（実験番号６）
反応時間を12時間とした以外は、実験番号４と同様に反応を行い、収率を算出した。詳細には、1Mのヘキサン（反応溶媒）中にTMPを溶解させ、1当量のSD、1.1当量のイソプレン、及び1当量のTMEDAを加え、25℃で12時間反応させた。Na-TMPの収率は89％であった。 (Experiment No. 6)
The reaction was conducted in the same manner as in Experiment No. 4 except that the reaction time was 12 hours, and the yield was calculated. Specifically, TMP was dissolved in 1M hexane (reaction solvent), 1 equivalent of SD, 1.1 equivalent of isoprene, and 1 equivalent of TMEDA were added and reacted at 25 ° C. for 12 hours. The yield of Na-TMP was 89%.
反応時間を12時間とした以外は、実験番号４と同様に反応を行い、収率を算出した。詳細には、1Mのヘキサン（反応溶媒）中にTMPを溶解させ、1当量のSD、1.1当量のイソプレン、及び1当量のTMEDAを加え、25℃で12時間反応させた。Na-TMPの収率は89％であった。 (Experiment No. 6)
The reaction was conducted in the same manner as in Experiment No. 4 except that the reaction time was 12 hours, and the yield was calculated. Specifically, TMP was dissolved in 1M hexane (reaction solvent), 1 equivalent of SD, 1.1 equivalent of isoprene, and 1 equivalent of TMEDA were added and reacted at 25 ° C. for 12 hours. The yield of Na-TMP was 89%.
（実験番号７）
添加剤として１当量のN,N,N',N'',N''-ペンタメチルジエチレントリアミンを添加し、1時間反応させた以外は実験番号３と同様に反応を行い、収率を算出した。詳細には、1Mのヘキサン（反応溶媒）中にTMPを溶解させ、1当量のSD、1.1当量のイソプレン、及び1当量のN,N,N',N'',N''-ペンタメチルジエチレントリアミンを加え、25℃で1時間反応させた。
Na-TMPの収率は60％であった。 (Experiment number 7)
The reaction was performed in the same manner as in Experiment No. 3 except that 1 equivalent of N, N, N ′, N ″, N ″ -pentamethyldiethylenetriamine was added and allowed to react for 1 hour, and the yield was calculated. . Specifically, TMP is dissolved in 1M hexane (reaction solvent), 1 equivalent of SD, 1.1 equivalents of isoprene, and 1 equivalent of N, N, N ', N'',N''-pentamethyldiethylenetriamine And reacted at 25 ° C. for 1 hour.
The yield of Na-TMP was 60%.
添加剤として１当量のN,N,N',N'',N''-ペンタメチルジエチレントリアミンを添加し、1時間反応させた以外は実験番号３と同様に反応を行い、収率を算出した。詳細には、1Mのヘキサン（反応溶媒）中にTMPを溶解させ、1当量のSD、1.1当量のイソプレン、及び1当量のN,N,N',N'',N''-ペンタメチルジエチレントリアミンを加え、25℃で1時間反応させた。
Na-TMPの収率は60％であった。 (Experiment number 7)
The reaction was performed in the same manner as in Experiment No. 3 except that 1 equivalent of N, N, N ′, N ″, N ″ -pentamethyldiethylenetriamine was added and allowed to react for 1 hour, and the yield was calculated. . Specifically, TMP is dissolved in 1M hexane (reaction solvent), 1 equivalent of SD, 1.1 equivalents of isoprene, and 1 equivalent of N, N, N ', N'',N''-pentamethyldiethylenetriamine And reacted at 25 ° C. for 1 hour.
The yield of Na-TMP was 60%.
（実験番号８）
添加剤として１当量の1,2-ジメトキシエタン（以下、「DME」と称する）を添加した以外は実験番号３と同様に反応を行い、収率を算出した。詳細には、1Mのヘキサン（反応溶媒）中にTMPを溶解させ、1当量のSD、1.1当量のイソプレン、及び1当量のDMEを加え、25℃で12時間反応させた。Na-TMPは痕跡量しか得られなかった。 (Experiment number 8)
The reaction was carried out in the same manner as in Experiment No. 3 except that 1 equivalent of 1,2-dimethoxyethane (hereinafter referred to as “DME”) was added as an additive, and the yield was calculated. Specifically, TMP was dissolved in 1M hexane (reaction solvent), 1 equivalent of SD, 1.1 equivalent of isoprene, and 1 equivalent of DME were added and reacted at 25 ° C. for 12 hours. Only trace amounts of Na-TMP were obtained.
添加剤として１当量の1,2-ジメトキシエタン（以下、「DME」と称する）を添加した以外は実験番号３と同様に反応を行い、収率を算出した。詳細には、1Mのヘキサン（反応溶媒）中にTMPを溶解させ、1当量のSD、1.1当量のイソプレン、及び1当量のDMEを加え、25℃で12時間反応させた。Na-TMPは痕跡量しか得られなかった。 (Experiment number 8)
The reaction was carried out in the same manner as in Experiment No. 3 except that 1 equivalent of 1,2-dimethoxyethane (hereinafter referred to as “DME”) was added as an additive, and the yield was calculated. Specifically, TMP was dissolved in 1M hexane (reaction solvent), 1 equivalent of SD, 1.1 equivalent of isoprene, and 1 equivalent of DME were added and reacted at 25 ° C. for 12 hours. Only trace amounts of Na-TMP were obtained.
図２に、反応スキーム、反応条件及び収率を要約する。添加剤なし、若しくは、添加剤としてアミン類であるTMEDA及びN,N,N',N'',N''-ペンタメチルジエチレントリアミンを添加した場合には、温和な条件でNa-TMPを合成することができることが確認できた。特に、反応溶媒としてヘキサンを用い、添加剤としてアミン類であるTMEDAを添加した場合に、合成反応の加速効果が確認でき、短時間の反応でも高い収率（約90％）でNa-TMPを合成することができることが判明した。N,N,N',N'',N''-ペンタメチルジエチレントリアミンを添加した場合においても、1時間という短時間の反応でNa-TMPを収率よく合成できることが判明した。
Figure 2 summarizes the reaction scheme, reaction conditions and yield. When no additive is added or when TMEDA and N, N, N ', N' ', N' '-pentamethyldiethylenetriamine are added as additives, Na-TMP is synthesized under mild conditions. It was confirmed that it was possible. In particular, when hexane is used as the reaction solvent and TMEDA, which is an amine, is added as an additive, the acceleration effect of the synthesis reaction can be confirmed, and Na-TMP can be obtained in a high yield (about 90%) even in a short reaction time. It has been found that it can be synthesized. Even when N, N, N ′, N ″, N ″ -pentamethyldiethylenetriamine was added, it was found that Na-TMP could be synthesized with a high yield in a short reaction of 1 hour.
実施例２．SDとの反応により得られた芳香環を有する有機ナトリウム化合物を用いたNa-TMPの合成方法における合成条件の検討－１
本実施例では、SDとの反応により得られた芳香環を有する有機ナトリウム化合物を用いたNa-TMPの合成について、反応溶媒、添加物、及び反応時間等の反応条件について検討を行った（図３参照）。 Example 2 Examination of synthesis conditions in the synthesis method of Na-TMP using organic sodium compounds with aromatic rings obtained by reaction with SD-1
In this example, for the synthesis of Na-TMP using an organic sodium compound having an aromatic ring obtained by reaction with SD, the reaction conditions such as reaction solvent, additives, and reaction time were examined (Fig. 3).
本実施例では、SDとの反応により得られた芳香環を有する有機ナトリウム化合物を用いたNa-TMPの合成について、反応溶媒、添加物、及び反応時間等の反応条件について検討を行った（図３参照）。 Example 2 Examination of synthesis conditions in the synthesis method of Na-TMP using organic sodium compounds with aromatic rings obtained by reaction with SD-1
In this example, for the synthesis of Na-TMP using an organic sodium compound having an aromatic ring obtained by reaction with SD, the reaction conditions such as reaction solvent, additives, and reaction time were examined (Fig. 3).
（実験番号１～９）
ヘキサン0.5ml中に、出発化合物である0.5 mmolのハロゲン化ベンゼンとYモル当量のSDを添加し、室温で30分間反応させ、フェニルナトリウムを合成し、合成されたフェニルナトリウムに、1.0モル当量のTMPと室温で30分間反応させ、得られたNa-TMPをフルオレンと反応させ、重水でクエンチし、クエンチ後の生成物を1H NMRで測定することにより行った。実験番号１～４はブロモベンゼンを出発物質とし、SDの添加量はブロモベンゼンに対してそれぞれ2.0、2.1、2.2、2.3モル当量であった。実験番号５～９はクロロベンゼンを出発物質としてSDの添加量はクロロベンゼンに対してそれぞれ1.95、2.0、2.1、2.2、2.3モル当量であった。 (Experiment numbers 1-9)
In 0.5 ml of hexane, 0.5 mmol of benzene as a starting compound and Y molar equivalent of SD were added and reacted at room temperature for 30 minutes to synthesize phenyl sodium, and 1.0 molar equivalent of phenyl sodium was synthesized. This was performed by reacting with TMP at room temperature for 30 minutes, reacting the obtained Na-TMP with fluorene, quenching with heavy water, and measuring the quenched product by 1H NMR. In Experiment Nos. 1 to 4, bromobenzene was used as a starting material, and the amount of SD added was 2.0, 2.1, 2.2, and 2.3 molar equivalents relative to bromobenzene, respectively. In Experiment Nos. 5 to 9, starting from chlorobenzene, the amount of SD added was 1.95, 2.0, 2.1, 2.2, and 2.3 molar equivalents relative to chlorobenzene, respectively.
