JP4381221B2 - Bactericidal pyridine compound - Google Patents
Bactericidal pyridine compound Download PDFInfo
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- JP4381221B2 JP4381221B2 JP2004142788A JP2004142788A JP4381221B2 JP 4381221 B2 JP4381221 B2 JP 4381221B2 JP 2004142788 A JP2004142788 A JP 2004142788A JP 2004142788 A JP2004142788 A JP 2004142788A JP 4381221 B2 JP4381221 B2 JP 4381221B2
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- butoxide
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- -1 pyridine compound Chemical class 0.000 title claims description 69
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 title claims description 59
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 title claims description 56
- 230000000844 anti-bacterial effect Effects 0.000 title claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 198
- 150000001875 compounds Chemical class 0.000 description 192
- 238000006243 chemical reaction Methods 0.000 description 71
- 238000004128 high performance liquid chromatography Methods 0.000 description 64
- WERYXYBDKMZEQL-UHFFFAOYSA-N butane-1,4-diol Chemical compound OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 description 62
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 61
- 239000011541 reaction mixture Substances 0.000 description 58
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- 239000000243 solution Substances 0.000 description 39
- 239000002904 solvent Substances 0.000 description 37
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- 239000013078 crystal Substances 0.000 description 35
- UZGLOGCJCWBBIV-UHFFFAOYSA-N 3-(chloromethyl)pyridin-1-ium;chloride Chemical compound Cl.ClCC1=CC=CN=C1 UZGLOGCJCWBBIV-UHFFFAOYSA-N 0.000 description 34
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 32
- CNQCWYFDIQSALX-UHFFFAOYSA-N 3-(chloromethyl)pyridine Chemical compound ClCC1=CC=CN=C1 CNQCWYFDIQSALX-UHFFFAOYSA-N 0.000 description 28
- 230000015572 biosynthetic process Effects 0.000 description 25
- 238000003786 synthesis reaction Methods 0.000 description 25
- 239000000203 mixture Substances 0.000 description 24
- 239000002002 slurry Substances 0.000 description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 23
- 239000002585 base Substances 0.000 description 22
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical group [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 20
- VMKOFRJSULQZRM-UHFFFAOYSA-N 1-bromooctane Chemical compound CCCCCCCCBr VMKOFRJSULQZRM-UHFFFAOYSA-N 0.000 description 19
- 239000007788 liquid Substances 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- 150000003839 salts Chemical class 0.000 description 18
- 239000000706 filtrate Substances 0.000 description 16
- 239000002994 raw material Substances 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 238000007792 addition Methods 0.000 description 14
- 238000001816 cooling Methods 0.000 description 13
- 238000000746 purification Methods 0.000 description 13
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- 239000007787 solid Substances 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 241000894006 Bacteria Species 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- ZDHKVKPZQKYREU-UHFFFAOYSA-N 4-(chloromethyl)pyridine;hydron;chloride Chemical group Cl.ClCC1=CC=NC=C1 ZDHKVKPZQKYREU-UHFFFAOYSA-N 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 239000012043 crude product Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- WZIYCIBURCPKAR-UHFFFAOYSA-N 4-(chloromethyl)pyridine Chemical compound ClCC1=CC=NC=C1 WZIYCIBURCPKAR-UHFFFAOYSA-N 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 230000008034 disappearance Effects 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 229910052783 alkali metal Inorganic materials 0.000 description 4
- 150000004703 alkoxides Chemical class 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- 239000011591 potassium Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- 241000233866 Fungi Species 0.000 description 3
- 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 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 3
- 125000004450 alkenylene group Chemical group 0.000 description 3
- 150000001450 anions Chemical class 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- ZENUHLSFOIKZKR-UHFFFAOYSA-N butane-1,4-diol;potassium Chemical class [K].OCCCCO ZENUHLSFOIKZKR-UHFFFAOYSA-N 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- VFNGKCDDZUSWLR-UHFFFAOYSA-N disulfuric acid Chemical class OS(=O)(=O)OS(O)(=O)=O VFNGKCDDZUSWLR-UHFFFAOYSA-N 0.000 description 3
- 230000003472 neutralizing effect Effects 0.000 description 3
- 239000002798 polar solvent Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- CZNUDDDMWNMMHL-UHFFFAOYSA-N (2-methylpyridin-3-yl) methanesulfonate Chemical compound CS(=O)(=O)OC=1C(=NC=CC1)C CZNUDDDMWNMMHL-UHFFFAOYSA-N 0.000 description 2
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- 241000206601 Carnobacterium mobile Species 0.000 description 2
- 241000192125 Firmicutes Species 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- XLUXHEZIGIDTCC-UHFFFAOYSA-N acetonitrile;ethyl acetate Chemical compound CC#N.CCOC(C)=O XLUXHEZIGIDTCC-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000003385 bacteriostatic effect Effects 0.000 description 2
- 229940077388 benzenesulfonate Drugs 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 2
- 238000002815 broth microdilution Methods 0.000 description 2
- CDQSJQSWAWPGKG-UHFFFAOYSA-N butane-1,1-diol Chemical compound CCCC(O)O CDQSJQSWAWPGKG-UHFFFAOYSA-N 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 2
- 238000013341 scale-up Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- WJCNZQLZVWNLKY-UHFFFAOYSA-N thiabendazole Chemical compound S1C=NC(C=2NC3=CC=CC=C3N=2)=C1 WJCNZQLZVWNLKY-UHFFFAOYSA-N 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- DWPIJVZSEIHYDR-UHFFFAOYSA-N (2-methylpyridin-3-yl) benzenesulfonate Chemical compound CC1=NC=CC=C1OS(=O)(=O)C1=CC=CC=C1 DWPIJVZSEIHYDR-UHFFFAOYSA-N 0.000 description 1
- JPMRGPPMXHGKRO-UHFFFAOYSA-N 2-(chloromethyl)pyridine hydrochloride Chemical compound Cl.ClCC1=CC=CC=N1 JPMRGPPMXHGKRO-UHFFFAOYSA-N 0.000 description 1
- KHCXGFNZZRXOND-UHFFFAOYSA-N 3-(bromomethyl)pyridine Chemical compound BrCC1=CC=CN=C1 KHCXGFNZZRXOND-UHFFFAOYSA-N 0.000 description 1
- UGLQALFLQMRSEC-UHFFFAOYSA-N 3-(iodomethyl)pyridine Chemical compound ICC1=CC=CN=C1 UGLQALFLQMRSEC-UHFFFAOYSA-N 0.000 description 1
- KRLKXOLFFQWKPZ-UHFFFAOYSA-N 4-(bromomethyl)pyridine Chemical compound BrCC1=CC=NC=C1 KRLKXOLFFQWKPZ-UHFFFAOYSA-N 0.000 description 1
- KQLHSXTTZXUVCW-UHFFFAOYSA-N 4-(iodomethyl)pyridine Chemical compound ICC1=CC=NC=C1 KQLHSXTTZXUVCW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- RHASWOUYVSBVAX-UHFFFAOYSA-N C1(=CC=CC=C1)S(=O)(=O)OC1=CC(=NC=C1)C Chemical compound C1(=CC=CC=C1)S(=O)(=O)OC1=CC(=NC=C1)C RHASWOUYVSBVAX-UHFFFAOYSA-N 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 229960001716 benzalkonium Drugs 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- JYIXVXDKNYJFIP-UHFFFAOYSA-N benzenesulfonic acid;3-(chloromethyl)pyridine Chemical compound ClCC1=CC=CN=C1.OS(=O)(=O)C1=CC=CC=C1 JYIXVXDKNYJFIP-UHFFFAOYSA-N 0.000 description 1
- CYDRXTMLKJDRQH-UHFFFAOYSA-N benzododecinium Chemical compound CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 CYDRXTMLKJDRQH-UHFFFAOYSA-N 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 238000006065 biodegradation reaction Methods 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- FITWXPZPWVWGJP-UHFFFAOYSA-N butane-1,4-diol;sodium Chemical compound [Na].OCCCCO FITWXPZPWVWGJP-UHFFFAOYSA-N 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 230000002900 effect on cell Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
Description
本発明は、殺菌性を有する新規なピリジン化合物に関する。 The present invention relates to a novel pyridine compound having bactericidal properties.
細菌や真菌などに抗菌活性を発揮するビス第四級アンモニウム塩化合物は古くから知られており、現在も抗菌剤として広く実用化されている。しかしながら、現在用いられている抗菌性のビス第四級アンモニウム塩化合物は、通常、抗菌活性は優れているが、同時に生分解生成物の残留毒性も高いため、実際の使用に関しては、環境に対する安全性と水に対する溶解性および安定性に問題があり、その適用範囲には制限があった。また、従来のビス第四級アンモニウム塩化合物は、抗菌力が糖質、蛋白質および脂質などに拮抗され、抗菌力がｐＨの低い（酸性）領域では低下し、かつ細胞芽胞に効果がないなどの欠点があった。 Bis quaternary ammonium salt compounds that exhibit antibacterial activity against bacteria and fungi have been known for a long time and are still widely used as antibacterial agents. However, currently used antibacterial bis-quaternary ammonium salt compounds are usually excellent in antibacterial activity, but at the same time, the residual toxicity of biodegradation products is also high. There was a problem in the solubility and solubility in water and stability, and the application range was limited. In addition, conventional bis quaternary ammonium salt compounds have antibacterial activity antagonized by carbohydrates, proteins, lipids, etc., and the antibacterial activity decreases in the low pH (acidic) region and has no effect on cell spores. There were drawbacks.
そこで、下記一般式（Ａ）および（Ｂ）で表されるビス第四級アンモニウム塩化合物（特許文献１参照）や、
下記一般式（Ｃ）で表されるビス第四級アンモニウム塩化合物（特許文献２参照）、
下記一般式（Ｄ）で表されるビス第四級アンモニウム塩化合物（特許文献３参照）が報告されている。
上記の従来公知のビス第四級アンモニウム塩化合物よりも抗菌活性に極めて優れ、かつ生分解後の化合物は、残留毒性が少なく、地球環境に優しいビス第四級アンモニウム塩化合物の開発が強く望まれている。
従って本発明の目的は、入手の容易なピリジン化合物を出発原料として、簡便、かつ安価に新規な殺菌性ピリジン化合物を提供することにある。
Development of a bis-quaternary ammonium salt compound that is extremely superior in antibacterial activity than the above-mentioned conventionally known bis-quaternary ammonium salt compounds and has little residual toxicity and is friendly to the global environment is strongly desired. ing.
Accordingly, an object of the present invention is to provide a novel bactericidal pyridine compound conveniently and inexpensively using a readily available pyridine compound as a starting material.
本発明は、下記一般式（１）または一般式（２）で表わされることを特徴とする殺菌性ピリジン化合物を提供する。
本発明によれば、入手の容易なピリジン化合物を出発原料として、簡便、かつ安価に新規な殺菌性ピリジン化合物を提供することができる。 According to the present invention, a novel bactericidal pyridine compound can be provided simply and inexpensively using a readily available pyridine compound as a starting material.
次に好ましい実施の形態を挙げて本発明をさらに詳しく説明する。
前記本発明の一般式（１）または一般式（２）で表わされる化合物は種々の方法で合成することができるが、１例を挙げれば、下記の通りである。すなわち、３−クロロメチルピリジン、４−クロロメチルピリジン、３−ブロモメチルピリジン、４−ブロモメチルピリジン、３−ヨードメチルピリジン、４−ヨードメチルピリジン、３−（メタンスルホニルオキシ）メチルピリジン、４−（メタンスルホニルオキシ）メチルピリジン、３−（ベンゼンスルホニルオキシ）メチルピリジン、４−（ベンゼンスルホニルオキシ）メチルピリジンまたはそれらの塩（以下「原料ピリジン化合物」という）と１，４−ブタンジオールとを反応させることにより、下記一般式（３）のピリジン化合物を合成する。該反応時においては、１，４−ブタンジオールに対して、原料ピリジン化合物の使用量は１当量モルから１．５当量モルが好ましく、１当量モルから１．１当量モルがさらに好ましい。
The compound represented by the general formula (1) or the general formula (2) of the present invention can be synthesized by various methods, and one example is as follows. That is, 3-chloromethylpyridine, 4-chloromethylpyridine, 3-bromomethylpyridine, 4-bromomethylpyridine, 3-iodomethylpyridine, 4-iodomethylpyridine, 3- (methanesulfonyloxy) methylpyridine, 4- Reaction of (methanesulfonyloxy) methylpyridine, 3- (benzenesulfonyloxy) methylpyridine, 4- (benzenesulfonyloxy) methylpyridine or a salt thereof (hereinafter referred to as “raw pyridine compound”) with 1,4-butanediol By doing so, a pyridine compound of the following general formula (3) is synthesized. In the reaction, the amount of the raw material pyridine compound used relative to 1,4-butanediol is preferably 1 equivalent mole to 1.5 equivalent mole, and more preferably 1 equivalent mole to 1.1 equivalent mole.
原料ピリジン化合物と１，４−ブタンジオールとの反応により一般式（３）で表されるピリジン化合物を製する際には、種々の反応条件が可能である。本反応の実施には強塩基の存在が必須であり、これは１，４−ブタンジオールから対応するアルコキシドを生成することが重要だからである。本反応に使用できる強塩基としては、金属リチウム、金属カリウム、金属ナトリウムおよびその水素化物、メチルリチウム、ブチルリチウムなどのアルキルリチウム類、フェニルリチウム、リチウムターシャリブトキサイド、カリウムターシャリブトキサイド、ナトリウムターシャリブトキサイドなどの第３級アルカリ金属アルコキサイドが挙げられ、経済性、安全性および簡便性から、ナトリウムターシャリブトキサイドおよびカリウムターシャリブトキサイドが好適である。これらの強塩基は単独で用いても、２種以上組み合わせて用いても差し支えない。 When producing the pyridine compound represented by General formula (3) by reaction with a raw material pyridine compound and 1, 4- butanediol, various reaction conditions are possible. The presence of a strong base is essential for carrying out this reaction because it is important to produce the corresponding alkoxide from 1,4-butanediol. Strong bases that can be used in this reaction include metallic lithium, metallic potassium, metallic sodium and hydrides thereof, alkyllithiums such as methyllithium and butyllithium, phenyllithium, lithium tertiary riboxide, potassium tertiary riboxide, sodium Tertiary alkali metal alkoxides such as tartaribtoxide are mentioned, and sodium tartariboxide and potassium tartariboxide are preferred from the viewpoint of economy, safety and simplicity. These strong bases may be used alone or in combination of two or more.
本反応においては、原料ピリジン化合物の遊離塩基を原料として使用する場合、使用する強塩基は約１当量モルである。さらに、原料ピリジン化合物が塩を形成している場合は、使用する強塩基は、塩を中和するに足る約１当量モルと所望の反応に消費される約１当量モルを合した約２当量モルである。但し、転化率が低い場合は、原料ピリジン化合物が消失するまで、強塩基を追加しても差し支えない。塩を中和する際に使用する強塩基と、所望の反応に使用する強塩基は、同一でも異なっていても差し支えない。本反応の実施にあたっては、原料ピリジン化合物が強塩基との接触によって変化しやすいため、予め、１，４−ブタンジオールと強塩基との反応によりアルコキシドを生成させ、該アルコキシドと原料ピリジン化合物を処理するか、原料ピリジン化合物と１，４−ブタンジオールとを予め混合しておき、次いで、混合物中に強塩基を添加することが好ましい。原料ピリジン化合物が塩を形成している場合は、該化合物を遊離化させ得る量の強塩基を事前に添加し、前述の手順で処理することが可能である。 In this reaction, when the free base of the starting pyridine compound is used as the starting material, the strong base used is about 1 equivalent mole. Further, when the raw pyridine compound forms a salt, the strong base used is about 2 equivalents, which is about 1 equivalent moles sufficient to neutralize the salt and about 1 equivalent moles consumed for the desired reaction. Is a mole. However, if the conversion rate is low, a strong base may be added until the starting pyridine compound disappears. The strong base used for neutralizing the salt and the strong base used for the desired reaction may be the same or different. In carrying out this reaction, since the starting pyridine compound is likely to change due to contact with a strong base, an alkoxide is generated in advance by a reaction between 1,4-butanediol and a strong base, and the alkoxide and the starting pyridine compound are treated. Alternatively, it is preferable that the raw material pyridine compound and 1,4-butanediol are mixed in advance, and then a strong base is added to the mixture. When the raw material pyridine compound forms a salt, it is possible to add in advance an amount of a strong base capable of liberating the compound, and to perform the treatment in the above-described procedure.
本反応は、通常、種々の溶媒の存在下に実施できるが、所望の反応に悪影響を及ぼさず、かつ、所望の反応において良好な転化率および選択率を与える溶媒としては、非プロトン性極性溶媒の使用が好ましい。非プロトン性極性溶媒としては、テトラヒドロフラン、ジオキサンなどの環状エーテル系溶媒、ジメチルホルムアミド、Ｎ−メチルピロリドン、ジメチルイミダゾリジノンなどのアミド系溶媒などが好適に使用されるが、経済性、後処理の簡便さなどを考慮すると、ジメチルホルムアミドが最も好適な溶媒である。これらの溶媒は、単独で用いても、２種以上を混合して用いても差し支えない。溶媒の使用量は、原料ピリジン化合物の溶解度および１，４−ブタンジオールの溶解度および反応中に生成するアルカリ金属塩の分散様態を加味して、適宜選択できる。 This reaction can usually be carried out in the presence of various solvents, but as a solvent that does not adversely affect the desired reaction and gives good conversion and selectivity in the desired reaction, an aprotic polar solvent Is preferred. As the aprotic polar solvent, cyclic ether solvents such as tetrahydrofuran and dioxane, amide solvents such as dimethylformamide, N-methylpyrrolidone, and dimethylimidazolidinone are preferably used. Considering simplicity, dimethylformamide is the most suitable solvent. These solvents may be used alone or in combination of two or more. The amount of the solvent used can be appropriately selected in consideration of the solubility of the starting pyridine compound, the solubility of 1,4-butanediol, and the dispersion state of the alkali metal salt produced during the reaction.
本反応の温度は、−２０℃から使用する溶媒の常圧における沸点までを選択できる。好ましい反応温度は、−２０℃から室温であり、さらに好ましい反応温度は、−１０℃から１０℃である。反応の進行は、薄層クロマトグラフィーや高速液体クロマトグラフィーなどで追跡でき、原料の消失をもって反応の終了を確認できる。 The temperature of this reaction can be selected from −20 ° C. to the boiling point of the solvent used at normal pressure. A preferable reaction temperature is −20 ° C. to room temperature, and a more preferable reaction temperature is −10 ° C. to 10 ° C. The progress of the reaction can be traced by thin layer chromatography or high performance liquid chromatography, and the completion of the reaction can be confirmed by disappearance of the raw material.
本反応によって得られた、一般式（３）で表されるピリジン化合物は常法により、反応混合物から取り出すことができる。例えば、反応終了後の混合物を固液分離することにより生成したアルカリ金属塩を取り除き、母液を減圧下に濃縮した後、残液を水に分散後に抽出し、抽出液を減圧濃縮すればよい。より高純度の化合物は、一般式（３）で表されるピリジン化合物の塩酸塩、酢酸塩、硫酸塩などの無機もしくは有機酸の塩を生成させ、必要により、それらの再結晶を行った後に塩を中和し、常法で処理することで得ることができる。 The pyridine compound represented by the general formula (3) obtained by this reaction can be removed from the reaction mixture by a conventional method. For example, the alkali metal salt generated by solid-liquid separation of the mixture after completion of the reaction is removed, the mother liquor is concentrated under reduced pressure, the residual liquid is extracted after dispersion in water, and the extract is concentrated under reduced pressure. Higher purity compounds are produced by generating salts of inorganic or organic acids such as hydrochlorides, acetates and sulfates of pyridine compounds represented by the general formula (3), and if necessary after recrystallization thereof. It can be obtained by neutralizing the salt and treating it in a conventional manner.
次いで、一般式（３）で表されるピリジン化合物を、前記と同じ原料ピリジン化合物と強塩基の存在下に反応させることにより、下記一般式（４）で表されるピリジン化合物を製することができる。
一般式（４）で表されるピリジン化合物は、前記一般式（３）で表される化合物を単離することなく製造することも可能である。例えば、前述のような操作で一般式（３）で表されるピリジン化合物を反応系に生成させ、次いで、強塩基の存在下に原料ピリジン化合物を作用させればよい。一般式（３）で表されるピリジン化合物もしくはその塩の使用量は、原料ピリジン化合物に対して、１〜１．５当量の使用が好ましく、さらに、１〜１．１当量の使用が好ましい。 The pyridine compound represented by the general formula (4) can also be produced without isolating the compound represented by the general formula (3). For example, the pyridine compound represented by the general formula (3) is generated in the reaction system by the above-described operation, and then the raw material pyridine compound is allowed to act in the presence of a strong base. As for the usage-amount of the pyridine compound represented by General formula (3) or its salt, use of 1-1.5 equivalent is preferable with respect to a raw material pyridine compound, Furthermore, use of 1-1.1 equivalent is preferable.
前述したように、原料ピリジン化合物と一般式（３）で表されるピリジン化合物もしくはその塩の反応においては、原料ピリジン化合物が強塩基との接触によって変化しやすいため、予め、原料ピリジン化合物と強塩基の反応により、アルコキサイドを生成させた後に一般式（３）で表されるピリジン化合物を加えるか、一般式（３）で表されるピリジン化合物と原料ピリジン化合物とを予め混合しておき、次いで、強塩基を添加することが好ましい。原料ピリジン化合物が塩を形成している場合は、該化合物を遊離化させ得る量、通常は約１当量モルの強塩基を事前に添加し、前述の手順で処理することが可能である。 As described above, in the reaction of the raw material pyridine compound with the pyridine compound represented by the general formula (3) or a salt thereof, the raw material pyridine compound is easily changed by contact with a strong base. After generating alkoxide by the reaction of the base, the pyridine compound represented by the general formula (3) is added, or the pyridine compound represented by the general formula (3) and the raw material pyridine compound are mixed in advance, It is preferable to add a strong base. When the starting pyridine compound forms a salt, an amount capable of liberating the compound, usually about 1 equivalent mole of a strong base, is added in advance and can be treated by the procedure described above.
本反応においては、原料ピリジン化合物と１，４−ブタンジオールの反応において選択した強塩基の使用が可能であり、それらは単独で用いても２種以上を組み合わせて用いても差し支えない。強塩基の使用量は、原料ピリジン化合物が遊離塩基の場合、その約１当量モルが好ましい。但し、転化率が低い場合は、一般式（３）で表されるピリジン化合物および原料ピリジン化合物が消失するまで、強塩基を追加しても差し支えない。 In this reaction, the strong base selected in the reaction of the raw material pyridine compound and 1,4-butanediol can be used, and these may be used alone or in combination of two or more. When the starting pyridine compound is a free base, the amount of strong base used is preferably about 1 equivalent mole. However, when the conversion rate is low, a strong base may be added until the pyridine compound represented by the general formula (3) and the starting pyridine compound disappear.
本反応においては、原料ピリジン化合物と１，４−ブタンジオールとの反応において選択した溶媒の使用が可能であり、それらは単独で用いても、２種以上を組み合わせて用いても差し支えない。溶媒の使用量は、一般式（３）で表されるピリジン化合物および原料ピリジン化合物の溶解度や反応中に生成するアルカリ金属塩の分散様態により、適宜選択できる。 In this reaction, it is possible to use the solvent selected in the reaction of the raw material pyridine compound and 1,4-butanediol, which may be used alone or in combination of two or more. The amount of the solvent used can be appropriately selected depending on the solubility of the pyridine compound represented by the general formula (3) and the raw material pyridine compound and the dispersion state of the alkali metal salt produced during the reaction.
本反応は、−２０℃から使用する溶媒の常圧下での沸点までを選択できる。好ましい反応温度は、−２０℃から室温であり、さらに好ましい反応温度は、−１０℃から１０℃である。反応の進行は、薄層クロマトグラフィーや高速液体クロマトグラフィーで追跡でき、原料の消失により反応の終了が確認できる。一般式（４）で表されるピリジン化合物は、常法により反応混合物から取り出すことが可能である。該化合物が結晶性の場合、再結晶を行うことでより高純度の化合物を得ることができる。該化合物が非結晶性の場合、該化合物の一塩酸塩、二塩酸塩、一酢酸塩、二酢酸塩などの無機もしくは有機酸塩を生成させ、必要に応じてそれらの再結晶を行った後に塩を中和し、常法により取り出すことで、高純度の化合物を得ることができる。 This reaction can be selected from −20 ° C. to the boiling point of the solvent used under normal pressure. A preferable reaction temperature is −20 ° C. to room temperature, and a more preferable reaction temperature is −10 ° C. to 10 ° C. The progress of the reaction can be traced by thin layer chromatography or high performance liquid chromatography, and the completion of the reaction can be confirmed by disappearance of the raw material. The pyridine compound represented by the general formula (4) can be taken out from the reaction mixture by a conventional method. When the compound is crystalline, a higher purity compound can be obtained by recrystallization. When the compound is non-crystalline, after forming an inorganic or organic acid salt such as monohydrochloride, dihydrochloride, monoacetate, diacetate, etc. of the compound and recrystallizing them as necessary A high-purity compound can be obtained by neutralizing the salt and removing it by a conventional method.
次いで、一般式（４）で表されるピリジン化合物と、下記一般式（５）で表わされる化合物を反応させることにより、前記一般式（１）または一般式（２）で表される本発明の殺菌性ピリジン化合物を得ることができる。
本反応において、一般式（４）で表されるピリジン化合物に対する一般式（５）で表される化合物の使用量は、理論的に２当量モルである。但し、転化率が低い場合、さらに一般式（５）で表わされる化合物を多く用いても差し支えなく、大過剰に用いた場合は、回収して再使用することも可能である。 In this reaction, the amount of the compound represented by the general formula (5) used relative to the pyridine compound represented by the general formula (4) is theoretically 2 equivalent moles. However, when the conversion rate is low, a large amount of the compound represented by the general formula (5) may be used, and when used in a large excess, it can be recovered and reused.
一般式（４）で表されるピリジン化合物と一般式（５）で表わされる化合物の反応においては溶媒の使用が可能である。好ましい溶媒としては、低級脂肪族アルコール、非プロトン性極性溶媒が挙げられ、具体的には、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、イソブタノール、ターシャリブタノール、アセトニトリル、プロピオニトリル、アセトン、メチルエチルケトン、メチルイソブチルケトン、テトラヒドロフラン、ジオキサン、ジメチルホルムアミド、Ｎ−メチルピロリドン、ジメチルイミダゾリジノン、ジメチルスルホキシドなどが使用できる。ジメチルホルムアミドは、該反応の転化率および選択率が良好であること、後処理が簡便であること、経済性に優れていることなどから最も好ましい溶媒である。 In the reaction of the pyridine compound represented by the general formula (4) and the compound represented by the general formula (5), a solvent can be used. Preferred solvents include lower aliphatic alcohols and aprotic polar solvents. Specifically, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tertiary butanol, acetonitrile, propionitrile, acetone, methyl ethyl ketone. , Methyl isobutyl ketone, tetrahydrofuran, dioxane, dimethylformamide, N-methylpyrrolidone, dimethylimidazolidinone, dimethyl sulfoxide and the like can be used. Dimethylformamide is the most preferred solvent because of good conversion and selectivity of the reaction, simple post-treatment, and excellent economic efficiency.
これらの溶媒は、単独で用いても、２種以上を混合して用いても差し支えない。溶媒の使用量は、一般式（４）で表されるピリジン化合物、一般式（５）で表わされる化合物の該溶媒への溶解度を考慮して適宜選択できる。 These solvents may be used alone or in combination of two or more. The amount of the solvent used can be appropriately selected in consideration of the solubility of the pyridine compound represented by the general formula (4) and the compound represented by the general formula (5) in the solvent.
一方、該反応は、溶媒を使用せず、一般式（５）で表わされる化合物を過剰に使用して実施することも可能である。この場合、反応終了後に、未反応の一般式（５）で表される化合物は、反応混合物から分離、回収して再使用することができ、極めて効率的、かつ、経済的である。 On the other hand, this reaction can also be carried out using an excess of the compound represented by the general formula (5) without using a solvent. In this case, after completion of the reaction, the unreacted compound represented by the general formula (5) can be separated from the reaction mixture, recovered and reused, and is extremely efficient and economical.
本反応は、０℃から使用する溶媒もしくは一般式（５）で表される化合物の常圧における沸点で実施できる。好ましい温度は、室温から１００℃であり、さらに好ましい温度は、４０℃から８０℃である。反応の進行は、高速液体クロマトグラフィーなどで追跡でき、原料の消失と目的とする前記一般式（１）または一般式（２）の殺菌性ピリジン化合物の生成量から反応の終了を判断できる。 This reaction can be carried out from 0 ° C. at the boiling point at normal pressure of the solvent used or the compound represented by the general formula (5). A preferred temperature is from room temperature to 100 ° C, and a more preferred temperature is from 40 ° C to 80 ° C. The progress of the reaction can be traced by high performance liquid chromatography or the like, and the end of the reaction can be judged from the disappearance of the raw material and the amount of the bactericidal pyridine compound of the general formula (1) or (2).
さらに、該反応は、一般式（４）で表されるピリジン化合物を単離することなしに、一般式（４）で表されるピリジン化合物を含有する反応混合物に一般式（５）で表される化合物を添加して連続的に実施することも可能である。この場合、一般式（４）の化合物の製造に使用した溶媒をそのまま使用すればよい。 Further, the reaction is represented by the general formula (5) in the reaction mixture containing the pyridine compound represented by the general formula (4) without isolating the pyridine compound represented by the general formula (4). It is also possible to carry out continuously by adding a compound. In this case, what is necessary is just to use the solvent used for manufacture of the compound of General formula (4) as it is.
前記一般式（１）または一般式（２）で表される本発明の殺菌性ピリジン化合物は、常法により取り出すことが可能であり、常温で固体の化合物は、適切な溶媒系からの結晶化が可能である。また、この場合、適切な溶媒系を選択することにより、再結晶による精製が可能であり、高純度の目的物を得ることができる。 The bactericidal pyridine compound of the present invention represented by the general formula (1) or the general formula (2) can be taken out by a conventional method, and a solid compound at room temperature is crystallized from an appropriate solvent system. Is possible. In this case, by selecting an appropriate solvent system, purification by recrystallization is possible, and a high-purity target product can be obtained.
以下の実施例で本発明をさらに詳細に説明する。
＜実施例１＞
［下記構造式で示される化合物（３−Ａ）の合成］
<Example 1>
[Synthesis of Compound (3-A) represented by Structural Formula below]
このスラリー液に−８〜−３℃で３−クロロメチルピリジン塩酸塩１．０ｇ（６．１０ｍｍｏｌ）およびカリウムtert−ブトキシド０．６８ｇ（６．０６ｍｍｏｌ）を交互に添加し、これを１５回繰り返し、全量で３−クロロメチルピリジン塩酸塩１５．０ｇ（９１．４５ｍｍｏｌ）およびカリウムtert−ブトキシド１０．２ｇ（９０．９ｍｍｏｌ）を添加した。 To this slurry solution, 1.0 g (6.10 mmol) of 3-chloromethylpyridine hydrochloride and 0.68 g (6.06 mmol) of potassium tert-butoxide were alternately added at −8 to −3 ° C., and this was repeated 15 times. In total, 15.0 g (91.45 mmol) of 3-chloromethylpyridine hydrochloride and 10.2 g (90.9 mmol) of potassium tert-butoxide were added.