ヘキサン0.5ml中に、出発化合物である0.5 mmolのハロゲン化ベンゼンとYモル当量のSDを添加し、室温で30分間反応させ、フェニルナトリウムを合成し、合成されたフェニルナトリウムに、1.0モル当量のTMPと室温で30分間反応させ、得られたNa-TMPをフルオレンと反応させ、重水でクエンチし、クエンチ後の生成物を1H NMRで測定することにより行った。実験番号１～４はブロモベンゼンを出発物質とし、SDの添加量はブロモベンゼンに対してそれぞれ2.0、2.1、2.2、2.3モル当量であった。実験番号５～９はクロロベンゼンを出発物質としてSDの添加量はクロロベンゼンに対してそれぞれ1.95、2.0、2.1、2.2、2.3モル当量であった。 (Experiment numbers 1-9)
In 0.5 ml of hexane, 0.5 mmol of benzene as a starting compound and Y molar equivalent of SD were added and reacted at room temperature for 30 minutes to synthesize phenyl sodium, and 1.0 molar equivalent of phenyl sodium was synthesized. This was performed by reacting with TMP at room temperature for 30 minutes, reacting the obtained Na-TMP with fluorene, quenching with heavy water, and measuring the quenched product by 1H NMR. In Experiment Nos. 1 to 4, bromobenzene was used as a starting material, and the amount of SD added was 2.0, 2.1, 2.2, and 2.3 molar equivalents relative to bromobenzene, respectively. In Experiment Nos. 5 to 9, starting from chlorobenzene, the amount of SD added was 1.95, 2.0, 2.1, 2.2, and 2.3 molar equivalents relative to chlorobenzene, respectively.
収率として、反応系に添加したハロゲン化ベンゼンから理論的に生成することができるNa-TMPに対する、実際に取得できたNa-TMPの割合（％）を算出した。また、ハロゲン化ベンゼン同士がカップリングするウルツ反応が誘発されているか否かを評価するため、カップリング生成物（Ph-Ph）の生成を1H NMRで測定し、Ph-Ph生成率（％）を算出した。
As the yield, the ratio (%) of actually obtained Na-TMP to Na-TMP that can theoretically be generated from halogenated benzene added to the reaction system was calculated. In addition, in order to evaluate whether or not the Wurtz reaction that couples halogenated benzenes is induced, the production of the coupling product (Ph-Ph) was measured by 1H-NMR and the Ph-Ph production rate (%) Was calculated.
図３に、反応スキーム、反応条件、塩基の種類、収率を要約する。その結果、出発化合物としてブロモベンゼンを用いた場合にはSDを2.2モル当量以上で反応させると99％以上の高収率でNa-TMPを合成できることが理解できる。また、出発化合物としてクロロベンゼンを用いた場合にはSDを2.1モル当量以上で反応させると99％以上の高収率でNa-TMPを合成できることが理解できる。一方、SDが2.0モル当量未満となると、副反応であるウルツ反応を誘発し、Na-TMPの収率が低下することが判明した。
FIG. 3 summarizes the reaction scheme, reaction conditions, base type, and yield. As a result, when bromobenzene is used as a starting compound, it can be understood that Na-TMP can be synthesized with a high yield of 99% or more by reacting SD with 2.2 molar equivalents or more. In addition, when chlorobenzene is used as a starting compound, it can be understood that Na-TMP can be synthesized with a high yield of 99% or more by reacting SD with 2.1 molar equivalents or more. On the other hand, when the SD was less than 2.0 molar equivalents, it was found that the wurtz reaction, which is a side reaction, was induced and the yield of Na-TMP decreased.
実施例３．Na-TMPの安定性の検討
本実施例では、SDを用いて合成したNa-TMPの安定性を検討した（図４参照）。なお、当量はモル当量である。また、ここで収率とは、実際に取得できたNa-TMP量を、添加したSD量で除し、その割合を百分率で示したものである。 Example 3 Examination of stability of Na-TMP In this example, the stability of Na-TMP synthesized using SD was examined (see FIG. 4). In addition, an equivalent is a molar equivalent. Here, the yield is obtained by dividing the actually obtained amount of Na-TMP by the amount of added SD, and showing the percentage as a percentage.
本実施例では、SDを用いて合成したNa-TMPの安定性を検討した（図４参照）。なお、当量はモル当量である。また、ここで収率とは、実際に取得できたNa-TMP量を、添加したSD量で除し、その割合を百分率で示したものである。 Example 3 Examination of stability of Na-TMP In this example, the stability of Na-TMP synthesized using SD was examined (see FIG. 4). In addition, an equivalent is a molar equivalent. Here, the yield is obtained by dividing the actually obtained amount of Na-TMP by the amount of added SD, and showing the percentage as a percentage.
1Mのヘキサン（反応溶媒）中に1.1当量のTMPを溶解させ、1当量のSD、1.1当量のイソプレン、添加剤として1当量のTMEDAを加え、25℃で0.5、1、3、6、12、又は24時間反応させた（実験番号１～７）。反応後、生成物に1.1当量のフルオレンを添加し25℃で1時間反応させた後、重水でクエンチし得られた重水素化フルオレンを1H-NMRで解析することで生成物を評価し収率を算出した。Na-TMPの収率は、79％（0.5時間）、88％（1時間）、87％（3時間）、86％（6時間）、89％（12時間）、80％（24時間）であった。
Dissolve 1.1 equivalents of TMP in 1M hexane (reaction solvent), add 1 equivalent of SD, 1.1 equivalents of isoprene, 1 equivalent of TMEDA as additive, 0.5, 1, 3, 6, 12, Or it was made to react for 24 hours (experiment number 1-7). After the reaction, 1.1 equivalents of fluorene was added to the product and reacted at 25 ° C for 1 hour, and then the product was evaluated by analyzing the deuterated fluorene obtained by quenching with heavy water by 1H-NMR. Was calculated. Na-TMP yields are 79% (0.5 hours), 88% (1 hour), 87% (3 hours), 86% (6 hours), 89% (12 hours), 80% (24 hours) there were.
図４に、反応スキーム、反応条件及び収率を要約する。SDを用いて合成したNa-TMPは反応時間が長くなっても、収率はほぼ一定であることが確認できた。これにより、Na-TMPは、ヘキサン溶媒中では、活性を保ち安定に存在し得ることが判明した。
Figure 4 summarizes the reaction scheme, reaction conditions and yield. It was confirmed that the yield of Na-TMP synthesized using SD was almost constant even when the reaction time was long. As a result, it has been found that Na-TMP can remain stable and maintain activity in a hexane solvent.
また、ヘキサンを反応溶媒とし、SDとの反応により得られた芳香環を有する有機ナトリウム化合物を用いて合成されたNa-TMPにTHFを添加したときのNa-TMPの安定性を検討した（図５参照）。なお、当量はモル当量である。また、ここで収率とは、反応系に添加したTMPから理論的に生成することができるNa-TMPに対する、実際に取得できたNa-TMPの割合を百分率で示したものである。
In addition, we investigated the stability of Na-TMP when THF was added to Na-TMP synthesized using organic sodium compounds with aromatic rings obtained by reaction with SD using hexane as the reaction solvent (Fig. 5). In addition, an equivalent is a molar equivalent. Here, the yield is the percentage of Na-TMP actually obtained with respect to Na-TMP that can be theoretically generated from TMP added to the reaction system.
0.5 Mのヘキサン（反応溶媒）中に2.2当量のSDを加え、1当量のクロロベンゼンを滴下してフェニルナトリウムを調製した後、TMPを加えて25℃で30分間反応させた。反応後、生成物にTHFを加え0℃（実験番号１～７）又は-20℃（実験番号８～１４）で0、1、3、6、12、18、又は24時間保管し、1.2当量のフルオレンを添加し0℃で1時間反応させた後、重水でクエンチし得られた重水素化フルオレンを1H-NMRで解析することで生成物を評価し収率を算出した。Na-TMPの収率は、0℃で保管した実験系（実験番号１～７）では、98％（0時間）、91%（1時間）、75％（3時間）、63％（6時間）、63％（12時間）、44％（18時間）、38％（24時間）であり、-20℃で保管した実験系（実験番号８～１４）では、98％（0時間）、89%（1時間）、90％（3時間）、84％（6時間）、73％（12時間）、56％（18時間）、51％（24時間）であった。実験結果より、Na-TMPは、THFの存在下では0℃で1時間まで、-20℃で3時間まで安定して存在することを見出した。
After adding 2.2 equivalents of SD in 0.5 M hexane (reaction solvent) and adding 1 equivalent of chlorobenzene dropwise to prepare phenyl sodium, TMP was added and reacted at 25 ° C. for 30 minutes. After the reaction, THF was added to the product and stored at 0 ° C. (experiment number 1-7) or -20 ° C. (experiment number 8-14) for 0, 1, 3, 6, 12, 18, or 24 hours, 1.2 equivalents After adding 1 fluorene and reacting at 0 ° C. for 1 hour, the product was evaluated by analyzing the deuterated fluorene obtained by quenching with heavy water by 1H-NMR, and the yield was calculated. The yield of Na-TMP was 98% (0 hours), 91% (1 hour), 75% (3 hours), 63% (6 hours) in the experimental system (experiment numbers 1-7) stored at 0 ° C. ), 63% (12 hours), 44% (18 hours), 38% (24 hours), and 98% (0 hours), 89 in the experimental system (Experiment Nos. 8 to 14) stored at −20 ° C. % (1 hour), 90% (3 hours), 84% (6 hours), 73% (12 hours), 56% (18 hours), 51% (24 hours). From the experimental results, it was found that Na-TMP was stably present at 0 ° C. for up to 1 hour and at −20 ° C. for up to 3 hours in the presence of THF.