添加終了後、反応混合物をＨＰＬＣ（条件１）で分析すると、３−クロロメチルピリジンのピークが確認されたので、３−クロロメチルピリジンのピークが消失するまで、カリウムtert−ブトキシドを５℃以下で添加した。追加したカリウムtert−ブトキシドは１．１３ｇ（１０．０７ｍｍｏｌ）であった。 After completion of the addition, the reaction mixture was analyzed by HPLC (condition 1). As a result, a peak of 3-chloromethylpyridine was confirmed. Therefore, potassium tert-butoxide was kept at 5 ° C. or lower until the peak of 3-chloromethylpyridine disappeared. Added. The added potassium tert-butoxide was 1.13 g (10.07 mmol).
反応混合物を固液分離し、ケークをＤＭＦ３０ｍｌで洗浄、ろ洗液からＤＭＦを減圧下に留去して油状の粗生成物（化合物（３−Ａ））１７．１ｇを得た。得られたオイルをＨＰＬＣ（条件１）で分析すると、前記化合物（３−Ａ）の面積％は７６．０％であった。 The reaction mixture was subjected to solid-liquid separation, the cake was washed with 30 ml of DMF, and DMF was distilled off from the filtrate under reduced pressure to obtain 17.1 g of an oily crude product (compound (3-A)). When the obtained oil was analyzed by HPLC (Condition 1), the area% of the compound (3-A) was 76.0%.
前記化合物（３−Ａ）の粗生成物を水３０ｍｌに溶解し、トルエンで洗浄した。その後、水層に食塩６ｇを加え、ジクロロメタン２０ｍｌ×２で抽出し、無水硫酸マグネシウムで脱水後、溶媒を留去し、油状の前記化合物（３−Ａ）９．２１ｇ（収率（１，４−ブタンジオールより）：５７．２％）を得た。得られたオイルをＨＰＬＣ（条件１）で分析すると、面積％は９９．４％であった。（1Ｈ−ＮＭＲ（ＣＤＣｌ3）：δ１．６７−１．７５（４Ｈ，ｍ，−（ＣＨ 2）2−）、δ２．３５（１Ｈ，ｓ，ＯＨ）、δ３．５２−３．５６（２Ｈ，ｔ，Ｊ＝６．０Ｈｚ，ＣＨ 2）、δ３．６４−３．６８（２Ｈ，ｔ，Ｊ＝６．０Ｈｚ，ＣＨ 2）、δ４．５２（２Ｈ，ｓ，ＣＨ 2）、δ７．２７−７．３１（１Ｈ，ｍ，ａｒｏｍＨ）、δ７．６６−７．７０（１Ｈ，ｍ，ａｒｏｍＨ）、δ８．５２−８．５６（２Ｈ，ｍ，ａｒｏｍＨ×２）、ＭＳ（ＡＰＣｌ）：ｍ／ｚ＝１８２［Ｍ＋Ｈ］+） The crude product of the compound (3-A) was dissolved in 30 ml of water and washed with toluene. Thereafter, 6 g of sodium chloride was added to the aqueous layer, followed by extraction with 20 ml × 2 dichloromethane, dehydration with anhydrous magnesium sulfate, the solvent was distilled off, and 9.21 g of the oily compound (3-A) (yield (1,4 -From butanediol): 57.2%). When the obtained oil was analyzed by HPLC (Condition 1), the area% was 99.4%. (1 H-NMR (CDCl 3 ): δ1.67-1.75 (4H, m, - (C H 2) 2 -), δ2.35 (1H, s, O H), δ3.52-3. 56 (2H, t, J = 6.0 Hz, C H 2 ), δ 3.64-3.68 (2H, t, J = 6.0 Hz, C H 2 ), δ 4.52 (2H, s, C H 2 ), δ 7.27-7.31 (1H, m, arom H ), δ 7.66-7.70 (1 H, m, arom H ), δ 8.52-8.56 (2H, m, arom H × 2), MS (APCl): m / z = 182 [M + H] + )
ＨＰＬＣ（条件１）
・カラム：Inertsil ODS-3(GL Sciences)４．６ｍｍφ×２５０ｍｍ
・カラム温度：１５℃付近の一定温度
・移動相：Ａ−０．５％酢酸アンモニウム水溶液、Ｂ−アセトニトリル Ａ：Ｂ＝７０：３０（一定）
・流量：１．０ｍｌ／ｍｉｎ
・検出器：ＵＶ２５４ｎｍ
・注入量：２０μＬ
HPLC (condition 1)
Column: Inertsil ODS-3 (GL Sciences) 4.6 mmφ × 250 mm
Column temperature: constant temperature around 15 ° C. Mobile phase: A-0.5% ammonium acetate aqueous solution, B-acetonitrile A: B = 70: 30 (constant)
・ Flow rate: 1.0ml / min
・ Detector: UV254nm
・ Injection volume: 20μL
＜実施例２＞
［下記構造式で示される化合物（４−Ａ）の合成］
[Synthesis of Compound (4-A) represented by Structural Formula below]
添加終了後、反応混合物をＨＰＬＣ（条件１）で分析すると、３−クロロメチルピリジンおよび前記化合物（３−Ａ）のピークが確認されたので、３−クロロメチルピリジンのピークおよび前記化合物（３−Ａ）のピークが消失するまで、カリウムtert−ブトキシドを５℃以下で添加した。追加したカリウムtert−ブトキシドは０．６２ｇ（５．５３ｍｍｏｌ）であった。 After completion of the addition, the reaction mixture was analyzed by HPLC (condition 1). As a result, peaks of 3-chloromethylpyridine and the compound (3-A) were confirmed. Therefore, the peak of 3-chloromethylpyridine and the compound (3- Potassium tert-butoxide was added at 5 ° C. or lower until the peak of A) disappeared. The added potassium tert-butoxide was 0.62 g (5.53 mmol).
反応混合物を固液分離し、ケークをＤＭＦ３０ｍｌで洗浄、ろ洗液からＤＭＦを減圧下に留去した。この濃縮残液にジクロロメタン２０ｍｌを添加し、溶解液を飽和食塩水で洗浄後、溶媒を留去し、油状物５．８ｇを得た。この粗生成物０．５ｇについてシリカゲルカラムクロマトグラフィー（展開溶媒：クロロホルム−メタノール）で精製を行い、油状の前記化合物（４−Ａ）０．３ｇを得た。（1Ｈ−ＮＭＲ：δ１．７０−１．７４（４Ｈ，ｍ，−（ＣＨ 2）2−）、δ３．５０−３．５４（４Ｈ，ｍ，ＣＨ 2×２）、δ４．５１（４Ｈ，ｓ，ＣＨ 2×２）、δ７．２５−７．２９（２Ｈ，ｄｄ，Ｊ＝４．９Ｈｚ，７．９Ｈｚ，ａｒｏｍＨ×２）、δ７．６５−７．６９（２Ｈ，ｄｔ，Ｊ＝１．７Ｈｚ，７．９Ｈｚ，ａｒｏｍ Ｈ×２）、δ８．５２−８．５７（４Ｈ，ｄｄ，Ｊ＝１．７Ｈｚ，４．９Ｈｚ，ａｒｏｍＨ×４）、ＭＳ（ＡＰＣｌ）：ｍ／ｚ＝２７３［Ｍ＋Ｈ］+） The reaction mixture was separated into solid and liquid, the cake was washed with 30 ml of DMF, and DMF was distilled off from the filtrate under reduced pressure. To this concentrated residue, 20 ml of dichloromethane was added, and the solution was washed with saturated brine, and then the solvent was distilled off to obtain 5.8 g of an oily substance. About 0.5 g of this crude product was purified by silica gel column chromatography (developing solvent: chloroform-methanol) to obtain 0.3 g of the oily compound (4-A). ( 1 H-NMR: δ 1.70-1.74 (4H, m,-(C H 2 ) 2- ), δ 3.50-3.54 (4H, m, C H 2 × 2), δ 4.51 (4H, s, C H 2 × 2), δ 7.25-7.29 (2H, dd, J = 4.9 Hz, 7.9 Hz, arom H × 2), δ 7.65-7.69 (2H, dt, J = 1.7 Hz, 7.9 Hz, arom H × 2), δ 8.52-8.57 (4H, dd, J = 1.7 Hz, 4.9 Hz, arom H × 4), MS (APCl) : M / z = 273 [M + H] + )
＜実施例３＞
［下記構造式の化合物（１）の合成］
[Synthesis of Compound (1) of Structural Formula below]
反応混合物をＨＰＬＣ（条件２）で分析すると、前記化合物（４−Ａ）のピークは消失していた。反応混合物より上層のオクチルブロマイド層を分離し、下層油状物をアセトニトリル−酢酸エチル＝１：３（ｖ／ｖ）混液に注加した。混合物を冷却し、析出結晶を０℃でろ過、減圧乾燥を行い、灰白色結晶９．７ｇ（粗収率（前記化合物（４−Ａ）より）：８５％）を得た。 When the reaction mixture was analyzed by HPLC (condition 2), the peak of the compound (4-A) disappeared. The upper octyl bromide layer was separated from the reaction mixture, and the lower oil layer was poured into a mixture of acetonitrile-ethyl acetate = 1: 3 (v / v). The mixture was cooled, and the precipitated crystals were filtered at 0 ° C. and dried under reduced pressure to obtain 9.7 g of grayish white crystals (crude yield (from the compound (4-A)): 85%).
得られた結晶２ｇについてアセトニトリル−酢酸エチル＝１：３（ｖ／ｖ）混液で再結晶を行い、微灰白色結晶の化合物（１）１．６ｇを得た。（ｍ．ｐ．５２〜５３℃、1Ｈ−ＮＭＲ（ｄ6−ＤＭＳＯ）：δ０．８２−０．８９（６Ｈ，ｔ，Ｊ＝５．３Ｈｚ，ＣＨ 3×２）、δ１．２５−１．３４（２０Ｈ，ｍ，−（ＣＨ 2）5−×２）、δ１．７７−１．８０（４Ｈ，ｍ，−（ＣＨ 2）2−×２）、δ２．０４−２．０９（４Ｈ，ｔ，Ｊ＝７．０Ｈｚ，ＣＨ 2×２）、δ３．７０−３．７２（４Ｈ，ｔ，Ｊ＝５．９Ｈｚ，ＣＨ 2×２）、δ４．６７−４．７１（４Ｈ，ｔ，Ｊ＝７．０Ｈｚ，ＣＨ 2×２）、δ４．８４（４Ｈ，ｓ，ＣＨ 2×２）、δ８．１１−８．１５（２Ｈ，ｄｄ，Ｊ＝６．０Ｈｚ，８．０Ｈｚ，ａｒｏｍＨ×２）、δ８．５６−８．５９（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ，ａｒｏｍＨ×２）、δ８．６９−８．９２（４Ｈ，ｄｄ，Ｊ＝６．０Ｈｚ，１３．１Ｈｚ，ａｒｏｍＨ×４）、ＭＳ（ＥＳＩ）：ｍ／ｚ＝５７９［Ｍ−Ｂｒ］+）。 2 g of the obtained crystal was recrystallized with a mixed solution of acetonitrile-ethyl acetate = 1: 3 (v / v) to obtain 1.6 g of compound (1) as a fine grayish white crystal. (Mp 52-53 ° C., 1 H-NMR (d 6 -DMSO): δ 0.82-0.89 (6H, t, J = 5.3 Hz, C H 3 × 2), δ 1.25- 1.34 (20H, m, - ( C H 2) 5 - × 2), δ1.77-1.80 (4H, m, - (C H 2) 2 - × 2), δ2.04-2. 09 (4H, t, J = 7.0 Hz, C H 2 × 2), δ 3.70-3.72 (4H, t, J = 5.9 Hz, C H 2 × 2), δ 4.67-4. 71 (4H, t, J = 7.0 Hz, C H 2 × 2), δ 4.84 (4H, s, C H 2 × 2), δ 8.11-8.15 (2H, dd, J = 6. 0 Hz, 8.0 Hz, arom H × 2), δ 8.56-8.59 (2H, d, J = 8.0 Hz, arom H × 2), δ 8.69-8.92 (4H, dd, J = 6.0Hz, 13.1Hz, arom H × 4), MS (ESI): m / z = 579 [M-Br] + ).
ＨＰＬＣ（条件２）
・カラム：Inertsil ODS-3(GL Sciences)４．６ｍｍφ×２５０ｍｍ
・カラム温度：１５℃付近の一定温度
・移動相：Ａ−０．５％酢酸アンモニウム水溶液、Ｂ−アセトニトリル Ａ：７０％（１２ｍｉｎ保持）→（１０ｍｉｎ）→Ａ：５０％（１４ｍｉｎ保持）→Ａ：７０％
・流量：１．０ｍｌ／ｍｉｎ
・検出器：ＵＶ２５４ｎｍ
・注入量：２０μＬ
HPLC (condition 2)
Column: Inertsil ODS-3 (GL Sciences) 4.6 mmφ × 250 mm
Column temperature: constant temperature around 15 ° C. Mobile phase: A-0.5% ammonium acetate aqueous solution, B-acetonitrile A: 70% (12 min hold) → (10 min) → A: 50% (14 min hold) → A : 70%
・ Flow rate: 1.0ml / min
・ Detector: UV254nm
・ Injection volume: 20μL
＜実施例４＞
［前記化合物（４−Ａ）の合成：１，４−ブタンジオールカリウム塩−ＤＭＦスラリーに３−クロロメチルピリジン−ＤＭＦスラリーを滴下］
ＤＭＦ２０ｍｌに１，４−ブタンジオール１．３７ｇ（１５．２０ｍｍｏｌ）を加え、氷冷下カリウムtert−ブトキシド１．７１ｇ（１５．２４ｍｍｏｌ）を添加し、室温で１時間撹拌した。
<Example 4>
[Synthesis of Compound (4-A): 3-chloromethylpyridine-DMF slurry added dropwise to 1,4-butanediol potassium salt-DMF slurry]
1,4-butanediol (1.37 g, 15.20 mmol) was added to DMF (20 ml), and potassium tert-butoxide (1.71 g, 15.24 mmol) was added under ice cooling, followed by stirring at room temperature for 1 hour.
一方、ＤＭＦ１５ｍｌに３−クロロメチルピリジン塩酸塩２．５ｇ（１５．２４ｍｍｏｌ）を加え、氷冷下カリウムtert−ブトキシド１．７１ｇ（１５．２４ｍｍｏｌ）を添加した。１，４−ブタンジオール−ＤＭＦスラリーに３−クロロメチルピリジン−ＤＭＦスラリーを−１７〜−１４℃で滴下した。 On the other hand, 2.5 g (15.24 mmol) of 3-chloromethylpyridine hydrochloride was added to 15 ml of DMF, and 1.71 g (15.24 mmol) of potassium tert-butoxide was added under ice cooling. To the 1,4-butanediol-DMF slurry, 3-chloromethylpyridine-DMF slurry was added dropwise at -17 to -14 ° C.
反応混合物をＨＰＬＣ（条件１）で分析すると、３−クロロメチルピリジンのピークが確認されたので、カリウムtert−ブトキシドを−１０℃以下で３−クロロメチルピリジンのピークが消失するまで添加した。３−クロロメチルピリジンのピーク消失確認後、反応混合物に氷冷下カリウムtert−ブトキシド１．７１ｇ（１５．２４ｍｍｏｌ）を添加し、先に調製したものと同量の３−クロロメチルピリジン−ＤＭＦスラリーを−２０〜−１７℃で滴下した。反応混合物をＨＰＬＣ（条件１）で分析すると、３−クロロメチルピリジンのピークが確認されたので、カリウムtert−ブトキシドを−１０℃以下で３−クロロメチルピリジンのピークが消失するまで添加した。３−クロロメチルピリジンのピーク消失確認後、反応混合物を固液分離し、ケークをＤＭＦ２５ｍｌで洗浄、ろ洗液からＤＭＦを減圧下に留去した。 When the reaction mixture was analyzed by HPLC (condition 1), a peak of 3-chloromethylpyridine was confirmed, and potassium tert-butoxide was added at -10 ° C. or lower until the peak of 3-chloromethylpyridine disappeared. After confirming the disappearance of the peak of 3-chloromethylpyridine, 1.71 g (15.24 mmol) of potassium tert-butoxide was added to the reaction mixture under ice-cooling, and the same amount of 3-chloromethylpyridine-DMF slurry as prepared above was added. Was added dropwise at -20 to -17 ° C. When the reaction mixture was analyzed by HPLC (condition 1), a peak of 3-chloromethylpyridine was confirmed, and potassium tert-butoxide was added at -10 ° C. or lower until the peak of 3-chloromethylpyridine disappeared. After confirming disappearance of the peak of 3-chloromethylpyridine, the reaction mixture was subjected to solid-liquid separation, the cake was washed with 25 ml of DMF, and DMF was distilled off from the filtrate under reduced pressure.
この濃縮残液にジクロロメタン２０ｍｌを添加し、溶解液を飽和食塩水で洗浄後、溶媒を留去し、油状の前記化合物（４−Ａ）３．７９ｇ（粗収率（１，４−ブタンジオールより）：９１．８％）を得た。得られたオイルをＨＰＬＣ（条件１）で分析すると、前記化合物（４−Ａ）の面積％は６４．５％であった。 To this concentrated residue was added 20 ml of dichloromethane, and the solution was washed with saturated brine, and then the solvent was distilled off to obtain 3.79 g of the oily compound (4-A) (crude yield (1,4-butanediol). More): 91.8%). When the obtained oil was analyzed by HPLC (condition 1), the area% of the compound (4-A) was 64.5%.
＜実施例５＞
［前記化合物（４−Ａ）の合成：ＤＭＦ−１，４−ブタンジオール−３−クロロメチルピリジン塩酸塩のスラリーにカリウムtert−ブトキシドを分割して添加］
ＤＭＦ５０ｍｌに１，４−ブタンジオール１．３７ｇ（１５．２０ｍｍｏｌ）および３−クロロメチルピリジン塩酸塩５．０ｇ（３０．４８ｍｍｏｌ）を加え、−２０〜−１３℃でカリウムtert−ブトキシド６．８４ｇ（６０．９６ｍｍｏｌ）を１０分割して添加した。
<Example 5>
[Synthesis of Compound (4-A): Potassium tert-butoxide is added in portions to a slurry of DMF-1,4-butanediol-3-chloromethylpyridine hydrochloride]
1.37 g (15.20 mmol) of 1,4-butanediol and 5.0 g (30.48 mmol) of 3-chloromethylpyridine hydrochloride were added to 50 ml of DMF, and 6.84 g of potassium tert-butoxide at −20 to −13 ° C. 60.96 mmol) was added in 10 portions.
反応混合物をＨＰＬＣ（条件１）で分析すると、３−クロロメチルピリジンのピークおよび前記化合物（３−Ａ）のピークが確認されたので、３−クロロメチルピリジンのピークおよび前記化合物（３−Ａ）のピークが消失するまで、３−クロロメチルピリジン塩酸塩とカリウムtert−ブトキシドを−１０℃以下で添加した。追加した３−クロロメチルピリジン塩酸塩は１．０ｇ（６．１０ｍｍｏｌ）、カリウムtert−ブトキシドは８．７ｇ（７７．５３ｍｍｏｌ）であった。 When the reaction mixture was analyzed by HPLC (condition 1), the peak of 3-chloromethylpyridine and the peak of the compound (3-A) were confirmed, so the peak of 3-chloromethylpyridine and the compound (3-A) were confirmed. Until the peak disappeared, 3-chloromethylpyridine hydrochloride and potassium tert-butoxide were added at -10 ° C or lower. The added 3-chloromethylpyridine hydrochloride was 1.0 g (6.10 mmol), and potassium tert-butoxide was 8.7 g (77.53 mmol).
反応混合物を固液分離し、ケークをＤＭＦ２５ｍｌで洗浄、ろ洗液からＤＭＦを減圧下に留去した。この濃縮残液にジクロロメタン２０ｍｌを添加し、溶解液を飽和食塩水で洗浄後、溶媒を留去し、油状の前記化合物（４−Ａ）４．３１ｇ（粗収率（３−クロロメチルピリジン塩酸塩より）：８６．５％）を得た。得られたオイルをＨＰＬＣ（条件１）で分析すると、前記化合物（４−Ａ）の面積％は７２．８％であった。 The reaction mixture was separated into solid and liquid, the cake was washed with 25 ml of DMF, and DMF was distilled off from the filtrate under reduced pressure. To this concentrated residue was added 20 ml of dichloromethane, and the solution was washed with saturated brine, and then the solvent was distilled off to give 4.31 g of the oily compound (4-A) (crude yield (3-chloromethylpyridine hydrochloride). From the salt): 86.5%). When the obtained oil was analyzed by HPLC (condition 1), the area% of the compound (4-A) was 72.8%.
＜実施例６＞
［前記化合物（４−Ａ）の合成：実施例５のスケールアップ］
ＤＭＦ２５０ｍｌに１，４−ブタンジオール１３．７３ｇ（０．１５２４ｍｏｌ）、３−クロロメチルピリジン塩酸塩５０．０ｇ（０．３０４８ｍｏｌ）を加え、−１９〜−１２℃でカリウムtert−ブトキシド６８．４ｇ（０．６０９６ｍｏｌ）を２０分割して添加した。
<Example 6>
[Synthesis of Compound (4-A): Scale-up of Example 5]
1,4-butanediol (13.73 g, 0.1524 mol) and 3-chloromethylpyridine hydrochloride (50.0 g, 0.3048 mol) were added to DMF (250 ml), and potassium tert-butoxide (68.4 g) was added at -19 to -12 ° C. 0.6096 mol) was added in 20 portions.
反応混合物をＨＰＬＣ（条件１）で分析すると、３−クロロメチルピリジンおよび前記化合物（３−Ａ）のピークが確認されたので、３−クロロメチルピリジンのピークおよび前記化合物（３−Ａ）のピークが消失するまで、３−クロロメチルピリジン塩酸塩とカリウムtert−ブトキシドを−１０℃以下で添加した。 When the reaction mixture was analyzed by HPLC (condition 1), the peak of 3-chloromethylpyridine and the compound (3-A) was confirmed, so the peak of 3-chloromethylpyridine and the peak of the compound (3-A) were confirmed. 3-Chloromethylpyridine hydrochloride and potassium tert-butoxide were added at −10 ° C. or lower until disappeared.
追加した３−クロロメチルピリジン塩酸塩は８．０ｇ（０．０３６６ｍｏｌ）、カリウムtert−ブトキシドは２３．９ｇ（０．２１３０ｍｏｌ）であった。反応混合物を固液分離し、ケークをＤＭＦ１２５ｍｌで洗浄、ろ洗液からＤＭＦを減圧下に留去した。この濃縮残液にジクロロメタン２００ｍｌを添加し、溶解液を飽和食塩水で洗浄後、溶媒を留去し、油状の前記化合物（４−Ａ）４１．０ｇ（粗収率（１，４−ブタンジオールより）：９８．８％）を得た。得られたオイルをＨＰＬＣ（条件１）で分析すると、前記化合物（４−Ａ）の面積％は６８．８％であった。 The added 3-chloromethylpyridine hydrochloride was 8.0 g (0.0366 mol), and potassium tert-butoxide was 23.9 g (0.2130 mol). The reaction mixture was separated into solid and liquid, the cake was washed with 125 ml of DMF, and DMF was distilled off from the filtrate under reduced pressure. To this concentrated residue, 200 ml of dichloromethane was added, and the solution was washed with saturated brine, and then the solvent was distilled off. 41.0 g of the oily compound (4-A) (crude yield (1,4-butanediol) More): 98.8%). When the obtained oil was analyzed by HPLC (condition 1), the area% of the compound (4-A) was 68.8%.
＜実施例７＞
［前記化合物（４−Ａ）の合成：１，４−ブタンジオールモノカリウム塩−ＤＭＦスラリーに３−クロロメチルピリジン塩酸塩とカリウムtert−ブトキシドを交互に添加］
<Example 7>
[Synthesis of Compound (4-A): 3-Chloromethylpyridine Hydrochloride and Potassium tert-Butoxide Added to 1,4-Butanediol Monopotassium Salt-DMF Slurry Alternately]
ＤＭＦ２５０ｍｌに１，４−ブタンジオール１３．７３ｇ（０．１５２４ｍｏｌ）を加え、氷冷下カリウムtert−ブトキシド１７．１ｇ（０．１５２４ｍｏｌ）を添加し、室温で２時間撹拌した。このスラリーに−１５〜−１０℃で３−クロロメチルピリジン塩酸塩５．０ｇ（３０．４８ｍｍｏｌ）、カリウムtert−ブトキシド３．４２ｇ（３０．４８ｍｍｏｌ）を交互に添加し、これを５回繰り返した。これ以降の添加は、−１６〜−７℃で３−クロロメチルピリジン塩酸塩５．０ｇ（３０．４８ｍｍｏｌ）、カリウムtert−ブトキシド６．８４ｇ（６０．９６ｍｍｏｌ）を交互に添加し、これを５回繰り返し、全量で３−クロロメチルピリジン塩酸塩５０．０ｇ（０．３０４８ｍｏｌ）、カリウムtert−ブトキシド５１．３ｇ（０．４５７２ｍｏｌ）を添加した。 1,4-butanediol (13.73 g, 0.1524 mol) was added to DMF (250 ml), and potassium tert-butoxide (17.1 g, 0.1524 mol) was added under ice cooling, followed by stirring at room temperature for 2 hours. To this slurry, 5.0 g (30.48 mmol) of 3-chloromethylpyridine hydrochloride and 3.42 g (30.48 mmol) of potassium tert-butoxide were alternately added at −15 to −10 ° C., and this was repeated 5 times. . Subsequent additions were carried out by alternately adding 5.0 g (30.48 mmol) of 3-chloromethylpyridine hydrochloride and 6.84 g (60.96 mmol) of potassium tert-butoxide at −16 to −7 ° C. Repeatedly, 50.0 g (0.3048 mol) of 3-chloromethylpyridine hydrochloride and 51.3 g (0.4572 mol) of potassium tert-butoxide were added in total.
添加終了後、反応混合物をＨＰＬＣ（条件１）で分析すると、３−クロロメチルピリジンおよび前記化合物（３−Ａ）のピークが確認されたので、３−クロロメチルピリジンのピークおよび前記化合物（３−Ａ）のピークが消失するまで、３−クロロメチルピリジン塩酸塩とカリウムtert−ブトキシドを０℃以下で添加した。 After completion of the addition, the reaction mixture was analyzed by HPLC (condition 1). As a result, peaks of 3-chloromethylpyridine and the compound (3-A) were confirmed. Therefore, the peak of 3-chloromethylpyridine and the compound (3- 3-Chloromethylpyridine hydrochloride and potassium tert-butoxide were added at 0 ° C. or lower until the peak of A) disappeared.
追加した３−クロロメチルピリジン塩酸塩は２．６５ｇ（０．０３６６ｍｏｌ）、カリウムtert−ブトキシドは４．９６ｇ（０．０４４２ｍｏｌ）であった。反応混合物を固液分離し、ケークをＤＭＦ１２５ｍｌで洗浄、ろ洗液からＤＭＦを減圧下に留去した。 The added 3-chloromethylpyridine hydrochloride was 2.65 g (0.0366 mol), and potassium tert-butoxide was 4.96 g (0.0442 mol). The reaction mixture was separated into solid and liquid, the cake was washed with 125 ml of DMF, and DMF was distilled off from the filtrate under reduced pressure.
この濃縮残液にジクロロメタン２００ｍｌを添加し、溶解液を飽和食塩水で洗浄後、溶媒を留去し、油状の前記化合物（４−Ａ）４０．９ｇ（粗収率（１，４−ブタンジオールより）：９８．６％）を得た。得られたオイルをＨＰＬＣ（条件１）で分析すると、前記化合物（４−Ａ）の面積％は８９．２％であった。 200 ml of dichloromethane was added to the concentrated residue, and the solution was washed with saturated brine, and then the solvent was distilled off to obtain 40.9 g of the oily compound (4-A) (crude yield (1,4-butanediol). More): 98.6%). When the obtained oil was analyzed by HPLC (condition 1), the area% of the compound (4-A) was 89.2%.
得られた粗生成物２ｇ（７．４１ｍｍｏｌ）をイソプロピルアルコール１０ｇに溶解し、溶解液に塩化水素ガス０．２７ｇ（７．４１ｍｍｏｌ）を吹き込んだ。混合物を１０℃に冷却し、析出した結晶をろ過、減圧乾燥して、前記化合物（４−Ａ）の１塩酸塩１．１ｇを得た（収率：４８．０％）。得られた結晶をＨＰＬＣ（条件１）で分析すると、化合物の面積％は９７．５％であった。 2 g (7.41 mmol) of the obtained crude product was dissolved in 10 g of isopropyl alcohol, and 0.27 g (7.41 mmol) of hydrogen chloride gas was blown into the solution. The mixture was cooled to 10 ° C., and the precipitated crystals were filtered and dried under reduced pressure to obtain 1.1 g of the monohydrochloride salt of the compound (4-A) (yield: 48.0%). When the obtained crystal was analyzed by HPLC (condition 1), the area% of the compound was 97.5%.
＜実施例８＞
［前記化合物（４−Ａ）の合成：１，４−ブタンジオール−カリウムtert−ブトキシド−ＤＭＦスラリーに３−クロロメチルピリジン塩酸塩−ＤＭＦ溶液を滴下して前記化合物（３−Ａ）を生成させ、その反応混合物に３−クロロメチルピリジン塩酸塩を加えたスラリーにカリウムtert−ブトキシド−ＤＭＦ溶液を滴下］
ＤＭＦ１００ｍｌに１，４−ブタンジオール１３．７３ｇ（０．１５２４ｍｏｌ）を加え、氷冷下カリウムtert−ブトキシド３４．２ｇ（０．３０４８ｍｏｌ）を添加し、５℃以下で３０分撹拌した。このスラリーに４〜１０℃で３−クロロメチルピリジン塩酸塩２５．０ｇ（０．１５２４ｍｏｌ）のＤＭＦ（１５０ｍｌ）溶液を１．５時間かけて滴下した。
<Example 8>
[Synthesis of Compound (4-A): A 3-chloromethylpyridine hydrochloride-DMF solution was dropped into 1,4-butanediol-potassium tert-butoxide-DMF slurry to form the compound (3-A). The potassium tert-butoxide-DMF solution was added dropwise to the slurry obtained by adding 3-chloromethylpyridine hydrochloride to the reaction mixture.
To 100 ml of DMF, 13.73 g (0.1524 mol) of 1,4-butanediol was added, and 34.2 g (0.3048 mol) of potassium tert-butoxide was added under ice cooling, followed by stirring at 5 ° C. or lower for 30 minutes. To this slurry, a DMF (150 ml) solution of 25.0 g (0.1524 mol) of 3-chloromethylpyridine hydrochloride was added dropwise at 4 to 10 ° C. over 1.5 hours.
次に反応混合物に３−クロロメチルピリジン塩酸塩２５．０ｇ（０．１５２４ｍｏｌ）、カリウムtert−ブトキシド１７．１ｇ（０．１５２４ｍｏｌ）を０℃以下で添加後、カリウムtert−ブトキシド１７．１ｇ（０．１５２４ｍｏｌ）のＤＭＦ（１００ｍｌ）溶液を−１０〜０℃で３０分かけて滴下した。滴下終了後、反応混合物をＨＰＬＣ（条件１）で分析すると、３−クロロメチルピリジンおよび前記化合物（３−Ａ）のピークが確認されたので、３−クロロメチルピリジンのピークおよび前記化合物（３−Ａ）のピークが消失するまで、３−クロロメチルピリジン塩酸塩とカリウムtert−ブトキシドを０℃以下で添加した。 Next, 25.0 g (0.1524 mol) of 3-chloromethylpyridine hydrochloride and 17.1 g (0.1524 mol) of potassium tert-butoxide were added to the reaction mixture at 0 ° C. or lower, and then 17.1 g (0 of potassium tert-butoxide). .1524 mol) in DMF (100 ml) was added dropwise at −10 to 0 ° C. over 30 minutes. After completion of the dropwise addition, the reaction mixture was analyzed by HPLC (condition 1). As a result, peaks of 3-chloromethylpyridine and the compound (3-A) were confirmed. Therefore, the peak of 3-chloromethylpyridine and the compound (3- 3-Chloromethylpyridine hydrochloride and potassium tert-butoxide were added at 0 ° C. or lower until the peak of A) disappeared.