実施例４．SDの経時安定性の検討
本実施例では、SDの品質の経時的変化を評価した（図６参照）。なお、当量はモル当量である。また、ここで収率とは、実際に取得できたNa-TMP量を、添加したSD量で除し、その割合を百分率で示したものである。 Example 4 Examination of Stability of SD over Time In this example, the change in quality of SD over time was evaluated (see FIG. 6). In addition, an equivalent is a molar equivalent. Here, the yield is obtained by dividing the actually obtained amount of Na-TMP by the amount of added SD, and showing the percentage as a percentage.
本実施例では、SDの品質の経時的変化を評価した（図６参照）。なお、当量はモル当量である。また、ここで収率とは、実際に取得できたNa-TMP量を、添加したSD量で除し、その割合を百分率で示したものである。 Example 4 Examination of Stability of SD over Time In this example, the change in quality of SD over time was evaluated (see FIG. 6). In addition, an equivalent is a molar equivalent. Here, the yield is obtained by dividing the actually obtained amount of Na-TMP by the amount of added SD, and showing the percentage as a percentage.
（実験番号１）
1Mのヘキサン（反応溶媒）中に1.1当量のTMPを溶解させ、1当量のSD、1.1当量のイソプレン、及び1当量のTMEDAを加え、25℃で0.5時間反応させた。SDは包装材を開封後4日経過のものを用いた。反応後、生成物に1.1当量のフルオレンを添加し25℃で1時間反応させた後、重水でクエンチし得られた重水素化フルオレンを1H-NMRで解析することで生成物を評価し収率を算出した。Na-TMPの収率は90％であった。 (Experiment number 1)
1.1 equivalents of TMP was dissolved in 1M hexane (reaction solvent), 1 equivalent of SD, 1.1 equivalents of isoprene, and 1 equivalent of TMEDA were added and reacted at 25 ° C. for 0.5 hour. SD used 4 days after opening the packaging. After the reaction, 1.1 equivalents of fluorene was added to the product and reacted at 25 ° C for 1 hour, and then the product was evaluated by analyzing the deuterated fluorene obtained by quenching with heavy water by 1H-NMR. Was calculated. The yield of Na-TMP was 90%.
1Mのヘキサン（反応溶媒）中に1.1当量のTMPを溶解させ、1当量のSD、1.1当量のイソプレン、及び1当量のTMEDAを加え、25℃で0.5時間反応させた。SDは包装材を開封後4日経過のものを用いた。反応後、生成物に1.1当量のフルオレンを添加し25℃で1時間反応させた後、重水でクエンチし得られた重水素化フルオレンを1H-NMRで解析することで生成物を評価し収率を算出した。Na-TMPの収率は90％であった。 (Experiment number 1)
1.1 equivalents of TMP was dissolved in 1M hexane (reaction solvent), 1 equivalent of SD, 1.1 equivalents of isoprene, and 1 equivalent of TMEDA were added and reacted at 25 ° C. for 0.5 hour. SD used 4 days after opening the packaging. After the reaction, 1.1 equivalents of fluorene was added to the product and reacted at 25 ° C for 1 hour, and then the product was evaluated by analyzing the deuterated fluorene obtained by quenching with heavy water by 1H-NMR. Was calculated. The yield of Na-TMP was 90%.
（実験番号２～７）
TMP類と、SD、イソプレン、TMEDAとを、ヘキサン中で1時間、実験番号１と同様に反応させてNa-TMPの収率を算出した。SDは、開封後6日（実験番号２）、8日（実験番号３）、10日（実験番号４）、13日（実験番号５）、30日（実験番号６）、32日（実験番号７）経過のものを用いた。Na-TMPの収率は、89％（実験番号２）、88％（実験番号３）、87％（実験番号４）、82％（実験番号５）、77％（実験番号６）、72％（実験番号７）であった。 (Experiment numbers 2-7)
TMPs were reacted with SD, isoprene, and TMEDA in hexane for 1 hour in the same manner as in Experiment No. 1, and the yield of Na-TMP was calculated. SD is 6 days (experiment number 2), 8 days (experiment number 3), 10 days (experiment number 4), 13 days (experiment number 5), 30 days (experiment number 6), 32 days (experiment number). 7) The past ones were used. The yields of Na-TMP are 89% (experiment number 2), 88% (experiment number 3), 87% (experiment number 4), 82% (experiment number 5), 77% (experiment number 6), 72%. (Experiment No. 7).
TMP類と、SD、イソプレン、TMEDAとを、ヘキサン中で1時間、実験番号１と同様に反応させてNa-TMPの収率を算出した。SDは、開封後6日（実験番号２）、8日（実験番号３）、10日（実験番号４）、13日（実験番号５）、30日（実験番号６）、32日（実験番号７）経過のものを用いた。Na-TMPの収率は、89％（実験番号２）、88％（実験番号３）、87％（実験番号４）、82％（実験番号５）、77％（実験番号６）、72％（実験番号７）であった。 (Experiment numbers 2-7)
TMPs were reacted with SD, isoprene, and TMEDA in hexane for 1 hour in the same manner as in Experiment No. 1, and the yield of Na-TMP was calculated. SD is 6 days (experiment number 2), 8 days (experiment number 3), 10 days (experiment number 4), 13 days (experiment number 5), 30 days (experiment number 6), 32 days (experiment number). 7) The past ones were used. The yields of Na-TMP are 89% (experiment number 2), 88% (experiment number 3), 87% (experiment number 4), 82% (experiment number 5), 77% (experiment number 6), 72%. (Experiment No. 7).
図６に、反応スキーム、反応条件、SDの開封後の経過時間（日齢）、及び収率を要約する。開封後、時間の経過共に、SDの活性が低下し再現性が低下するが、検討期間内においては大幅な低下は確認されなかった。特に開封後10日以内であれば、SDは活性を保持し良好な再現性を示すことが判明した。
FIG. 6 summarizes the reaction scheme, reaction conditions, elapsed time after opening the SD (age), and yield. After opening, the SD activity decreased with time, and the reproducibility decreased. However, no significant decrease was observed within the study period. In particular, within 10 days after opening, it was found that SD retains its activity and exhibits good reproducibility.
実施例５．Na-TMPを用いる反応－１
本実施例では、Na-TMPを用いたウィッティヒ（Wittig）反応について検討した（図７参照）。ウィッティヒ反応は、ウィッティヒ試薬（リンイリド）とアルデヒド（またはケトン）が反応して、アルケンが生じる反応であり、ウィッティヒ試薬はトリフェニルホスフィンとハロゲン化アルキルを反応させることで生成するホスホニウム塩を塩基で処理することで合成することができる。Embodiment 5 FIG. Reaction with Na-TMP-1
In this example, the Wittig reaction using Na-TMP was examined (see FIG. 7). The Wittig reaction is a reaction in which a Wittig reagent (phosphorus ylide) and an aldehyde (or ketone) react to produce an alkene. The Wittig reagent treats the phosphonium salt produced by reacting triphenylphosphine with an alkyl halide with a base. Can be synthesized.
本実施例では、Na-TMPを用いたウィッティヒ（Wittig）反応について検討した（図７参照）。ウィッティヒ反応は、ウィッティヒ試薬（リンイリド）とアルデヒド（またはケトン）が反応して、アルケンが生じる反応であり、ウィッティヒ試薬はトリフェニルホスフィンとハロゲン化アルキルを反応させることで生成するホスホニウム塩を塩基で処理することで合成することができる。
In this example, the Wittig reaction using Na-TMP was examined (see FIG. 7). The Wittig reaction is a reaction in which a Wittig reagent (phosphorus ylide) and an aldehyde (or ketone) react to produce an alkene. The Wittig reagent treats the phosphonium salt produced by reacting triphenylphosphine with an alkyl halide with a base. Can be synthesized.
（実験番号１～３）
実験番号１～３では、塩基として1.25モル当量のLi-TMP（実験番号１）、1.4モル当量のLi-TMP/ NaOtBu（実験番号２）、1.25モル当量のNa-TMP（実験番号３）を用いて、ホスホニウム塩とTHF/ヘキサン中で、0℃で1時間反応させた後、1.25モル当量のアルデヒド化合物と25℃で一晩反応させ、アルケンを生成した。反応後、1H-NMRで解析することで生成物であるアルケンを評価し収率を算出した。更に、GCで、生成したアルケンのシス-トランス異性体の生成率を評価した。Li-TMP、Li-TMP/ NaOtBu、及び、Na-TMPを塩基とした場合の収率は、それぞれ89％、96％、及び、92％であった。また、シス-トランス選択性（E/Z）は、それぞれ18/82、12/88、及び、8/92であった。 (Experiment numbers 1 to 3)
In Experiment Nos. 1 to 3, 1.25 molar equivalents of Li-TMP (Experiment No. 1), 1.4 molar equivalents of Li-TMP / NaO t Bu (Experiment No. 2), and 1.25 molar equivalents of Na-TMP (Experiment No. 3) were used as bases. ) And phosphonium salt in THF / hexane at 0 ° C. for 1 hour, and then reacted with 1.25 molar equivalents of an aldehyde compound at 25 ° C. overnight to produce an alkene. After the reaction, the product was analyzed by 1H-NMR, and the yield was calculated. Furthermore, the production rate of the cis-trans isomer of the produced alkene was evaluated by GC. The yields using Li-TMP, Li-TMP / NaO t Bu, and Na-TMP as a base were 89%, 96%, and 92%, respectively. The cis-trans selectivity (E / Z) was 18/82, 12/88, and 8/92, respectively.