追加した３−クロロメチルピリジン塩酸塩は６．５ｇ（０．０３９６ｍｏｌ）、カリウムtert−ブトキシドは８．８９ｇ（０．０７９２ｍｏｌ）であった。反応混合物を固液分離し、ケークをＤＭＦ１５０ｍｌで洗浄、ろ洗液からＤＭＦを減圧下に留去した。この濃縮残液にジクロロメタン２００ｍｌを添加し、溶解液を飽和食塩水で洗浄後、溶媒を留去し、油状の前記化合物（４−Ａ）４３．２ｇ（粗収率（３−クロロメチルピリジン塩酸塩より）：９２．１％）を得た。得られたオイルをＨＰＬＣ（条件１）で分析すると、前記化合物（４−Ａ）の面積％は８７．８％であった。 The added 3-chloromethylpyridine hydrochloride was 6.5 g (0.0396 mol), and potassium tert-butoxide was 8.89 g (0.0792 mol). The reaction mixture was separated into solid and liquid, the cake was washed with 150 ml of DMF, and DMF was distilled off from the filtrate under reduced pressure. To this concentrated residue, 200 ml of dichloromethane was added, and the solution was washed with saturated brine, and then the solvent was distilled off to obtain 43.2 g of the oily compound (4-A) (crude yield (3-chloromethylpyridine hydrochloride). From the salt): 92.1%). When the obtained oil was analyzed by HPLC (condition 1), the area% of the compound (4-A) was 87.8%.
＜実施例９＞
［前記化合物（４−Ａ）の合成：ＤＭＦ−１，４−ブタンジオール−３−クロロメチルピリジン塩酸塩のスラリーにカリウムtert−ブトキシドのＤＭＦ溶液を滴下］
ＤＭＦ２００ｍｌに１，４−ブタンジオール６．８７ｇ（０．０７６２ｍｏｌ）、３−クロロメチルピリジン塩酸塩２５．０ｇ（０．１５２４ｍｏｌ）を加え、−１１〜−５℃でカリウムtert−ブトキシド３５．９ｇ（０．３１９９ｍｏｌ）のＤＭＦ（１００ｍｌ）溶液を１．５時間かけて滴下した。室温で一晩熟成後、反応混合物をＨＰＬＣ（条件１）で分析すると、前記化合物（３−Ａ）のピークが確認されたので、前記化合物（３−Ａ）のピークが消失するまで、３−クロロメチルピリジン塩酸塩とカリウムtert−ブトキシドを０℃以下で添加した。追加した３−クロロメチルピリジン塩酸塩は２．５ｇ（０．０１５２ｍｏｌ）、カリウムtert−ブトキシドは３．４２ｇ（０．０３０５ｍｏｌ）であった。反応混合物を固液分離し、ケークをＤＭＦ１５０ｍｌで洗浄、ろ洗液からＤＭＦを減圧下に留去した。この濃縮残液にジクロロメタン１００ｍｌを添加し、溶解液を飽和食塩水で洗浄後、溶媒を留去し、油状の前記化合物（４−Ａ）２０．１ｇ（粗収率（１，４−ブタンジオールより）：９６．６％）を得た。得られたオイルをＨＰＬＣ（条件１）で分析すると、前記化合物（４−Ａ）の面積％は８０．３％であった。
<Example 9>
[Synthesis of Compound (4-A): DMF solution of potassium tert-butoxide is added dropwise to a slurry of DMF-1,4-butanediol-3-chloromethylpyridine hydrochloride]
To 200 ml of DMF, 6.87 g (0.0762 mol) of 1,4-butanediol and 25.0 g (0.1524 mol) of 3-chloromethylpyridine hydrochloride were added, and 35.9 g of potassium tert-butoxide was added at −11 to −5 ° C. 0.3199 mol) of DMF (100 ml) was added dropwise over 1.5 hours. After aging overnight at room temperature, the reaction mixture was analyzed by HPLC (condition 1). As a result, the peak of the compound (3-A) was confirmed. Therefore, until the peak of the compound (3-A) disappeared, Chloromethylpyridine hydrochloride and potassium tert-butoxide were added below 0 ° C. The added 3-chloromethylpyridine hydrochloride was 2.5 g (0.0152 mol), and potassium tert-butoxide was 3.42 g (0.0305 mol). The reaction mixture was separated into solid and liquid, the cake was washed with 150 ml of DMF, and DMF was distilled off from the filtrate under reduced pressure. To this concentrated residue, 100 ml of dichloromethane was added, and the solution was washed with saturated brine, and then the solvent was distilled off to obtain 20.1 g of the oily compound (4-A) (crude yield (1,4-butanediol). More): 96.6%). When the obtained oil was analyzed by HPLC (condition 1), the area% of the compound (4-A) was 80.3%.
＜実施例１０＞
［前記化合物（４−Ａ）の合成：実施例７のスケールアップ］
ＤＭＦ７５０ｍｌに１，４−ブタンジオール４１．２ｇ（０．４５７ｍｏｌ）を加え、氷冷下カリウムtert−ブトキシド５１．３ｇ（０．４５７ｍｏｌ）を添加し、室温で１時間撹拌した。このスラリーに−５〜０℃で３−クロロメチルピリジン塩酸塩７．５ｇ（４５．７２ｍｍｏｌ）、カリウムtert−ブトキシド５．１ｇ（４５．４５ｍｍｏｌ）を交互に添加し、これを１０回繰り返した。これ以降の添加は、−６〜−１℃で３−クロロメチルピリジン塩酸塩７．５ｇ（４５．７２ｍｍｏｌ）、カリウムtert−ブトキシド１０．２ｇ（９０．９ｍｍｏｌ）を交互に添加し、これを１０回繰り返し、全量で３−クロロメチルピリジン塩酸塩１５０．０ｇ（０．９１４５ｍｏｌ）、カリウムtert−ブトキシド１５３．０ｇ（１．３６４ｍｏｌ）を添加した。
<Example 10>
[Synthesis of Compound (4-A): Scale Up of Example 7]
To 750 ml of DMF, 41.2 g (0.457 mol) of 1,4-butanediol was added, and 51.3 g (0.457 mol) of potassium tert-butoxide was added under ice cooling, followed by stirring at room temperature for 1 hour. To this slurry, 7.5 g (45.72 mmol) of 3-chloromethylpyridine hydrochloride and 5.1 g (45.45 mmol) of potassium tert-butoxide were alternately added at −5 to 0 ° C., and this was repeated 10 times. Subsequent addition was carried out by alternately adding 7.5 g (45.72 mmol) of 3-chloromethylpyridine hydrochloride and 10.2 g (90.9 mmol) of potassium tert-butoxide at −6 to −1 ° C. Repeatedly, 150.0 g (0.9145 mol) of 3-chloromethylpyridine hydrochloride and 153.0 g (1.364 mol) of potassium tert-butoxide were added in total.
添加終了後、反応混合物をＨＰＬＣ（条件１）で分析すると、３−クロロメチルピリジンおよび前記化合物（３−Ａ）のピークが確認されたので、３−クロロメチルピリジンのピークおよび前記化合物（３−Ａ）のピークが消失するまで、３−クロロメチルピリジン塩酸塩とカリウムtert−ブトキシドを５℃以下で添加した。追加した３−クロロメチルピリジン塩酸塩はなく、カリウムtert−ブトキシドは１０．３ｇ（９１．７９ｍｍｏｌ）であった。反応混合物を固液分離し、ケークをＤＭＦ３００ｍｌで洗浄、ろ洗液からＤＭＦを減圧下に留去した。この濃縮残液にジクロロメタン５００ｍｌを添加し、溶解液を飽和食塩水で洗浄後、溶媒を留去し、油状の前記化合物（４−Ａ）１１１．９ｇ（粗収率（１，４−ブタンジオールより）：８９．９％）を得た。得られたオイルをＨＰＬＣ（条件１）で分析すると、前記化合物（４−Ａ）の面積％は９３．９％であった。 After completion of the addition, the reaction mixture was analyzed by HPLC (condition 1). As a result, peaks of 3-chloromethylpyridine and the compound (3-A) were confirmed. Therefore, the peak of 3-chloromethylpyridine and the compound (3- 3-Chloromethylpyridine hydrochloride and potassium tert-butoxide were added at 5 ° C. or lower until the peak of A) disappeared. There was no added 3-chloromethylpyridine hydrochloride, and potassium tert-butoxide was 10.3 g (91.79 mmol). The reaction mixture was separated into solid and liquid, the cake was washed with 300 ml of DMF, and DMF was distilled off from the filtrate under reduced pressure. Dichloromethane (500 ml) was added to the concentrated residue, the solution was washed with saturated brine, and the solvent was distilled off to give 111.9 g of the oily compound (4-A) (crude yield (1,4-butanediol). More): 89.9%). When the obtained oil was analyzed by HPLC (condition 1), the area% of the compound (4-A) was 93.9%.
＜実施例１１＞
［前記化合物（１）の合成：反応溶媒−メタノール／アセトニトリル混液］
メタノール／アセトニトリル＝３：１（ｖ／ｖ）混液５０ｇに前記化合物（４−Ａ）１０．０ｇ（３６．７２ｍｍｏｌ）とオクチルブロマイド７０．９ｇ（０．３６７ｍｏｌ）を加え、還流下１３５時間反応を行った。反応混合物をＨＰＬＣ（条件２）で分析すると、前記化合物（４−Ａ）のピークは消失していた。上層のオクチルブロマイド層を分離し、下層に酢酸エチルを添加して混合物を冷却、析出した結晶を−１８℃で濾別、ケークを酢酸エチル１０ｍｌで洗浄し、減圧乾燥して前記化合物（１）２０．３ｇ（粗収率：８３．９％）を得た。得られた結晶をＨＰＬＣ（条件２）で分析すると、前記化合物（１）のピークの面積％は９１．４％であった。
<Example 11>
[Synthesis of Compound (1): Reaction Solvent-Methanol / Acetonitrile Mixture]
10.0 g (36.72 mmol) of the above compound (4-A) and 70.9 g (0.367 mol) of octyl bromide were added to 50 g of a methanol / acetonitrile = 3: 1 (v / v) mixture, and the reaction was allowed to proceed for 135 hours under reflux. went. When the reaction mixture was analyzed by HPLC (condition 2), the peak of the compound (4-A) disappeared. The upper octyl bromide layer was separated, ethyl acetate was added to the lower layer, the mixture was cooled, the precipitated crystals were filtered off at -18 ° C, the cake was washed with 10 ml of ethyl acetate, dried under reduced pressure, and the compound (1) 20.3 g (crude yield: 83.9%) was obtained. When the obtained crystal was analyzed by HPLC (condition 2), the peak area% of the compound (1) was 91.4%.
＜実施例１２＞
［前記化合物（１）の合成：反応溶媒−ＤＭＦ］
ＤＭＦ２５ｍｌに前記化合物（４−Ａ）５．０ｇ（１８．３６ｍｍｏｌ）とオクチルブロマイド３５．５ｇ（０．１８４ｍｏｌ）を加え、５０〜５５℃で８６時間反応を行った。反応混合物をＨＰＬＣ（条件２）で分析すると、前記化合物（４−Ａ）のピークは消失していた。反応混合物からＤＭＦとオクチルブロマイドを減圧下で留去し、油状の前記化合物（１）１２．９ｇ（粗収率：１０６．６％）を得た。得られたオイルをＨＰＬＣ（条件２）で分析すると、前記化合物（１）のピークの面積％は９３．０％であった。
<Example 12>
[Synthesis of Compound (1): Reaction Solvent-DMF]
5.0 g (18.36 mmol) of the compound (4-A) and 35.5 g (0.184 mol) of octyl bromide were added to 25 ml of DMF, and reacted at 50 to 55 ° C. for 86 hours. When the reaction mixture was analyzed by HPLC (condition 2), the peak of the compound (4-A) disappeared. From the reaction mixture, DMF and octyl bromide were distilled off under reduced pressure to obtain 12.9 g (crude yield: 106.6%) of the oily compound (1). When the obtained oil was analyzed by HPLC (condition 2), the peak area% of the compound (1) was 93.0%.
＜実施例１３＞
［前記化合物（１）の合成：無溶媒での反応、反応温度４５〜５５℃］
前記化合物（４−Ａ）１０．０ｇ（３６．７２ｍｍｏｌ）にオクチルブロマイド７０．９ｇ（０．３６７１ｍｏｌ）を加え、４９〜５２℃で５０時間反応を行った。反応混合物をＨＰＬＣ（条件２）で分析すると、前記化合物（４−Ａ）のピークは消失していた。反応混合物を冷却し、析出結晶を室温で濾別、酢酸エチル２０ｍｌで結晶を洗浄し、減圧乾燥して前記化合物（１）２１．２ｇ（粗収率：８７．６％）を得た。得られた結晶をＨＰＬＣ（条件２）で分析すると、前記化合物（１）のピークの面積％は９３．３％であった。
<Example 13>
[Synthesis of Compound (1): Reaction without Solvent, Reaction Temperature 45-55 ° C.]
70.0 g (0.3671 mol) of octyl bromide was added to 10.0 g (36.72 mmol) of the compound (4-A), and reacted at 49 to 52 ° C. for 50 hours. When the reaction mixture was analyzed by HPLC (condition 2), the peak of the compound (4-A) disappeared. The reaction mixture was cooled, the precipitated crystals were filtered off at room temperature, washed with 20 ml of ethyl acetate, and dried under reduced pressure to obtain 21.2 g (crude yield: 87.6%) of the compound (1). When the obtained crystal was analyzed by HPLC (condition 2), the peak area% of the compound (1) was 93.3%.
＜実施例１４＞
［前記化合物（１）の合成：無溶媒での反応、反応温度７５〜８０℃、エタノール／酢酸エチル混液で結晶化］
前記化合物（４−Ａ）１０．０ｇ（３６．７２ｍｍｏｌ）にオクチルブロマイド７０．９ｇ（０．３６７１ｍｏｌ）を加え、７５〜７７℃で２０時間反応を行った。反応混合物をＨＰＬＣ（条件２）で分析すると、前記化合物（４−Ａ）のピークは消失していた。反応混合物より上層のオクチルブロマイド層を分離し、下層にエタノール１０ｍｌを添加して溶解し、溶解液を酢酸エチル２００ｍｌ中に注加した。混合物を冷却し、析出した結晶を−１０℃で濾別、酢酸エチル１０ｍｌで結晶を洗浄、減圧乾燥して前記化合物（１）１７．４ｇ（粗収率：７１．９％）を得た。得られた結晶をＨＰＬＣ（条件２）で分析すると、前記化合物（１）のピークの面積％は９５．２％であった。
<Example 14>
[Synthesis of Compound (1): Reaction without Solvent, Reaction Temperature 75-80 ° C, Crystallization in Ethanol / Ethyl Acetate Mixture]
70.0 g (0.3671 mol) of octyl bromide was added to 10.0 g (36.72 mmol) of the compound (4-A), and the reaction was performed at 75 to 77 ° C. for 20 hours. When the reaction mixture was analyzed by HPLC (condition 2), the peak of the compound (4-A) disappeared. The upper octyl bromide layer was separated from the reaction mixture, 10 ml of ethanol was added to the lower layer to dissolve, and the solution was poured into 200 ml of ethyl acetate. The mixture was cooled, and the precipitated crystals were filtered off at −10 ° C., washed with 10 ml of ethyl acetate, and dried under reduced pressure to obtain 17.4 g (crude yield: 71.9%) of the compound (1). When the obtained crystal was analyzed by HPLC (condition 2), the peak area% of the compound (1) was 95.2%.