実験番号１～３では、塩基として1.25モル当量のLi-TMP（実験番号１）、1.4モル当量のLi-TMP/ NaOtBu（実験番号２）、1.25モル当量のNa-TMP（実験番号３）を用いて、ホスホニウム塩とTHF/ヘキサン中で、0℃で1時間反応させた後、1.25モル当量のアルデヒド化合物と25℃で一晩反応させ、アルケンを生成した。反応後、1H-NMRで解析することで生成物であるアルケンを評価し収率を算出した。更に、GCで、生成したアルケンのシス-トランス異性体の生成率を評価した。Li-TMP、Li-TMP/ NaOtBu、及び、Na-TMPを塩基とした場合の収率は、それぞれ89％、96％、及び、92％であった。また、シス-トランス選択性（E/Z）は、それぞれ18/82、12/88、及び、8/92であった。 (
In Experiment Nos. 1 to 3, 1.25 molar equivalents of Li-TMP (Experiment No. 1), 1.4 molar equivalents of Li-TMP / NaO t Bu (Experiment No. 2), and 1.25 molar equivalents of Na-TMP (Experiment No. 3) were used as bases. ) And phosphonium salt in THF / hexane at 0 ° C. for 1 hour, and then reacted with 1.25 molar equivalents of an aldehyde compound at 25 ° C. overnight to produce an alkene. After the reaction, the product was analyzed by 1H-NMR, and the yield was calculated. Furthermore, the production rate of the cis-trans isomer of the produced alkene was evaluated by GC. The yields using Li-TMP, Li-TMP / NaO t Bu, and Na-TMP as a base were 89%, 96%, and 92%, respectively. The cis-trans selectivity (E / Z) was 18/82, 12/88, and 8/92, respectively.
図７に、反応スキーム、反応条件、塩基の種類、収率、及びシス-トランス選択性を要約する。その結果、Na-TMPを塩基として用いることで、Liを含む化合物を塩基として用いた場合と同等の収率でアルケンを生成することが確認された。また、Na-TMPを用いることによりシス（Z）体のアルケンの生成率が高く、良好なZ体選択性を示すことが判明した。
FIG. 7 summarizes the reaction scheme, reaction conditions, base type, yield, and cis-trans selectivity. As a result, it was confirmed that by using Na-TMP as a base, an alkene was produced in a yield equivalent to that when a compound containing Li was used as a base. In addition, it was found that by using Na-TMP, the production rate of alkene in cis (Z) form was high and showed good Z form selectivity.
実施例６．Na-TMPを用いる反応－２
本実施例では、Na-TMPを用いたアリル位水素の脱プロトン化を経る異性化反応について検討した（図８参照）。ここでは、1個の二重結合を分子鎖中に有する1-ドデセンを用いて検討を行った。 Example 6 Reaction with Na-TMP-2
In this example, an isomerization reaction through deprotonation of allylic hydrogen using Na-TMP was examined (see FIG. 8). Here, the study was conducted using 1-dodecene having one double bond in the molecular chain.
本実施例では、Na-TMPを用いたアリル位水素の脱プロトン化を経る異性化反応について検討した（図８参照）。ここでは、1個の二重結合を分子鎖中に有する1-ドデセンを用いて検討を行った。 Example 6 Reaction with Na-TMP-2
In this example, an isomerization reaction through deprotonation of allylic hydrogen using Na-TMP was examined (see FIG. 8). Here, the study was conducted using 1-dodecene having one double bond in the molecular chain.
（実験番号１）
1-ドデセンに、塩基としてNa-TMPを反応溶媒中で所定時間反応させて脱プロトン化を行った後、プロトンを付加した。詳細には、1-ドデセンに対して1.25モル当量のNa-TMPをヘキサン溶媒中で0℃にて１時間反応させた後、プロトンを付加した。反応後、1H-NMRで解析することで生成物である1-ドデセン１又は2-ドデセン２を評価しそれぞれの収率を算出した。更にGCで2-ドデセン２についてシス-トランス異性体の生成率を評価した。1-ドデセン１及び2-ドデセン２の収率（シス-トランス選択性）は、それぞれ1％及び98％（E/Z=73/27）であった。 (Experiment number 1)
After 1-dodecene was deprotonated by reacting Na-TMP as a base in a reaction solvent for a predetermined time, a proton was added. Specifically, 1.25 molar equivalents of Na-TMP with respect to 1-dodecene was reacted in a hexane solvent at 0 ° C. for 1 hour, and then a proton was added. After the reaction, the product 1-dodecene 1 or 2-dodecene 2 was evaluated by analyzing by 1H-NMR, and the respective yields were calculated. Furthermore, the formation rate of the cis-trans isomer of 2-dodecene 2 was evaluated by GC. The yields (cis-trans selectivity) of 1-dodecene 1 and 2-dodecene 2 were 1% and 98% (E / Z = 73/27), respectively.
1-ドデセンに、塩基としてNa-TMPを反応溶媒中で所定時間反応させて脱プロトン化を行った後、プロトンを付加した。詳細には、1-ドデセンに対して1.25モル当量のNa-TMPをヘキサン溶媒中で0℃にて１時間反応させた後、プロトンを付加した。反応後、1H-NMRで解析することで生成物である1-ドデセン１又は2-ドデセン２を評価しそれぞれの収率を算出した。更にGCで2-ドデセン２についてシス-トランス異性体の生成率を評価した。1-ドデセン１及び2-ドデセン２の収率（シス-トランス選択性）は、それぞれ1％及び98％（E/Z=73/27）であった。 (Experiment number 1)
After 1-dodecene was deprotonated by reacting Na-TMP as a base in a reaction solvent for a predetermined time, a proton was added. Specifically, 1.25 molar equivalents of Na-TMP with respect to 1-dodecene was reacted in a hexane solvent at 0 ° C. for 1 hour, and then a proton was added. After the reaction, the product 1-
（実験番号２）
反応溶媒としてTHF：ヘキサン=1：2を用いた以外は実験番号１と同様に反応を行い、収率及びシス-トランス選択性を算出した。1-ドデセン１及び2-ドデセン２の収率（シス-トランス選択性）は、それぞれ3％及び90％（E/Z=78/22）であった。 (Experiment number 2)
The reaction was conducted in the same manner as in Experiment No. 1 except that THF: hexane = 1: 2 was used as a reaction solvent, and the yield and cis-trans selectivity were calculated. The yields (cis-trans selectivity) of 1-dodecene 1 and 2-dodecene 2 were 3% and 90% (E / Z = 78/22), respectively.
反応溶媒としてTHF：ヘキサン=1：2を用いた以外は実験番号１と同様に反応を行い、収率及びシス-トランス選択性を算出した。1-ドデセン１及び2-ドデセン２の収率（シス-トランス選択性）は、それぞれ3％及び90％（E/Z=78/22）であった。 (Experiment number 2)
The reaction was conducted in the same manner as in Experiment No. 1 except that THF: hexane = 1: 2 was used as a reaction solvent, and the yield and cis-trans selectivity were calculated. The yields (cis-trans selectivity) of 1-
（実験番号３）
反応温度を25℃とした以外は実験番号１と同様に反応を行い、収率及びシス-トランス選択性を算出した。1-ドデセン１及び2-ドデセン２の収率（シス-トランス選択性）は、それぞれ2％及び91％（E/Z=62/38）であった。 (Experiment No. 3)
The reaction was conducted in the same manner as in Experiment No. 1 except that the reaction temperature was 25 ° C., and the yield and cis-trans selectivity were calculated. The yields (cis-trans selectivity) of 1-dodecene 1 and 2-dodecene 2 were 2% and 91% (E / Z = 62/38), respectively.
反応温度を25℃とした以外は実験番号１と同様に反応を行い、収率及びシス-トランス選択性を算出した。1-ドデセン１及び2-ドデセン２の収率（シス-トランス選択性）は、それぞれ2％及び91％（E/Z=62/38）であった。 (Experiment No. 3)
The reaction was conducted in the same manner as in Experiment No. 1 except that the reaction temperature was 25 ° C., and the yield and cis-trans selectivity were calculated. The yields (cis-trans selectivity) of 1-
（実験番号４）
Na-TMPの添加量を10モル％とし、反応温度を25℃として5時間反応させた以外は実験番号１と同様に反応を行い、収率及びシス-トランス選択性を算出した。1-ドデセン１及び2-ドデセン２の収率（シス-トランス選択性）は、それぞれ1％及び98％（E/Z=73/27）であった。 (Experiment No. 4)
The reaction was carried out in the same manner as in Experiment No. 1 except that the addition amount of Na-TMP was 10 mol%, the reaction temperature was 25 ° C. and the reaction was performed for 5 hours, and the yield and cis-trans selectivity were calculated. The yields (cis-trans selectivity) of 1-dodecene 1 and 2-dodecene 2 were 1% and 98% (E / Z = 73/27), respectively.