＜実施例１５＞
［前記化合物（１）の合成：エタノール／酢酸エチル混液の比率を変更し、反応条件を以下の通りにした他は実施例１４と同様］
前記化合物（４−Ａ）１０．０ｇ（３６．７２ｍｍｏｌ）にオクチルブロマイド７０．９ｇ（０．３６７１ｍｏｌ）を加え、７５〜７７℃で２０時間反応を行った。反応混合物をＨＰＬＣ（条件２）で分析すると、前記化合物（４−Ａ）のピークは消失していた。反応混合物にエタノール１０ｍｌを添加して静置すると、上層が前記化合物（１）のエタノール溶液層、下層がオクチルブロマイド層となり、下層を分離した。次に上層を酢酸エチル５００ｍｌ中に注加した。混合物を冷却し、析出結晶を５℃で濾別、酢酸エチル１０ｍｌで結晶を洗浄、減圧乾燥して前記化合物（１）２０．８ｇ（粗収率：８６．０％）を得た。得られた結晶をＨＰＬＣ（条件２）で分析すると、前記化合物（１）のピークの面積％は９０．８％であった。
<Example 15>
[Synthesis of Compound (1): Same as Example 14 except that the ratio of ethanol / ethyl acetate mixture was changed and reaction conditions were as follows]
70.0 g (0.3671 mol) of octyl bromide was added to 10.0 g (36.72 mmol) of the compound (4-A), and the reaction was performed at 75 to 77 ° C. for 20 hours. When the reaction mixture was analyzed by HPLC (condition 2), the peak of the compound (4-A) disappeared. When 10 ml of ethanol was added to the reaction mixture and allowed to stand, the upper layer became an ethanol solution layer of the compound (1), the lower layer became an octyl bromide layer, and the lower layer was separated. The upper layer was then poured into 500 ml of ethyl acetate. The mixture was cooled, the precipitated crystals were filtered off at 5 ° C., washed with 10 ml of ethyl acetate, and dried under reduced pressure to obtain 20.8 g (crude yield: 86.0%) of the compound (1). When the obtained crystal was analyzed by HPLC (Condition 2), the peak area% of the compound (1) was 90.8%.
＜実施例１６＞
［前記化合物（１）の合成：エタノール／酢酸エチル混液の比率を変更し、反応条件を以下の通りにした他は実施例１４と同様。粗生成物をアセトニトリル／酢酸エチル混液で再結晶］
前記化合物（４−Ａ）１００．０ｇ（０．３６７ｍｏｌ）にオクチルブロマイド７０９．１ｇ（３．６７ｍｏｌ）を加え、７５〜７８℃で２０時間反応を行った。反応混合物をＨＰＬＣ（条件２）で分析すると、前記化合物（４−Ａ）のピークは消失していた。反応混合物にエタノール９７ｍｌを添加して静置すると、上層が前記化合物（１）のエタノール溶液層、下層がオクチルブロマイド層となり、下層を分離した。次に上層を酢酸エチル２９００ｍｌ中に注加した。混合物を冷却し、析出結晶を３℃で濾別、酢酸エチル１００ｍｌで結晶を洗浄、減圧乾燥して前記化合物（１）２１５．８ｇ（粗収率：８９．３％）を得た。得られた結晶をＨＰＬＣ（条件２）で分析すると、前記化合物（１）のピークの面積％は９３．１％であった。
<Example 16>
[Synthesis of Compound (1): Same as Example 14 except that the ratio of ethanol / ethyl acetate mixture was changed and the reaction conditions were as follows. Recrystallize crude product with acetonitrile / ethyl acetate mixture]
709.1 g (3.67 mol) of octyl bromide was added to 100.0 g (0.367 mol) of the compound (4-A), followed by reaction at 75 to 78 ° C. for 20 hours. When the reaction mixture was analyzed by HPLC (condition 2), the peak of the compound (4-A) disappeared. When 97 ml of ethanol was added to the reaction mixture and allowed to stand, the upper layer became an ethanol solution layer of the compound (1), the lower layer became an octyl bromide layer, and the lower layer was separated. The upper layer was then poured into 2900 ml of ethyl acetate. The mixture was cooled, the precipitated crystals were filtered off at 3 ° C., washed with 100 ml of ethyl acetate, and dried under reduced pressure to obtain 215.8 g (crude yield: 89.3%) of the compound (1). When the obtained crystal was analyzed by HPLC (condition 2), the peak area% of the compound (1) was 93.1%.
得られた結晶２１２ｇをアセトニトリル５９２ｍｌ、酢酸エチル１９５３ｍｌの混液で再結晶を行い、前記化合物（１）１９２．１ｇ（精製収率：９０．６％）を得た。得られた結晶をＨＰＬＣ（条件２）で分析すると、前記化合物（１）のピークの面積％は９６．４％であった。 212 g of the obtained crystals were recrystallized from a mixed solution of 592 ml of acetonitrile and 1953 ml of ethyl acetate to obtain 192.1 g of the compound (1) (purification yield: 90.6%). When the obtained crystal was analyzed by HPLC (condition 2), the peak area% of the compound (1) was 96.4%.
＜実施例１７＞
［前記化合物（１）の合成：３−クロロメチルピリジンのベンゼンスルホン酸塩から前記化合物（４−Ａ）を合成。前記化合物（４−Ａ）を単離せずに前記化合物（１）を合成］
ＤＭＦ３５ｇに１，４−ブタンジオール３．２ｇ（０．０３５ｍｏｌ）を加え、１０〜２０℃でカリウムtert−ブトキシド３．９ｇ（０．０３５ｍｏｌ）を添加した。このスラリーに１０〜２５℃で３−クロロメチルピリジン・ベンゼンスルホン酸塩２０．０ｇ（０．０７ｍｏｌ）のＤＭＦ（５５ｇ）溶液を滴下し、同時にカリウムtert−ブトキシド１６．８ｇ（０．１５ｍｏｌ）を分割して添加した。添加終了後、反応混合物をＨＰＬＣ（条件１）で分析すると、３−クロロメチルピリジンおよび前記化合物（３−Ａ）のピークが確認されたので、３−クロロメチルピリジンおよび前記化合物（３−Ａ）のピークが消失するまで、カリウムtert−ブトキシドを２０℃以下で添加した。追加したカリウムtert−ブトキシドは１．５ｇ（０．０１ｍｏｌ）であった。
<Example 17>
[Synthesis of Compound (1): Compound (4-A) is synthesized from benzenesulfonate of 3-chloromethylpyridine. Synthesis of Compound (1) without Isolating Compound (4-A)]
To 35 g of DMF, 3.2 g (0.035 mol) of 1,4-butanediol was added, and 3.9 g (0.035 mol) of potassium tert-butoxide was added at 10 to 20 ° C. To this slurry, a DMF (55 g) solution of 20.0 g (0.07 mol) of 3-chloromethylpyridine benzenesulfonate was added dropwise at 10 to 25 ° C., and simultaneously 16.8 g (0.15 mol) of potassium tert-butoxide was added. Added in portions. After completion of the addition, the reaction mixture was analyzed by HPLC (Condition 1). Since peaks of 3-chloromethylpyridine and the compound (3-A) were confirmed, 3-chloromethylpyridine and the compound (3-A) were confirmed. Potassium tert-butoxide was added at 20 ° C. or lower until the peak disappeared. The added potassium tert-butoxide was 1.5 g (0.01 mol).
反応混合物より無機塩を濾別、ケークを１０ｇのＤＭＦで洗浄した。ろ洗液にオクチルブロマイド９６．０ｇ（０．５ｍｏｌ）を添加、６０℃で７２時間反応を行った。反応混合物をＨＰＬＣ（条件２）で分析すると、前記化合物（４−Ａ）のピークは消失していた。反応混合物を固液分離し、ケークをＤＭＦ２０ｇで洗浄、ろ洗液からＤＭＦとオクチルブロマイドを減圧下に留去し、油状の前記化合物（１）４１．１ｇ（粗収率（３−クロロメチルピリジン・ベンゼンスルホン酸塩より）：８９．２％）を得た。得られたオイルをＨＰＬＣ（条件２）で分析すると、前記化合物（１）のピークの面積％は８７．８％であった。 Inorganic salts were filtered off from the reaction mixture, and the cake was washed with 10 g of DMF. 96.0 g (0.5 mol) of octyl bromide was added to the filtrate and the reaction was carried out at 60 ° C. for 72 hours. When the reaction mixture was analyzed by HPLC (condition 2), the peak of the compound (4-A) disappeared. The reaction mixture was subjected to solid-liquid separation, the cake was washed with 20 g of DMF, DMF and octyl bromide were distilled off from the filtrate under reduced pressure, and 41.1 g of the oily compound (1) (crude yield (3-chloromethylpyridine) was obtained. -From benzenesulfonate, 89.2%) was obtained. When the obtained oil was analyzed by HPLC (condition 2), the peak area% of the compound (1) was 87.8%.
＜実施例１８＞
［前記化合物（４−Ａ）の合成：塩基をナトリウム−tert−ブトキシドに代え、反応条件を以下の通りにした他は実施例７と同様］
ＤＭＦ２５０ｍｌに１，４−ブタンジオール１３．７３ｇ（０．１５２４ｍｏｌ）を加え、氷冷下ナトリウムtert−ブトキシド１４．６５ｇ（０．１５２４ｍｏｌ）を添加し、室温で１時間撹拌した。このスラリーに−１５〜−１０℃で３−クロロメチルピリジン塩酸塩５．０ｇ（３０．４８ｍｍｏｌ）、ナトリウムtert−ブトキシド２．９３ｇ（３０．４８ｍｍｏｌ）を交互に添加し、これを５回繰り返した。これ以降の添加は、−１６〜−７℃で３−クロロメチルピリジン塩酸塩５．０ｇ（３０．４８ｍｍｏｌ）、ナトリウムtert−ブトキシド５．８６ｇ（６０．９７ｍｍｏｌ）を交互に添加し、これを５回繰り返し、全量で３−クロロメチルピリジン塩酸塩５０．０ｇ（０．３０４８ｍｏｌ）、ナトリウムtert−ブトキシド４３．９５ｇ（０．４５７３ｍｏｌ）を添加した。
<Example 18>
[Synthesis of Compound (4-A): Same as Example 7 except that the base was replaced with sodium tert-butoxide and the reaction conditions were as follows]
1,4-butanediol (13.73 g, 0.1524 mol) was added to DMF (250 ml), and sodium tert-butoxide (14.65 g, 0.1524 mol) was added under ice cooling, followed by stirring at room temperature for 1 hour. To this slurry, 5.0 g (30.48 mmol) of 3-chloromethylpyridine hydrochloride and 2.93 g (30.48 mmol) of sodium tert-butoxide were alternately added at −15 to −10 ° C., and this was repeated 5 times. . Subsequent addition was carried out by alternately adding 5.0 g (30.48 mmol) of 3-chloromethylpyridine hydrochloride and 5.86 g (60.97 mmol) of sodium tert-butoxide at −16 to −7 ° C. Repeatedly, 50.0 g (0.3048 mol) of 3-chloromethylpyridine hydrochloride and 43.95 g (0.4573 mol) of sodium tert-butoxide were added in total.
添加終了後、反応混合物をＨＰＬＣ（条件１）で分析すると、３−クロロメチルピリジンおよび前記化合物（３−Ａ）のピークが確認されたので、３−クロロメチルピリジンのピークおよび前記化合物（３−Ａ）のピークが消失するまで、３−クロロメチルピリジン塩酸塩とナトリウムtert−ブトキシドを０℃以下で添加した。追加した３−クロロメチルピリジン塩酸塩は２．５ｇ（０．０１５２ｍｏｌ）、ナトリウムtert−ブトキシドは２．９３ｇ（０．０３０５ｍｏｌ）であった。反応混合物を固液分離し、ケークをＤＭＦ１２５ｍｌで洗浄、ろ洗液からＤＭＦを減圧下に留去した。この濃縮残液にジクロロメタン２００ｍｌを添加し、溶解液を飽和食塩水で洗浄後、溶媒を留去し、油状の前記化合物（４−Ａ）３９．４ｇ（粗収率（１，４−ブタンジオールより）：９４．９％）を得た。得られたオイルをＨＰＬＣ（条件１）で分析すると、前記化合物（４−Ａ）の面積％は８８．３％であった。 After completion of the addition, the reaction mixture was analyzed by HPLC (condition 1). As a result, peaks of 3-chloromethylpyridine and the compound (3-A) were confirmed. Therefore, the peak of 3-chloromethylpyridine and the compound (3- 3-Chloromethylpyridine hydrochloride and sodium tert-butoxide were added at 0 ° C. or lower until the peak of A) disappeared. The added 3-chloromethylpyridine hydrochloride was 2.5 g (0.0152 mol), and sodium tert-butoxide was 2.93 g (0.0305 mol). The reaction mixture was separated into solid and liquid, the cake was washed with 125 ml of DMF, and DMF was distilled off from the filtrate under reduced pressure. To this concentrated residue, 200 ml of dichloromethane was added, and the solution was washed with saturated brine, and then the solvent was distilled off to obtain 39.4 g of the oily compound (4-A) (crude yield (1,4-butanediol). More): 94.9%). When the obtained oil was analyzed by HPLC (condition 1), the area% of the compound (4-A) was 88.3%.
＜実施例１９＞
［前記化合物（４−Ａ）の合成：３−ピリジンメタノールベンゼンスルホン酸エステルを使用した反応］
ＤＭＦ１５ｍｌに１，４−ブタンジオール０．９ｇ（９．９９ｍｍｏｌ）を加え、氷冷下カリウムtert−ブトキシド１．１３ｇ（１０．０７ｍｍｏｌ）を添加し、室温で１時間撹拌した。このスラリーに−５〜０℃で３−ピリジンメタノールベンゼンスルホン酸エステル２．５ｇ（１０．０３ｍｍｏｌ）のＤＭＦ（５ｍｌ）溶液を滴下した。−５〜０℃で３０分撹拌後、反応混合物にカリウムtert−ブトキシド１．１３ｇ（１０．０７ｍｍｏｌ）を−５〜０℃で添加した。このスラリーに−５〜０℃で３−ピリジンメタノールベンゼンスルホン酸エステル２．５ｇ（１０．０３ｍｍｏｌ）のＤＭＦ（５ｍｌ）溶液を滴下した。
<Example 19>
[Synthesis of Compound (4-A): Reaction Using 3-Pyridinemethanolbenzenesulfonate]
1,4-butanediol (0.9 g, 9.99 mmol) was added to 15 ml of DMF, and 1.13 g (10.07 mmol) of potassium tert-butoxide was added under ice cooling, followed by stirring at room temperature for 1 hour. To this slurry, a DMF (5 ml) solution of 2.5 g (10.03 mmol) of 3-pyridinemethanolbenzenesulfonate was added dropwise at -5 to 0 ° C. After stirring at −5 to 0 ° C. for 30 minutes, 1.13 g (10.07 mmol) of potassium tert-butoxide was added to the reaction mixture at −5 to 0 ° C. To this slurry, a DMF (5 ml) solution of 2.5 g (10.03 mmol) of 3-pyridinemethanolbenzenesulfonate was added dropwise at -5 to 0 ° C.