Na-TMPの添加量を10モル％とし、反応温度を25℃として5時間反応させた以外は実験番号１と同様に反応を行い、収率及びシス-トランス選択性を算出した。1-ドデセン１及び2-ドデセン２の収率（シス-トランス選択性）は、それぞれ1％及び98％（E/Z=73/27）であった。 (Experiment No. 4)
The reaction was carried out in the same manner as in Experiment No. 1 except that the addition amount of Na-TMP was 10 mol%, the reaction temperature was 25 ° C. and the reaction was performed for 5 hours, and the yield and cis-trans selectivity were calculated. The yields (cis-trans selectivity) of 1-
（実験番号５）
Na-TMPに代え、Li-TMPを添加し、反応温度25℃にてTHF中で反応させた以外は実験番号１と同様に反応を行い、収率及びシス-トランス選択性を算出した。1-ドデセン１及び2-ドデセン２の収率（シス-トランス選択性）は、それぞれ95％及び4％（E/Z=45/55）であった。 (Experiment No. 5)
The reaction was carried out in the same manner as in Experiment No. 1 except that Li-TMP was added instead of Na-TMP and the reaction was conducted in THF at a reaction temperature of 25 ° C., and the yield and cis-trans selectivity were calculated. The yields (cis-trans selectivity) of 1-dodecene 1 and 2-dodecene 2 were 95% and 4% (E / Z = 45/55), respectively.
Na-TMPに代え、Li-TMPを添加し、反応温度25℃にてTHF中で反応させた以外は実験番号１と同様に反応を行い、収率及びシス-トランス選択性を算出した。1-ドデセン１及び2-ドデセン２の収率（シス-トランス選択性）は、それぞれ95％及び4％（E/Z=45/55）であった。 (Experiment No. 5)
The reaction was carried out in the same manner as in Experiment No. 1 except that Li-TMP was added instead of Na-TMP and the reaction was conducted in THF at a reaction temperature of 25 ° C., and the yield and cis-trans selectivity were calculated. The yields (cis-trans selectivity) of 1-
（実験番号６）
Na-TMPに代え、実験番号５と同様にLi-TMPを添加し、反応温度50℃にてTHF中で反応させた以外は実験番号１と同様に反応を行い、収率及びシス-トランス選択性を算出した。1-ドデセン１及び2-ドデセン２の収率（シス-トランス選択性）は、それぞれ59％及び39％（E/Z=47/53）であった。 (Experiment No. 6)
Instead of Na-TMP, Li-TMP was added in the same manner as in Experiment No. 5 and the reaction was conducted in the same manner as in Experiment No. 1 except that the reaction was conducted in THF at a reaction temperature of 50 ° C., yield and cis-trans selection. Sex was calculated. The yields of 1-dodecene 1 and 2-dodecene 2 (cis-trans selectivity) were 59% and 39% (E / Z = 47/53), respectively.
Na-TMPに代え、実験番号５と同様にLi-TMPを添加し、反応温度50℃にてTHF中で反応させた以外は実験番号１と同様に反応を行い、収率及びシス-トランス選択性を算出した。1-ドデセン１及び2-ドデセン２の収率（シス-トランス選択性）は、それぞれ59％及び39％（E/Z=47/53）であった。 (Experiment No. 6)
Instead of Na-TMP, Li-TMP was added in the same manner as in Experiment No. 5 and the reaction was conducted in the same manner as in Experiment No. 1 except that the reaction was conducted in THF at a reaction temperature of 50 ° C., yield and cis-trans selection. Sex was calculated. The yields of 1-
図８に、反応スキーム、反応条件、塩基の種類、収率、及びシス-トランス選択性を要約する。Na-TMPを塩基として用いた場合に、アリル位の水素の脱プロトン化を経て、酸性度の低いプロトンを引き抜くことができることが確認できた。一方、Li-TMPを塩基として用いた場合には、25℃の反応条件下では酸性度の低いプロトンの引き抜きがほとんど生じず2-ドデセンの生成率は非常に低いものであった。50℃の反応条件下においても2-ドデセンの生成率はNa-TMPを用いた場合に比べて非常に低いものであった。
FIG. 8 summarizes the reaction scheme, reaction conditions, base type, yield, and cis-trans selectivity. When Na-TMP was used as the base, it was confirmed that protons with low acidity could be extracted through deprotonation of hydrogen at the allylic position. On the other hand, when Li-TMP was used as the base, proton extraction with low acidity hardly occurred under the reaction conditions of 25 ° C., and the production rate of 2-dodecene was very low. Even under the reaction condition of 50 ° C., the production rate of 2-dodecene was very low compared with the case of using Na-TMP.
実施例７．Na-TMPを用いる反応－３
本実施例では、Na-TMPを用いたヘテロアレーンの脱プロトン化及び官能基化反応について検討した（図９参照）。ここでは、ヘテロアレーンとして、複素環化合物であるジベンゾフランを用いて検討を行った。 Example 7 Reaction with Na-TMP-3
In this example, the deprotonation and functionalization reaction of heteroarene using Na-TMP was examined (see FIG. 9). Here, examination was performed using dibenzofuran which is a heterocyclic compound as a heteroarene.
本実施例では、Na-TMPを用いたヘテロアレーンの脱プロトン化及び官能基化反応について検討した（図９参照）。ここでは、ヘテロアレーンとして、複素環化合物であるジベンゾフランを用いて検討を行った。 Example 7 Reaction with Na-TMP-3
In this example, the deprotonation and functionalization reaction of heteroarene using Na-TMP was examined (see FIG. 9). Here, examination was performed using dibenzofuran which is a heterocyclic compound as a heteroarene.
（実験番号１）
ジベンゾフランに、塩基としてnBuLiをヘキサン溶媒中で所定時間反応させて脱プロトン化を行った。詳細には、0.45モルのベンゾフランに対して1.1モル当量のNa-TMPをヘキサン溶媒中で25℃にて30分間反応させた後、重水でクエンチし得られた重水素化ジベンゾフランを1H-NMRで解析することで生成物を評価し収率を算出した。収率は79％であった。 (Experiment number 1)
The dibenzofuran was deprotonated by reacting n BuLi as a base in a hexane solvent for a predetermined time. Specifically, 1.1 mole equivalent of Na-TMP was reacted with 0.45 mole of benzofuran in hexane solvent at 25 ° C. for 30 minutes, and then deuterated dibenzofuran obtained by quenching with heavy water was analyzed by 1H-NMR. By analyzing the product, the yield was calculated. The yield was 79%.
ジベンゾフランに、塩基としてnBuLiをヘキサン溶媒中で所定時間反応させて脱プロトン化を行った。詳細には、0.45モルのベンゾフランに対して1.1モル当量のNa-TMPをヘキサン溶媒中で25℃にて30分間反応させた後、重水でクエンチし得られた重水素化ジベンゾフランを1H-NMRで解析することで生成物を評価し収率を算出した。収率は79％であった。 (Experiment number 1)
The dibenzofuran was deprotonated by reacting n BuLi as a base in a hexane solvent for a predetermined time. Specifically, 1.1 mole equivalent of Na-TMP was reacted with 0.45 mole of benzofuran in hexane solvent at 25 ° C. for 30 minutes, and then deuterated dibenzofuran obtained by quenching with heavy water was analyzed by 1H-NMR. By analyzing the product, the yield was calculated. The yield was 79%.
（実験番号２）
反応溶媒としてTHF：ヘキサン=1：2を用い0℃で反応させた以外は実験番号１と同様に反応を行い、収率を算出した。収率は85％であった。 (Experiment number 2)
The reaction was conducted in the same manner as in Experiment No. 1 except that THF: hexane = 1: 2 was used as a reaction solvent and the reaction was performed at 0 ° C., and the yield was calculated. The yield was 85%.
反応溶媒としてTHF：ヘキサン=1：2を用い0℃で反応させた以外は実験番号１と同様に反応を行い、収率を算出した。収率は85％であった。 (Experiment number 2)
The reaction was conducted in the same manner as in Experiment No. 1 except that THF: hexane = 1: 2 was used as a reaction solvent and the reaction was performed at 0 ° C., and the yield was calculated. The yield was 85%.
（実験番号３）
nBuLiに代え、Li-TMPを添加した以外は実験番号１と同様に反応を行い、収率を算出した。収率は14％であった。 (Experiment No. 3)
n The reaction was performed in the same manner as in Experiment No. 1 except that Li-TMP was added instead of BuLi, and the yield was calculated. The yield was 14%.
nBuLiに代え、Li-TMPを添加した以外は実験番号１と同様に反応を行い、収率を算出した。収率は14％であった。 (Experiment No. 3)
n The reaction was performed in the same manner as in Experiment No. 1 except that Li-TMP was added instead of BuLi, and the yield was calculated. The yield was 14%.
（実験番号４）
nBuLiに代え、実験番号３と同様にLi-TMPを添加し、反応溶媒としてTHF：ヘキサン=1：2を用い0℃で反応させた以外は実験番号１と同様に反応を行い、収率を算出した。収率は50％であった。 (Experiment No. 4)
n In place of BuLi, Li-TMP was added in the same manner as in Experiment No. 3, and the reaction was performed in the same manner as in Experiment No. 1 except that THF: hexane = 1: 2 was used as the reaction solvent and the reaction was carried out at 0 ° C. Yield Was calculated. The yield was 50%.
nBuLiに代え、実験番号３と同様にLi-TMPを添加し、反応溶媒としてTHF：ヘキサン=1：2を用い0℃で反応させた以外は実験番号１と同様に反応を行い、収率を算出した。収率は50％であった。 (Experiment No. 4)
n In place of BuLi, Li-TMP was added in the same manner as in Experiment No. 3, and the reaction was performed in the same manner as in Experiment No. 1 except that THF: hexane = 1: 2 was used as the reaction solvent and the reaction was carried out at 0 ° C. Yield Was calculated. The yield was 50%.
（実験番号５）
nBuLi に代え、Na-TMPを添加した以外は実験番号１と同様に反応を行い、収率を算出した。収率は90％であった。 (Experiment No. 5)
The reaction was carried out in the same manner as in Experiment No. 1 except that Na-TMP was added instead of n BuLi, and the yield was calculated. The yield was 90%.
nBuLi に代え、Na-TMPを添加した以外は実験番号１と同様に反応を行い、収率を算出した。収率は90％であった。 (Experiment No. 5)
The reaction was carried out in the same manner as in Experiment No. 1 except that Na-TMP was added instead of n BuLi, and the yield was calculated. The yield was 90%.
図９に、反応スキーム、反応条件、塩基の種類、及び、収率を要約する。Na-TMPを塩基として用いることにより、ヘテロアレーンの脱プロトン化を効率よく行うことができることが確認できた。nBuLi及びLi-TMPを用いる場合との比較でも、脱プロトン化の効率が高いことが確認された。
FIG. 9 summarizes the reaction scheme, reaction conditions, base type, and yield. It was confirmed that the deprotonation of the heteroarene can be efficiently performed by using Na-TMP as a base. n It was also confirmed that the deprotonation efficiency is high in comparison with the case of using BuLi and Li-TMP.
求電子剤と反応させた場合に、ヘテロアレーンの置換反応が効率よく進行することも判明した。例えば、求電子剤であるテトラブロモエタンとの反応により1-ブロモジベンゾフランが収率84％で生成した。また、求電子剤である塩化ベンゾイルとの反応により1-ベンゾイルジベンゾフランが収率72％で生成した。更に、求電子剤である臭化アリルとの反応によりアリル基で置換されたジベンゾフランが生成し、具体的には1-ブロモプロペンとの反応により、1-（2-プロペニル）-ジベンゾフランが収率37％で生成した。反応条件の好適化により更に収率の向上が期待され、Na-TMPは、種々の置換反応に用い得ることが判明した。
It was also found that the heteroarene substitution reaction proceeds efficiently when reacted with an electrophile. For example, 1-bromodibenzofuran was produced in a yield of 84% by reaction with tetrabromoethane, an electrophile. Also, 1-benzoyldibenzofuran was produced in a yield of 72% by reaction with benzoyl chloride, which is an electrophile. Furthermore, dibenzofuran substituted with an allyl group is produced by reaction with allyl bromide, which is an electrophile. Specifically, 1- (2-propenyl) -dibenzofuran is obtained by reaction with 1-bromopropene. Produced at 37%. The yield is expected to be further improved by optimizing the reaction conditions, and it has been found that Na-TMP can be used for various substitution reactions.
実施例８．Na-TMPを用いる反応－４
本実施例では、Na-TMPを用いた複素環化合物の官能基化反応について検討した（図１０参照）。 Example 8 FIG. Reaction with Na-TMP-4
In this example, the functionalization reaction of a heterocyclic compound using Na-TMP was examined (see FIG. 10).
本実施例では、Na-TMPを用いた複素環化合物の官能基化反応について検討した（図１０参照）。 Example 8 FIG. Reaction with Na-TMP-4
In this example, the functionalization reaction of a heterocyclic compound using Na-TMP was examined (see FIG. 10).
（実験番号１）
0.4mmolのベンゾ［b］チオフェン（アレーン）に対して、1.25モル当量のNa-TMPを0.5Mのヘキサン溶媒中で室温で1時間反応させた後、1.5モル当量のホウ酸エステル（ホウ酸トリメチル（B(OMe)3）：求電子試薬）を0.2Mのヘキサン溶媒中で0℃にて1時間反応させた。続いて、塩酸を添加し室温で2時間反応させた。1H-NMRで解析することで生成物を評価し、ベンゾ［b］チオフェンの2位にボロニル基（-B(OH)2）が付与されたチオフェンのベンゾ［b］チオフェン-2-ボロン酸の単離収率を算出した。単離収率は、出発原料の量から、反応後に回収された原料の量の差（正味使用した量）で生成物の量を除した値である。単離収率は64％であった。 (Experiment number 1)
After reacting 0.4 mmol of benzo [b] thiophene (arene) with 1.25 molar equivalent of Na-TMP in 0.5 M hexane solvent at room temperature for 1 hour, 1.5 molar equivalent of boric acid ester (trimethyl borate) (B (OMe) 3): electrophile) was reacted in a 0.2 M hexane solvent at 0 ° C. for 1 hour. Subsequently, hydrochloric acid was added and reacted at room temperature for 2 hours. The product was evaluated by analysis with 1H-NMR, and the benzo [b] thiophene-2-boronic acid of thiophene with a boronyl group (-B (OH) 2) attached to the 2-position of benzo [b] thiophene The isolation yield was calculated. The isolated yield is a value obtained by dividing the amount of the product by the difference in the amount of raw material recovered after the reaction (net amount used) from the amount of the starting raw material. The isolation yield was 64%.
0.4mmolのベンゾ［b］チオフェン（アレーン）に対して、1.25モル当量のNa-TMPを0.5Mのヘキサン溶媒中で室温で1時間反応させた後、1.5モル当量のホウ酸エステル（ホウ酸トリメチル（B(OMe)3）：求電子試薬）を0.2Mのヘキサン溶媒中で0℃にて1時間反応させた。続いて、塩酸を添加し室温で2時間反応させた。1H-NMRで解析することで生成物を評価し、ベンゾ［b］チオフェンの2位にボロニル基（-B(OH)2）が付与されたチオフェンのベンゾ［b］チオフェン-2-ボロン酸の単離収率を算出した。単離収率は、出発原料の量から、反応後に回収された原料の量の差（正味使用した量）で生成物の量を除した値である。単離収率は64％であった。 (Experiment number 1)
After reacting 0.4 mmol of benzo [b] thiophene (arene) with 1.25 molar equivalent of Na-TMP in 0.5 M hexane solvent at room temperature for 1 hour, 1.5 molar equivalent of boric acid ester (trimethyl borate) (B (OMe) 3): electrophile) was reacted in a 0.2 M hexane solvent at 0 ° C. for 1 hour. Subsequently, hydrochloric acid was added and reacted at room temperature for 2 hours. The product was evaluated by analysis with 1H-NMR, and the benzo [b] thiophene-2-boronic acid of thiophene with a boronyl group (-B (OH) 2) attached to the 2-position of benzo [b] thiophene The isolation yield was calculated. The isolated yield is a value obtained by dividing the amount of the product by the difference in the amount of raw material recovered after the reaction (net amount used) from the amount of the starting raw material. The isolation yield was 64%.
（実験番号２）
0.4mmolのベンゾ［b］チオフェン（アレーン）に対して、1.25モル当量のNa-TMPを0.5Mのヘキサン溶媒中で25℃で30分間反応させた後、1.5モル当量の重水（D2O：求電子試薬）を添加し0℃にて1時間反応させた。1H-NMRで解析することで生成物を評価し、ベンゾ［b］チオフェンの2位の水素が重水素で置換された重水素化ベンゾ［b］チオフェンの単離収率を実験番号１と同様にして算出した。単離収率は99％であった。 (Experiment number 2)
After reacting 0.4 mmol of benzo [b] thiophene (arene) with 1.25 molar equivalent of Na-TMP in 0.5M hexane solvent at 25 ° C for 30 minutes, 1.5 molar equivalent of heavy water (D2O: electrophilic) Reagent) was added and reacted at 0 ° C. for 1 hour. The product was evaluated by analysis with 1H-NMR, and the isolated yield of deuterated benzo [b] thiophene in which the hydrogen at the 2-position of benzo [b] thiophene was replaced with deuterium was the same as in Experiment No. 1. Was calculated as follows. The isolation yield was 99%.
0.4mmolのベンゾ［b］チオフェン（アレーン）に対して、1.25モル当量のNa-TMPを0.5Mのヘキサン溶媒中で25℃で30分間反応させた後、1.5モル当量の重水（D2O：求電子試薬）を添加し0℃にて1時間反応させた。1H-NMRで解析することで生成物を評価し、ベンゾ［b］チオフェンの2位の水素が重水素で置換された重水素化ベンゾ［b］チオフェンの単離収率を実験番号１と同様にして算出した。単離収率は99％であった。 (Experiment number 2)
After reacting 0.4 mmol of benzo [b] thiophene (arene) with 1.25 molar equivalent of Na-TMP in 0.5M hexane solvent at 25 ° C for 30 minutes, 1.5 molar equivalent of heavy water (D2O: electrophilic) Reagent) was added and reacted at 0 ° C. for 1 hour. The product was evaluated by analysis with 1H-NMR, and the isolated yield of deuterated benzo [b] thiophene in which the hydrogen at the 2-position of benzo [b] thiophene was replaced with deuterium was the same as in Experiment No. 1. Was calculated as follows. The isolation yield was 99%.
（実験番号３）
アレーンとしてベンゾ［b］チオフェン、求電子試薬としてヨードメタン（MeI）を用いて実験番号２と同様にして反応させた後、生成物を評価し、ベンゾ［b］チオフェンの2位にメチル基（-Me）が付与された2-メチル-ベンゾ［b］チオフェンの単離収率を算出した。単離収率は77％であった。 (Experiment No. 3)
After reacting in the same manner as in Experiment No. 2 using benzo [b] thiophene as the arene and iodomethane (MeI) as the electrophile, the product was evaluated, and a methyl group (− The isolated yield of 2-methyl-benzo [b] thiophene with Me) was calculated. The isolation yield was 77%.