滴下終了後、反応混合物をＨＰＬＣ（条件１）で分析すると、３−ピリジンメタノールベンゼンスルホン酸エステルのピークおよび前記化合物（３−Ａ）のピークが確認されたので、３−ピリジンメタノールベンゼンスルホン酸エステルのピークおよび前記化合物（３−Ａ）のピークが消失するまで、３−ピリジンメタノールベンゼンスルホン酸エステル化合物とカリウムtert−ブトキシドを０℃以下で添加した。追加した３−ピリジンメタノールベンゼンスルホン酸エステルは０．２５ｇ（１．００ｍｍｏｌ）、カリウムtert−ブトキシドは０．２２ｇ（１．９６ｍｍｏｌ）であった。反応混合物を固液分離し、ケークをＤＭＦ１０ｍｌで洗浄、ろ洗液からＤＭＦを減圧下に留去した。この濃縮残液にジクロロメタン２０ｍｌを添加し、溶解液を飽和食塩水で洗浄後、溶媒を留去し、油状の前記化合物（４−Ａ）２．４ｇ（粗収率（１，４−ブタンジオールより）：８８．２％）を得た。得られたオイルをＨＰＬＣ（条件１）で分析すると、前記化合物（４−Ａ）の面積％は８５．８％であった。 After completion of the dropwise addition, the reaction mixture was analyzed by HPLC (condition 1). As a result, the peak of 3-pyridinemethanolbenzenesulfonate and the peak of the compound (3-A) were confirmed. The 3-pyridinemethanolbenzenesulfonic acid ester compound and potassium tert-butoxide were added at 0 ° C. or lower until the above peak and the peak of the compound (3-A) disappeared. The added 3-pyridinemethanolbenzenesulfonic acid ester was 0.25 g (1.00 mmol), and potassium tert-butoxide was 0.22 g (1.96 mmol). The reaction mixture was separated into solid and liquid, the cake was washed with 10 ml of DMF, and DMF was distilled off from the filtrate under reduced pressure. To this concentrated residue, 20 ml of dichloromethane was added, and the solution was washed with saturated brine, and then the solvent was distilled off to give 2.4 g of the oily compound (4-A) (crude yield (1,4-butanediol). More): 88.2%). When the obtained oil was analyzed by HPLC (condition 1), the area% of the compound (4-A) was 85.8%.
＜実施例２０＞
［下記構造式で示される化合物（３−Ｂ）の合成：３−クロロメチルピリジン塩酸塩から４−クロロメチルピリジン塩酸塩に代え、反応条件を以下の通りにした他は実施例１と同様］
[Synthesis of Compound (3-B) Represented by Structural Formula: Same as Example 1 except that 3-chloromethylpyridine hydrochloride was replaced with 4-chloromethylpyridine hydrochloride and the reaction conditions were as follows]
添加終了後、反応混合物をＨＰＬＣ（条件１）で分析すると、４−クロロメチルピリジンのピークが確認されたので、４−クロロメチルピリジンのピークが消失するまでカリウムtert−ブトキシドを１０℃以下で添加した。追加したカリウムtert−ブトキシドは１．０３ｇ（９．１８ｍｍｏｌ）であった。反応混合物を固液分離し、ケークをＤＭＦ２０ｍｌで洗浄、ろ洗液からＤＭＦを減圧下に留去し油状の粗生成物１７．０ｇを得た。得られたオイルをＨＰＬＣ（条件１）で分析すると、前記化合物（３−Ｂ）の面積％は６３．０％であった。 After completion of the addition, the reaction mixture was analyzed by HPLC (condition 1). As a result, a peak of 4-chloromethylpyridine was confirmed, so potassium tert-butoxide was added at 10 ° C. or lower until the peak of 4-chloromethylpyridine disappeared. did. The added potassium tert-butoxide was 1.03 g (9.18 mmol). The reaction mixture was subjected to solid-liquid separation, the cake was washed with 20 ml of DMF, and DMF was distilled off from the filtrate under reduced pressure to obtain 17.0 g of an oily crude product. When the obtained oil was analyzed by HPLC (condition 1), the area% of the compound (3-B) was 63.0%.
粗生成物を水３０ｍｌに溶解し、トルエンで洗浄した。その後、水層に食塩６ｇを加え、ジクロロメタン２０ｍｌ×２で抽出し、無水硫酸マグネシウムで脱水後、溶媒を留去し、油状の前記化合物（３−Ｂ）９．２１ｇ（収率（１，４−ブタンジオールより）：５７．２％）を得た。得られたオイルをＨＰＬＣ（条件１）で分析すると、面積％は９９．４％であった。（1Ｈ−ＮＭＲ（ＣＤＣｌ3）：δ１．６５−１．８０（４Ｈ，ｍ，−（ＣＨ 2）2−）、δ２．４（１Ｈ，ｓ，ＯＨ）、δ３．５４−３．５８（２Ｈ，ｔ，Ｊ＝５．９Ｈｚ，ＣＨ 2）、δ３．６６−３．７０（２Ｈ，ｔ，Ｊ＝５．９Ｈｚ，ＣＨ 2）、δ４．５３（２Ｈ，ｓ，ＣＨ 2）、δ７．２４−７．２６（２Ｈ，ｄｄ，Ｊ＝１．５Ｈｚ，４．５Ｈｚ，ａｒｏｍＨ×２）、δ８．５５−８．５７（２Ｈ，ｄｄ，Ｊ＝１．５Ｈｚ，４．５Ｈｚ，ａｒｏｍＨ×２）、ＭＳ（ＡＰＣｌ）：ｍ／ｚ＝１８２［Ｍ＋Ｈ］+） The crude product was dissolved in 30 ml of water and washed with toluene. Thereafter, 6 g of sodium chloride was added to the aqueous layer, followed by extraction with 20 ml of dichloromethane × 2, dehydration with anhydrous magnesium sulfate, the solvent was distilled off, and 9.21 g of the oily compound (3-B) (yield (1,4 -From butanediol): 57.2%). When the obtained oil was analyzed by HPLC (Condition 1), the area% was 99.4%. (1 H-NMR (CDCl 3 ): δ1.65-1.80 (4H, m, - (C H 2) 2 -), δ2.4 (1H, s, O H), δ3.54-3. 58 (2H, t, J = 5.9 Hz, C H 2 ), δ 3.66-3.70 (2H, t, J = 5.9 Hz, C H 2 ), δ 4.53 (2H, s, C H 2 ), δ 7.24-7.26 (2H, dd, J = 1.5 Hz, 4.5 Hz, arom H × 2), δ 8.55-8.57 (2H, dd, J = 1.5 Hz, 4 .5 Hz, arom H × 2), MS (APCl): m / z = 182 [M + H] + )
＜実施例２１＞
［下記構造式で示される化合物（４−Ｂ）の合成：３−クロロメチルピリジン塩酸塩から４−クロロメチルピリジン塩酸塩に代え、反応条件を以下の通りにした他は実施例７と同様］
[Synthesis of Compound (4-B) Represented by Structural Formula below: Same as Example 7 except that 3-chloromethylpyridine hydrochloride was replaced with 4-chloromethylpyridine hydrochloride and the reaction conditions were as follows]
添加終了後、反応混合物をＨＰＬＣ（条件１）で分析すると、４−クロロメチルピリジンおよび前記化合物（３−Ｂ）のピークが確認されたので、４−クロロメチルピリジンのピークおよび前記化合物（３−Ｂ）のピークが消失するまで、４−クロロメチルピリジン塩酸塩とカリウムtert−ブトキシドを１０℃以下で添加した。追加した４−クロロメチルピリジン塩酸塩は２．０ｇ（１２ｍｍｏｌ）、カリウムtert−ブトキシドは２．６ｇ（２４ｍｍｏｌ）であった。反応混合物を固液分離し、ケークをＤＭＦ２０ｍｌで洗浄、ろ洗液からＤＭＦを減圧下に留去した。 After completion of the addition, the reaction mixture was analyzed by HPLC (condition 1). As a result, peaks of 4-chloromethylpyridine and the compound (3-B) were confirmed, and therefore the peak of 4-chloromethylpyridine and the compound (3- 4-Chloromethylpyridine hydrochloride and potassium tert-butoxide were added at 10 ° C. or lower until the peak of B) disappeared. The added 4-chloromethylpyridine hydrochloride was 2.0 g (12 mmol), and potassium tert-butoxide was 2.6 g (24 mmol). The reaction mixture was separated into solid and liquid, the cake was washed with 20 ml of DMF, and DMF was distilled off from the filtrate under reduced pressure.
この濃縮残液に酢酸エチル５０ｍｌを添加し、溶解液を水で洗浄後、溶媒を留去し、黄色結晶の前記化合物（４−Ｂ）を得た。該化合物の結晶をＨＰＬＣ（条件１）で分析すると、前記化合物（４−Ｂ）の面積％は７０．５％であった。得られた粗生成物５ｇ（１８ｍｍｏｌ）をイソプロピルアルコール２３．３ｇで再結晶を行い、白色結晶の前記化合物（４−Ｂ）２．７ｇを得た。（ｍ．ｐ．９８．６〜１００．２℃、1Ｈ−ＮＭＲ（ＣＤＣｌ3）：δ１．７５−１．７９（４Ｈ，ｍ，−（ＣＨ 2）2−）、δ３．５３−３．５７（４Ｈ，ｍ，ＣＨ 2×２）、δ４．５２（４Ｈ，ｓ，ＣＨ 2×２）、δ７．２３−７．２７（４Ｈ，ｄｄ，Ｊ＝０．８Ｈｚ，６．０Ｈｚ，ａｒｏｍＨ×４）、δ８．５５−８．５７（４Ｈ，ｄｄ，Ｊ＝１．６Ｈｚ，６．０Ｈｚ，ａｒｏｍＨ×４）、ＭＳ（ＡＰＣｌ）：ｍ／ｚ＝２７３［Ｍ＋Ｈ］+） 50 ml of ethyl acetate was added to the concentrated residue, and the solution was washed with water, and then the solvent was distilled off to obtain the compound (4-B) as yellow crystals. When the crystals of the compound were analyzed by HPLC (condition 1), the area% of the compound (4-B) was 70.5%. 5 g (18 mmol) of the obtained crude product was recrystallized with 23.3 g of isopropyl alcohol to obtain 2.7 g of the compound (4-B) as white crystals. (Mp 98.6 to 100.2 ° C., 1 H-NMR (CDCl 3 ): δ 1.75-1.79 (4H, m, — (C H 2 ) 2 —), δ 3.53-3 .57 (4H, m, C H 2 × 2), δ 4.52 (4H, s, C H 2 × 2), δ 7.23-7.27 (4H, dd, J = 0.8 Hz, 6.0 Hz) , Arom H × 4), δ 8.55-8.57 (4H, dd, J = 1.6 Hz, 6.0 Hz, arom H × 4), MS (APCl): m / z = 273 [M + H] + )
＜実施例２２＞
［下記構造式の化合物（２）の合成：前記化合物（４−Ｂ）を４−クロロメチルピリジン塩酸塩から誘導したものに代え、反応条件を以下の通りにした他は実施例３と同様］
[Synthesis of compound (2) having the following structural formula: the same as in Example 3 except that the compound (4-B) was replaced with one derived from 4-chloromethylpyridine hydrochloride and the reaction conditions were as follows]
＜実施例２３＞
［前記化合物（４−Ｂ）の精製：塩酸塩での精製。（塩酸モル比：前記化合物（４−Ｂ）に対して１．５）］
前記化合物（４−Ｂ）５．０ｇ（１８．３６ｍｍｏｌ、面積比９０．５％）をイソプロピルアルコール１５．０ｇに溶解し、溶解液に塩化水素ガス１．０１ｇ（２７．７０ｍｍｏｌ）を２０〜４０℃で吹き込んだ。混合物を１０℃に冷却し、析出した結晶をろ過、減圧乾燥して、前記化合物（４−Ｂ）の２塩酸塩４．４ｇを得た（収率：６９．８％）。得られた結晶をＨＰＬＣ（条件１）で分析すると、前記化合物（４−Ｂ）の面積％は９７．９％であった。
<Example 23>
[Purification of the compound (4-B): purification with hydrochloride. (Molar ratio of hydrochloric acid: 1.5 with respect to the compound (4-B))]
5.0 g (18.36 mmol, area ratio 90.5%) of the compound (4-B) was dissolved in 15.0 g of isopropyl alcohol, and 1.01 g (27.70 mmol) of hydrogen chloride gas was added to 20-40 in the solution. Blowed at ℃. The mixture was cooled to 10 ° C., and the precipitated crystals were filtered and dried under reduced pressure to obtain 4.4 g of the dihydrochloride salt of the compound (4-B) (yield: 69.8%). When the obtained crystal was analyzed by HPLC (condition 1), the area% of the compound (4-B) was 97.9%.
＜実施例２４＞
［前記化合物（４−Ｂ）の精製：塩酸塩での精製。（塩酸モル比：前記化合物（４−Ｂ）に対して２．０）］
前記化合物（４−Ｂ）５．０ｇ（１８．３６ｍｍｏｌ、面積比９０．５％）をイソプロピルアルコール１５．０ｇに溶解し、溶解液に塩化水素ガス１．３４ｇ（３６．７５ｍｍｏｌ）を２０〜４０℃で吹き込んだ。混合物を１０℃に冷却し、析出した結晶をろ過、減圧乾燥して、前記化合物（４−Ｂ）の２塩酸塩５．７ｇを得た（収率：９０．５％）。得られた結晶をＨＰＬＣ（条件１）で分析すると、前記化合物（４−Ｂ）の面積％は９６．１％であった。
<Example 24>
[Purification of the compound (4-B): purification with hydrochloride. (Molar ratio of hydrochloric acid: 2.0 with respect to the compound (4-B))]
5.0 g (18.36 mmol, area ratio 90.5%) of the compound (4-B) was dissolved in 15.0 g of isopropyl alcohol, and 1.34 g (36.75 mmol) of hydrogen chloride gas was added to 20-40 in the solution. Blowed at ℃. The mixture was cooled to 10 ° C., and the precipitated crystals were filtered and dried under reduced pressure to obtain 5.7 g of the dihydrochloride salt of the compound (4-B) (yield: 90.5%). When the obtained crystal was analyzed by HPLC (condition 1), the area% of the compound (4-B) was 96.1%.
＜実施例２５＞
［前記化合物（４−Ｂ）の精製：塩酸の吹き込み温度を６０〜６５℃に代え、反応条件を以下の通りにした他は実施例２３と同様］
前記化合物（４−Ｂ）１５．０ｇ（５５．０８ｍｍｏｌ、面積比９０．５％）をイソプロピルアルコール４５．０ｇに溶解し、溶解液に塩化水素ガス４．０ｇ（０．１０９７ｍｏｌ）を６０〜６５℃で吹き込んだ。混合物を５℃に冷却し、析出した結晶をろ過、減圧乾燥して、前記化合物（４−Ｂ）の２塩酸塩１７．２ｇを得た（収率：９０．５％）。得られた結晶をＨＰＬＣ（条件１）で分析すると、前記化合物（４−Ｂ）の面積％は９７．９％であった。
<Example 25>
[Purification of Compound (4-B): Same as Example 23, except that the blowing temperature of hydrochloric acid was changed to 60-65 ° C. and the reaction conditions were as follows]
15.0 g (55.08 mmol, area ratio 90.5%) of the compound (4-B) was dissolved in 45.0 g of isopropyl alcohol, and 4.0 g (0.1097 mol) of hydrogen chloride gas was added to the solution at 60 to 65. Blowed at ℃. The mixture was cooled to 5 ° C., and the precipitated crystals were filtered and dried under reduced pressure to obtain 17.2 g of the dihydrochloride salt of the compound (4-B) (yield: 90.5%). When the obtained crystal was analyzed by HPLC (condition 1), the area% of the compound (4-B) was 97.9%.
＜実施例２６＞
［前記化合物（４−Ｂ）の精製：硫酸塩での精製（硫酸モル比：前記化合物（４−Ｂ）に対して１．０）］
前記化合物（４−Ｂ）１５．０ｇ（５５．０８ｍｍｏｌ、面積比９０．５％）をイソプロピルアルコール２２．５ｇに溶解し、溶解液に９８％硫酸５．５ｇ（５４．９６ｍｍｏｌ）を７０〜７５℃で滴下した。混合物を５℃に冷却し、析出した結晶をろ過、減圧乾燥して、前記化合物（４−Ｂ）の２硫酸塩１７．２ｇを得た（収率：４７．５％）。得られた結晶をＨＰＬＣ（条件１）で分析すると、前記化合物（４−Ｂ）の面積％は９４．６％であった。
<Example 26>
[Purification of Compound (4-B): Purification with Sulfate (Sulfuric Acid Molar Ratio: 1.0 with respect to Compound (4-B))]
15.0 g (55.08 mmol, area ratio 90.5%) of the compound (4-B) was dissolved in 22.5 g of isopropyl alcohol, and 5.5 g (54.96 mmol) of 98% sulfuric acid was added to 70 to 75 in the solution. It was dripped at ° C. The mixture was cooled to 5 ° C., and the precipitated crystals were filtered and dried under reduced pressure to obtain 17.2 g of the disulfate salt of the compound (4-B) (yield: 47.5%). When the obtained crystal was analyzed by HPLC (condition 1), the area% of the compound (4-B) was 94.6%.