アレーンとしてベンゾ［b］チオフェン、求電子試薬としてヨードメタン（MeI）を用いて実験番号２と同様にして反応させた後、生成物を評価し、ベンゾ［b］チオフェンの2位にメチル基（-Me）が付与された2-メチル-ベンゾ［b］チオフェンの単離収率を算出した。単離収率は77％であった。 (Experiment No. 3)
After reacting in the same manner as in Experiment No. 2 using benzo [b] thiophene as the arene and iodomethane (MeI) as the electrophile, the product was evaluated, and a methyl group (− The isolated yield of 2-methyl-benzo [b] thiophene with Me) was calculated. The isolation yield was 77%.
（実験番号４）
アレーンとしてベンゾ［b］チオフェン、求電子試薬としてアリルブロミド（allylBr）を用いて実験番号２と同様にして反応させた後、生成物を評価し、ベンゾ［b］チオフェンの2位にアリル基が付与された2-アリル-ベンゾ［b］チオフェンの単離収率を算出した。単離収率は82％であった。 (Experiment No. 4)
After reacting in the same manner as in Experiment No. 2 using benzo [b] thiophene as the arene and allyl bromide (allylBr) as the electrophile, the product was evaluated and an allyl group was located at the 2-position of the benzo [b] thiophene. The isolated yield of 2-allyl-benzo [b] thiophene provided was calculated. The isolation yield was 82%.
アレーンとしてベンゾ［b］チオフェン、求電子試薬としてアリルブロミド（allylBr）を用いて実験番号２と同様にして反応させた後、生成物を評価し、ベンゾ［b］チオフェンの2位にアリル基が付与された2-アリル-ベンゾ［b］チオフェンの単離収率を算出した。単離収率は82％であった。 (Experiment No. 4)
After reacting in the same manner as in Experiment No. 2 using benzo [b] thiophene as the arene and allyl bromide (allylBr) as the electrophile, the product was evaluated and an allyl group was located at the 2-position of the benzo [b] thiophene. The isolated yield of 2-allyl-benzo [b] thiophene provided was calculated. The isolation yield was 82%.
（実験番号５）
アレーンとしてベンゾ［b］チオフェン、求電子試薬としてベンゾイルクロリド（PhC(O)Cl）を用いて実験番号２と同様にして反応させた後、生成物を評価し、ベンゾ［b］チオフェンの2位にベンゾイル基が付与された2-ベンゾイル-ベンゾ［b］チオフェンの単離収率を算出した。単離収率は66％であった。 (Experiment No. 5)
After reacting in the same manner as in Experiment No. 2 using benzo [b] thiophene as arene and benzoyl chloride (PhC (O) Cl) as the electrophile, the product was evaluated and the 2-position of benzo [b] thiophene The isolated yield of 2-benzoyl-benzo [b] thiophene to which benzoyl group was added was calculated. The isolation yield was 66%.
アレーンとしてベンゾ［b］チオフェン、求電子試薬としてベンゾイルクロリド（PhC(O)Cl）を用いて実験番号２と同様にして反応させた後、生成物を評価し、ベンゾ［b］チオフェンの2位にベンゾイル基が付与された2-ベンゾイル-ベンゾ［b］チオフェンの単離収率を算出した。単離収率は66％であった。 (Experiment No. 5)
After reacting in the same manner as in Experiment No. 2 using benzo [b] thiophene as arene and benzoyl chloride (PhC (O) Cl) as the electrophile, the product was evaluated and the 2-position of benzo [b] thiophene The isolated yield of 2-benzoyl-benzo [b] thiophene to which benzoyl group was added was calculated. The isolation yield was 66%.
（実験番号６）
アレーンとしてベンゾ［b］チオフェン、求電子試薬として二酸化炭素（CO2）を用いて実験番号２と同様にして反応させた後、生成物を評価し、ベンゾ［b］チオフェンの2位にカルボキシ基（-CO2H）が付与されたベンゾ［b］チオフェン-2-カルボン酸の単離収率を算出した。単離収率は89％であった。 (Experiment No. 6)
After reacting in the same manner as in Experiment No. 2 using benzo [b] thiophene as the arene and carbon dioxide (CO2) as the electrophile, the product was evaluated and a carboxy group (positioned at the 2-position of benzo [b] thiophene ( The isolated yield of benzo [b] thiophene-2-carboxylic acid provided with -CO2H) was calculated. The isolation yield was 89%.
アレーンとしてベンゾ［b］チオフェン、求電子試薬として二酸化炭素（CO2）を用いて実験番号２と同様にして反応させた後、生成物を評価し、ベンゾ［b］チオフェンの2位にカルボキシ基（-CO2H）が付与されたベンゾ［b］チオフェン-2-カルボン酸の単離収率を算出した。単離収率は89％であった。 (Experiment No. 6)
After reacting in the same manner as in Experiment No. 2 using benzo [b] thiophene as the arene and carbon dioxide (CO2) as the electrophile, the product was evaluated and a carboxy group (positioned at the 2-position of benzo [b] thiophene ( The isolated yield of benzo [b] thiophene-2-carboxylic acid provided with -CO2H) was calculated. The isolation yield was 89%.
（実験番号７）
アレーンとしてベンゾ［b］チオフェン、求電子試薬として1,1,2,2-テトラブロモエタン（Br2HCCHBr2）を用いた。実験番号２と同様にしてアレーンとNa-TMPとを反応させた後、求電子試薬を添加し-78℃で１時間を反応させ、続いて、生成物を評価し、ベンゾ［b］チオフェンの2位にブロモ基（-Br）が付与された2-ブロモ-ベンゾ［b］チオフェンの単離収率を算出した。単離収率は81％であった。 (Experiment number 7)
Benzo [b] thiophene was used as the arene and 1,1,2,2-tetrabromoethane (Br2HCCHBr2) was used as the electrophile. After reacting arene and Na-TMP in the same manner as in Experiment No. 2, an electrophile was added and reacted at −78 ° C. for 1 hour. Subsequently, the product was evaluated, and benzo [b] thiophene The isolated yield of 2-bromo-benzo [b] thiophene having a bromo group (—Br) attached at the 2-position was calculated. The isolation yield was 81%.
アレーンとしてベンゾ［b］チオフェン、求電子試薬として1,1,2,2-テトラブロモエタン（Br2HCCHBr2）を用いた。実験番号２と同様にしてアレーンとNa-TMPとを反応させた後、求電子試薬を添加し-78℃で１時間を反応させ、続いて、生成物を評価し、ベンゾ［b］チオフェンの2位にブロモ基（-Br）が付与された2-ブロモ-ベンゾ［b］チオフェンの単離収率を算出した。単離収率は81％であった。 (Experiment number 7)
Benzo [b] thiophene was used as the arene and 1,1,2,2-tetrabromoethane (Br2HCCHBr2) was used as the electrophile. After reacting arene and Na-TMP in the same manner as in Experiment No. 2, an electrophile was added and reacted at −78 ° C. for 1 hour. Subsequently, the product was evaluated, and benzo [b] thiophene The isolated yield of 2-bromo-benzo [b] thiophene having a bromo group (—Br) attached at the 2-position was calculated. The isolation yield was 81%.
（実験番号８）
アレーンとしてベンゾ［b］チオフェン、求電子試薬としてヘキサクロロエタン（Cl3CCCl3）を用いた。実験番号２と同様にしてアレーンとNa-TMPと反応させた後、求電子試薬を添加し-78℃で１時間を反応させ、続いて、生成物を評価し、ベンゾ［b］チオフェンの2位にクロロ基（-Cl）が付与された2-クロロ-ベンゾ［b］チオフェンの単離収率を算出した。単離収率は91％であった。 (Experiment number 8)
Benzo [b] thiophene was used as the arene and hexachloroethane (Cl3CCCl3) was used as the electrophile. After reacting arene with Na-TMP in the same manner as in Experiment No. 2, an electrophile was added and reacted at −78 ° C. for 1 hour. Subsequently, the product was evaluated and benzo [b]thiophene 2 The isolated yield of 2-chloro-benzo [b] thiophene with a chloro group (—Cl) attached at the position was calculated. The isolation yield was 91%.
アレーンとしてベンゾ［b］チオフェン、求電子試薬としてヘキサクロロエタン（Cl3CCCl3）を用いた。実験番号２と同様にしてアレーンとNa-TMPと反応させた後、求電子試薬を添加し-78℃で１時間を反応させ、続いて、生成物を評価し、ベンゾ［b］チオフェンの2位にクロロ基（-Cl）が付与された2-クロロ-ベンゾ［b］チオフェンの単離収率を算出した。単離収率は91％であった。 (Experiment number 8)
Benzo [b] thiophene was used as the arene and hexachloroethane (Cl3CCCl3) was used as the electrophile. After reacting arene with Na-TMP in the same manner as in Experiment No. 2, an electrophile was added and reacted at −78 ° C. for 1 hour. Subsequently, the product was evaluated and benzo [b]
（実験番号９）
アレーンとしてベンゾ［b］チオフェン、求電子試薬としてクロロトリメチルシラン（Me3SiCl）を用いて実験番号２と同様にして反応させた後、生成物を評価し、ベンゾ［b］チオフェンの2位にトリメチルシリル基（-SiMe3）が付与された2-トリメチルシリル-ベンゾ［b］チオフェンの単離収率を算出した。単離収率は98％であった。 (Experiment No. 9)
After reacting in the same manner as in Experiment No. 2 using benzo [b] thiophene as arene and chlorotrimethylsilane (Me3SiCl) as the electrophile, the product was evaluated, and a trimethylsilyl group at the 2-position of benzo [b] thiophene The isolated yield of 2-trimethylsilyl-benzo [b] thiophene provided with (-SiMe3) was calculated. The isolation yield was 98%.