＜実施例２７＞
［前記化合物（４−Ｂ）の精製：硫酸塩での精製（硫酸モル比：前記化合物（４−Ｂ）に対して１．５）］
前記化合物（４−Ｂ）１０．０ｇ（３６．７２ｍｍｏｌ、面積比９０．５％）をイソプロピルアルコール２０ｍｌに溶解し、溶解液に９８％硫酸５．５ｇ（５４．９６ｍｍｏｌ）を４５〜６０℃で滴下した。混合物を５℃に冷却し、析出した結晶をろ過、減圧乾燥して、前記化合物（４−Ｂ）の２硫酸塩１０．６ｇを得た（収率：６１．６％）。得られた結晶をＨＰＬＣ（条件１）で分析すると、前記化合物（４−Ｂ）の面積％は９４．９％であった。
<Example 27>
[Purification of Compound (4-B): Purification with Sulfate (Sulfuric Acid Molar Ratio: 1.5 with respect to Compound (4-B))]
10.0 g (36.72 mmol, area ratio 90.5%) of the compound (4-B) was dissolved in 20 ml of isopropyl alcohol, and 5.5 g (54.96 mmol) of 98% sulfuric acid was added to the solution at 45-60 ° C. It was dripped. The mixture was cooled to 5 ° C., and the precipitated crystals were filtered and dried under reduced pressure to obtain 10.6 g of the disulfate salt of the compound (4-B) (yield: 61.6%). When the obtained crystal was analyzed by HPLC (Condition 1), the area% of the compound (4-B) was 94.9%.
＜実施例２８＞
［前記化合物（４−Ｂ）の精製：硫酸塩での精製（硫酸モル比：前記化合物（４−Ｂ）に対して２．０）］
前記化合物（４−Ｂ）２０．０ｇ（７３．４３ｍｍｏｌ、面積比９０．５％）をイソプロピルアルコール４０ｍｌに溶解し、溶解液に９８％硫酸１４．７ｇ（０．１４６８ｍｏｌ）を６０〜８０℃で滴下した。混合物を５℃に冷却し、析出した結晶をろ過、減圧乾燥して、前記化合物（４−Ｂ）の２硫酸塩２７．５ｇを得た（収率：７９．９％）。得られた結晶をＨＰＬＣ（条件１）で分析すると、前記化合物（４−Ｂ）の面積％は９４．７％であった。
<Example 28>
[Purification of Compound (4-B): Purification with Sulfate (Sulfuric Acid Molar Ratio: 2.0 with respect to Compound (4-B))]
20.0 g (73.43 mmol, area ratio 90.5%) of the compound (4-B) was dissolved in 40 ml of isopropyl alcohol, and 14.7 g (0.1468 mol) of 98% sulfuric acid was added to the solution at 60 to 80 ° C. It was dripped. The mixture was cooled to 5 ° C., and the precipitated crystals were filtered and dried under reduced pressure to obtain 27.5 g of the disulfate salt of the compound (4-B) (yield: 79.9%). When the obtained crystal was analyzed by HPLC (condition 1), the area% of the compound (4-B) was 94.7%.
＜実施例２９＞
［前記化合物（４−Ｂ）の合成：１，４−ブタンジオールのモノナトリウム塩スラリーに４−クロロメチルピリジン塩酸塩−ＤＭＦスラリーとナトリウム−tert−ブトキシドのＤＭＦ溶液を同時に滴下］
ＤＭＦ８０ｍｌに１，４−ブタンジオール８．４３ｇ（０．０９３５ｍｏｌ）を加え、氷冷下ナトリウムtert−ブトキシド９．０ｇ（０．０９３６ｍｏｌ）を添加し、室温で１時間撹拌した。このスラリーに０〜５℃で４−クロロメチルピリジン塩酸塩３４．１ｇ（４５．７２ｍｍｏｌ）／ＤＭＦ１００ｍｌのスラリーとナトリウムtert−ブトキシド３７．０ｇ（０．３８５０ｍｏｌ）／ＤＭＦ６０ｍｌの溶液を同時に滴下した。
<Example 29>
[Synthesis of Compound (4-B): 4-chloromethylpyridine hydrochloride-DMF slurry and DMF solution of sodium tert-butoxide are added dropwise to 1,4-butanediol monosodium salt slurry]
To 80 ml of DMF, 8.43 g (0.0935 mol) of 1,4-butanediol was added, and 9.0 g (0.0936 mol) of sodium tert-butoxide was added under ice cooling, followed by stirring at room temperature for 1 hour. To this slurry, a solution of 34.1 g (45.72 mmol) of 4-chloromethylpyridine hydrochloride / 100 ml of DMF and a solution of 37.0 g (0.3850 mol) of sodium tert-butoxide / 60 ml of DMF were simultaneously added dropwise at 0 to 5 ° C.
滴下終了後、室温で１時間反応して、反応混合物をＨＰＬＣ（条件１）で分析すると、４−クロロメチルピリジンのピークは検出されず、前記化合物（３−Ｂ）のピークもほぼ消失した。反応混合物を固液分離し、ケークをＤＭＦ６０ｍｌで洗浄、ろ洗液からＤＭＦを減圧下に留去した。得られた残液２８．３ｇにイソプロピルアルコール８４．９ｇを加えて溶解し、溶解液に塩化水素ガス６．９ｇ（０．１８９２ｍｏｌ）を６０〜６５℃で吹き込んだ。混合物を５℃に冷却し、析出した結晶をろ過、イソプロピルアルコール１４．２ｍｌで結晶を洗浄して、前記化合物（４−Ｂ）の２塩酸塩の湿体３６．１ｇを得た。得られた湿体を水１８．１ｇで溶解後、液苛性ソーダでｐＨ１０〜１１．５に調整し、トルエン１００ｍｌで抽出、トルエン層を水２０ｍｌで洗浄後、トルエンを減圧下に留去して油状の前記化合物（４−Ｂ）２２．２ｇ（収率（１，４−ブタンジオールより）：８７．２％）を得た。得られたオイルをＨＰＬＣ（条件１）で分析すると、前記化合物（４−Ｂ）の面積％は９７．５％であった。 After completion of the dropwise addition, the mixture was reacted at room temperature for 1 hour, and when the reaction mixture was analyzed by HPLC (condition 1), the peak of 4-chloromethylpyridine was not detected, and the peak of the compound (3-B) almost disappeared. The reaction mixture was subjected to solid-liquid separation, the cake was washed with 60 ml of DMF, and DMF was distilled off from the filtrate under reduced pressure. To 28.3 g of the obtained residual liquid, 84.9 g of isopropyl alcohol was added and dissolved, and 6.9 g (0.1892 mol) of hydrogen chloride gas was blown into the solution at 60 to 65 ° C. The mixture was cooled to 5 ° C., the precipitated crystals were filtered, and the crystals were washed with 14.2 ml of isopropyl alcohol to obtain 36.1 g of a wet dihydrochloride salt of the compound (4-B). The obtained wet substance was dissolved in 18.1 g of water, adjusted to pH 10 to 11.5 with liquid caustic soda, extracted with 100 ml of toluene, the toluene layer was washed with 20 ml of water, and then toluene was distilled off under reduced pressure to give an oil. Of the compound (4-B) was obtained (yield (from 1,4-butanediol): 87.2%). When the obtained oil was analyzed by HPLC (condition 1), the area% of the compound (4-B) was 97.5%.
＜実施例３０＞
［前記化合物（２）の合成：精製した前記化合物（４−Ｂ）を使用し、反応条件を以下の通りにした他は実施例１４と同様］
前記化合物（４−Ｂ）２０．０ｇ（０．０７３４ｍｏｌ、ＨＰＬＣ（条件１）：９８．２面積％）にオクチルブロマイド１４１．８ｇ（０．７３４３ｍｏｌ）を加え、７５〜７８℃で２０．５時間反応を行った。反応混合物をＨＰＬＣ（条件２）で分析すると、前記化合物（４−Ｂ）のピークは消失していた。反応混合物にアセトニトリル１９．３ｍｌを添加して静置すると、上層が前記化合物（２）のアセトニトリル溶液層、下層がオクチルブロマイド層となり、下層を分離した。次に上層を８０℃１０Ｔｏｒｒまで減圧濃縮し、油状の前記化合物（２）４４．９ｇ（粗収率：９３．０％）を得た。得られた油状物をＨＰＬＣ（条件２）で分析すると、前記化合物（２）のピークの面積％は９７．５％であった。（1Ｈ−ＮＭＲ（ｄ6−ＤＭＳＯ）：δ０．８６−０．９０（６Ｈ，ｔ，Ｊ＝５．５Ｈｚ，ＣＨ 3×２）、δ１．２６−１．３５（２０Ｈ，ｍ，−（ＣＨ 2）5−×２）、δ１．８０−１．８５（４Ｈ，ｍ，−（ＣＨ 2）2−×２）、δ２．０５−３．０２（４Ｈ，ｍ，ＣＨ 2×２）、δ３．７２−３．７５（４Ｈ，ｍ，ＣＨ 2×２）、δ４．６８−４．７２（４Ｈ，ｍ，ＣＨ 2×２）、δ４．８５（４Ｈ，ｓ，ＣＨ 2×２）、δ８．１３（４Ｈ，ｄｄ，Ｊ＝０．８Ｈｚ，６．５Ｈｚ，ａｒｏｍＨ×４）、δ８．８５（４Ｈ，ｄｄ，Ｊ＝１．６Ｈｚ，６．５Ｈｚ，ａｒｏｍＨ×４）
<Example 30>
[Synthesis of Compound (2): Same as Example 14 except that purified compound (4-B) was used and the reaction conditions were as follows]
141.8 g (0.7343 mol) of octyl bromide was added to 20.0 g (0.0734 mol, HPLC (condition 1): 98.2 area%) of the compound (4-B), and the mixture was heated at 75 to 78 ° C. for 20.5 hours. Reaction was performed. When the reaction mixture was analyzed by HPLC (condition 2), the peak of the compound (4-B) disappeared. When 19.3 ml of acetonitrile was added to the reaction mixture and allowed to stand, the upper layer was an acetonitrile solution layer of the compound (2), the lower layer was an octyl bromide layer, and the lower layer was separated. Next, the upper layer was concentrated under reduced pressure to 80 ° C. and 10 Torr to obtain 44.9 g (crude yield: 93.0%) of the oily compound (2). When the obtained oil was analyzed by HPLC (condition 2), the area% of the peak of the compound (2) was 97.5%. ( 1 H-NMR (d 6 -DMSO): δ0.86-0.90 (6H, t, J = 5.5 Hz, C H 3 × 2), δ1.26-1.35 (20H, m, − (C H 2 ) 5- × 2), δ 1.80-1.85 (4H, m,-(C H 2 ) 2- × 2), δ 2.05-3.02 (4H, m, C H 2 × 2), δ 3.72-3.75 (4H, m, C H 2 × 2), δ 4.68-4.72 (4H, m, C H 2 × 2), δ 4.85 (4H, s, C H 2 × 2), δ 8.13 (4H, dd, J = 0.8 Hz, 6.5 Hz, arom H × 4), δ 8.85 (4H, dd, J = 1.6 Hz, 6.5 Hz, arom) H x 4)
試験例１＜本発明の前記化合物（１）の各種細菌に対する静菌活性＞
対照化合物には塩化ベンザルコニウムを用いて最小発育阻止濃度（ＭＩＣ）を測定した。
最小発育阻止濃度（ＭＩＣ）の測定は一般的なブロス希釈法に従い、ニュトリエントブロスを用いて、菌懸濁濃度が１０6ｃｅｌｌ／ｍｌになるように調整した定常期状態の菌液を段階希釈した薬剤溶液と混合し、３７℃、２４時間静置培養後、増殖の有無によりＭＩＣ値を決定した。
供試菌としてグラム陰性菌１０種およびグラム陽性菌６種を用いた。その結果を表１に示す。
Test Example 1 <Bacteriostatic activity against various bacteria of the compound (1) of the present invention>
The minimum inhibitory concentration (MIC) was measured using benzalkonium chloride as a control compound.
The minimum inhibitory concentration (MIC) was measured according to a general broth dilution method. Using a nutrient broth, a steady-state bacterial solution adjusted to a cell suspension concentration of 10 6 cells / ml was serially diluted. The MIC value was determined based on the presence or absence of proliferation after mixing with the drug solution and standing culture at 37 ° C. for 24 hours.
Ten gram-negative bacteria and six gram-positive bacteria were used as test bacteria. The results are shown in Table 1.
試験例２＜本発明の化合物（１）の各種細菌に対する殺菌活性（ＭＢＣ）＞
対照化合物には、ヨウ化ベンザルコニウムを用いた。供試菌としてグラム陰性菌５種およびグラム陽性菌４種を用い、前記と同様にして最小殺菌０濃度（ＭＢＣ）を測定した。その結果を表２に示す。
Test Example 2 <bactericidal activity (MBC) against various bacteria of the compound (1) of the present invention>
Benzalkonium iodide was used as a control compound. Five gram-negative bacteria and four gram-positive bacteria were used as test bacteria, and the minimum bactericidal concentration (MBC) was measured in the same manner as described above. The results are shown in Table 2.
試験例３＜本発明の化合物（１）の真菌に対する最小発育阻止濃度（ＭＩＣ）の測定＞
対照化合物にはＴＢＺ（２−（４’−チアゾリル）ベンズイミダゾール）を用いた。最小発育阻止濃度（ＭＩＣ）の測定は、一般的なブロス希釈法に従い、サブロー培地を用い、前培養した供試菌を湿潤剤添加殺菌水で胞子液を調製した。希釈薬剤溶液１ｍｌと胞子液１ｍｌを混合し、インキュベーダー中で３０℃、１週間培養後、増殖の有無を濁度で判定し、濁度を生じていないところをＭＩＣとした。その結果を表３に示す。
Test Example 3 <Measurement of Minimum Growth Inhibitory Concentration (MIC) of Fungus of Compound (1) of the Present Invention>
TBZ (2- (4′-thiazolyl) benzimidazole) was used as a reference compound. The minimum inhibitory concentration (MIC) was measured according to a general broth dilution method, using a Sabouraud medium, and preparing a spore solution of pre-cultured test bacteria with humectant-added sterilized water. Diluted drug solution (1 ml) and spore solution (1 ml) were mixed, cultured in an incubator at 30 ° C. for 1 week, the presence or absence of growth was determined by turbidity, and the place where no turbidity occurred was defined as MIC. The results are shown in Table 3.
試験例４＜本発明の前記化合物（２）の各種細菌に対する静菌活性＞
前記試験例１と同様にして表４に記載の結果を得た。
The results shown in Table 4 were obtained in the same manner as in Test Example 1.
試験例５＜本発明の化合物（２）の各種細菌に対する殺菌活性（ＭＢＣ）＞
前記試験例２と同様にして表５に記載の結果を得た。
The results shown in Table 5 were obtained in the same manner as in Test Example 2.
試験例６＜本発明の化合物（２）の真菌に対する最小発育阻止濃度（ＭＩＣ）の測定＞
前記試験例３と同様にして表６に記載の結果を得た。
The results shown in Table 6 were obtained in the same manner as in Test Example 3.
本発明によれば、入手の容易なピリジン化合物を出発原料として、簡便、かつ安価に新規な殺菌性ピリジン化合物を提供することができる。 According to the present invention, a novel bactericidal pyridine compound can be provided simply and inexpensively using a readily available pyridine compound as a starting material.
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