アレーンとしてベンゾ［b］チオフェン、求電子試薬としてクロロトリメチルシラン（Me3SiCl）を用いて実験番号２と同様にして反応させた後、生成物を評価し、ベンゾ［b］チオフェンの2位にトリメチルシリル基（-SiMe3）が付与された2-トリメチルシリル-ベンゾ［b］チオフェンの単離収率を算出した。単離収率は98％であった。 (Experiment No. 9)
After reacting in the same manner as in Experiment No. 2 using benzo [b] thiophene as arene and chlorotrimethylsilane (Me3SiCl) as the electrophile, the product was evaluated, and a trimethylsilyl group at the 2-position of benzo [b] thiophene The isolated yield of 2-trimethylsilyl-benzo [b] thiophene provided with (-SiMe3) was calculated. The isolation yield was 98%.
（実験番号１０）
アレーンとしてベンゾ［b］チオフェン、求電子試薬としてクロロジフェニルホスフィン（Ph2PCl）を用いて実験番号２と同様にして反応させた後、生成物を評価し、ベンゾ［b］チオフェンの2位にジフェニルホスフィノ基（-PPh2）が付与された2-ジフェニルホスフィノ-ベンゾ［b］チオフェンの単離収率を算出した。単離収率は72％であった。 (Experiment No. 10)
After reacting in the same manner as in Experiment No. 2 using benzo [b] thiophene as arene and chlorodiphenylphosphine (Ph2PCl) as the electrophile, the product was evaluated and diphenylphosphine was positioned at the 2-position of benzo [b] thiophene. The isolated yield of 2-diphenylphosphino-benzo [b] thiophene provided with a fino group (-PPh2) was calculated. The isolation yield was 72%.
アレーンとしてベンゾ［b］チオフェン、求電子試薬としてクロロジフェニルホスフィン（Ph2PCl）を用いて実験番号２と同様にして反応させた後、生成物を評価し、ベンゾ［b］チオフェンの2位にジフェニルホスフィノ基（-PPh2）が付与された2-ジフェニルホスフィノ-ベンゾ［b］チオフェンの単離収率を算出した。単離収率は72％であった。 (Experiment No. 10)
After reacting in the same manner as in Experiment No. 2 using benzo [b] thiophene as arene and chlorodiphenylphosphine (Ph2PCl) as the electrophile, the product was evaluated and diphenylphosphine was positioned at the 2-position of benzo [b] thiophene. The isolated yield of 2-diphenylphosphino-benzo [b] thiophene provided with a fino group (-PPh2) was calculated. The isolation yield was 72%.
（実施例１１）
アレーンとしてベンゾ［b］フラン、求電子試薬としてクロロトリメチルシラン（Me3SiCl）を用いて実験番号２と同様にして反応させた後、生成物を評価し、ベンゾ［b］フランの2位にトリメチルシリル基（-SiMe3）が付与された2-トリメチルシリル-ベンゾ［b］フランの単離収率を算出した。単離収率は82％であった。 (Example 11)
After reacting in the same manner as in Experiment No. 2 using benzo [b] furan as arene and chlorotrimethylsilane (Me3SiCl) as the electrophile, the product was evaluated, and a trimethylsilyl group at the 2-position of benzo [b] furan The isolated yield of 2-trimethylsilyl-benzo [b] furan provided with (-SiMe3) was calculated. The isolation yield was 82%.
アレーンとしてベンゾ［b］フラン、求電子試薬としてクロロトリメチルシラン（Me3SiCl）を用いて実験番号２と同様にして反応させた後、生成物を評価し、ベンゾ［b］フランの2位にトリメチルシリル基（-SiMe3）が付与された2-トリメチルシリル-ベンゾ［b］フランの単離収率を算出した。単離収率は82％であった。 (Example 11)
After reacting in the same manner as in Experiment No. 2 using benzo [b] furan as arene and chlorotrimethylsilane (Me3SiCl) as the electrophile, the product was evaluated, and a trimethylsilyl group at the 2-position of benzo [b] furan The isolated yield of 2-trimethylsilyl-benzo [b] furan provided with (-SiMe3) was calculated. The isolation yield was 82%.
（実施例１２）
アレーンとしてジベンゾフラン、求電子試薬としてクロロトリメチルシラン（Me3SiCl）を用いて実験番号２と同様にして反応させた後、生成物を評価し、ジベンゾフランの4位にトリメチルシリル基（-SiMe3）が付与された4-トリメチルシリル-ジベンゾフランの単離収率を算出した。単離収率は83％であった。 (Example 12)
After reacting in the same manner as in Experiment No. 2 using dibenzofuran as arene and chlorotrimethylsilane (Me3SiCl) as the electrophile, the product was evaluated and a trimethylsilyl group (-SiMe3) was added to the 4-position of dibenzofuran. The isolated yield of 4-trimethylsilyl-dibenzofuran was calculated. The isolation yield was 83%.
アレーンとしてジベンゾフラン、求電子試薬としてクロロトリメチルシラン（Me3SiCl）を用いて実験番号２と同様にして反応させた後、生成物を評価し、ジベンゾフランの4位にトリメチルシリル基（-SiMe3）が付与された4-トリメチルシリル-ジベンゾフランの単離収率を算出した。単離収率は83％であった。 (Example 12)
After reacting in the same manner as in Experiment No. 2 using dibenzofuran as arene and chlorotrimethylsilane (Me3SiCl) as the electrophile, the product was evaluated and a trimethylsilyl group (-SiMe3) was added to the 4-position of dibenzofuran. The isolated yield of 4-trimethylsilyl-dibenzofuran was calculated. The isolation yield was 83%.
（実施例１３）
アレーンとしてジベンゾフラン、求電子試薬としてベンゾイルクロリド（PhC(O)Cl）を用いて実験番号２と同様にして反応させた後、生成物を評価し、ジベンゾフランの4位にベンゾイル基が付与された4-ベンゾイル-ジベンゾフランの単離収率を算出した。単離収率は73％であった。 (Example 13)
After reacting in the same manner as in Experiment No. 2 using dibenzofuran as arene and benzoyl chloride (PhC (O) Cl) as the electrophile, the product was evaluated and a benzoyl group was added to the 4-position ofdibenzofuran 4 The isolated yield of -benzoyl-dibenzofuran was calculated. The isolation yield was 73%.
アレーンとしてジベンゾフラン、求電子試薬としてベンゾイルクロリド（PhC(O)Cl）を用いて実験番号２と同様にして反応させた後、生成物を評価し、ジベンゾフランの4位にベンゾイル基が付与された4-ベンゾイル-ジベンゾフランの単離収率を算出した。単離収率は73％であった。 (Example 13)
After reacting in the same manner as in Experiment No. 2 using dibenzofuran as arene and benzoyl chloride (PhC (O) Cl) as the electrophile, the product was evaluated and a benzoyl group was added to the 4-position of
図１０に、反応スキーム、反応条件、及び、単離収率を要約する。Na-TMPを塩基として用いることにより、ベンゾチオフェンからのボロン酸の合成できる等、複素環化合物に置換基付与できることが確認できた。このようにNa-TMPを用いることで、温和な条件下で短時間に複素環化合物に置換基を付与することができ、ボロン酸等の種々の化合物を合成できるとの利点を有する。
FIG. 10 summarizes the reaction scheme, reaction conditions, and isolated yield. It was confirmed that by using Na-TMP as a base, it was possible to give a substituent to the heterocyclic compound, such as synthesis of boronic acid from benzothiophene. Thus, by using Na-TMP, it is possible to give a substituent to a heterocyclic compound in a short time under mild conditions, and there is an advantage that various compounds such as boronic acid can be synthesized.
本発明は、Na-TMP類の合成方法、及びかかる合成方法により得られるNa-TMP類を利用する全ての技術分野、特には、医薬、動物薬や農薬等の有機合成のために利用することができる。
The present invention is a method for synthesizing Na-TMPs, and all technical fields using Na-TMPs obtained by such a synthesis method, in particular, for organic synthesis of drugs, animal drugs, agricultural chemicals and the like. Can do.
The present invention is a method for synthesizing Na-TMPs, and all technical fields using Na-TMPs obtained by such a synthesis method, in particular, for organic synthesis of drugs, animal drugs, agricultural chemicals and the like. Can do.
Claims (2)
- ナトリウム2,2,6,6-テトラメチルピペリジド類の合成方法であって、
2,2,6,6-テトラメチルピペリジン類と、ナトリウムを分散溶媒に分散させた分散体、又はナトリウムを分散溶媒に分散させた分散体との反応により得られた芳香環を有する有機ナトリウム化合物とを反応溶媒中で反応させて、ナトリウム2,2,6,6-テトラメチルピペリジド類を得る工程を有する、ナトリウム2,2,6,6-テトラメチルピペリジド類の合成方法。 A method for synthesizing sodium 2,2,6,6-tetramethylpiperidides, comprising:
Organic sodium compound having an aromatic ring obtained by reaction of 2,2,6,6-tetramethylpiperidines with a dispersion in which sodium is dispersed in a dispersion solvent or a dispersion in which sodium is dispersed in a dispersion solvent And 2, in a reaction solvent, to obtain sodium 2,2,6,6-tetramethylpiperidide, a method for synthesizing sodium 2,2,6,6-tetramethylpiperidide. - 前記工程が、アミン類の存在下で行われる請求項１に記載のナトリウム2,2,6,6-テトラメチルピペリジド類の合成方法。
The method for synthesizing sodium 2,2,6,6-tetramethylpiperidide according to claim 1, wherein the step is performed in the presence of an amine.
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| EP18744965.7A EP3575306A4 (en) | 2017-01-27 | 2018-01-24 | Method for synthesizing sodium 2,2,6,6-tetramethylpiperidide compound |
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