JP5148836B2 - Process for producing nicotinic acid derivative or salt thereof - Google Patents
Process for producing nicotinic acid derivative or salt thereof Download PDFInfo
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- JP5148836B2 JP5148836B2 JP2006090743A JP2006090743A JP5148836B2 JP 5148836 B2 JP5148836 B2 JP 5148836B2 JP 2006090743 A JP2006090743 A JP 2006090743A JP 2006090743 A JP2006090743 A JP 2006090743A JP 5148836 B2 JP5148836 B2 JP 5148836B2
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- 150000003839 salts Chemical class 0.000 title claims description 43
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical class OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 title claims description 33
- 238000000034 method Methods 0.000 title claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 37
- 238000006243 chemical reaction Methods 0.000 claims description 28
- 125000000217 alkyl group Chemical group 0.000 claims description 24
- 229910052801 chlorine Inorganic materials 0.000 claims description 24
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 21
- 229910052783 alkali metal Inorganic materials 0.000 claims description 19
- -1 alkali metal alkoxide Chemical class 0.000 claims description 19
- 238000004519 manufacturing process Methods 0.000 claims description 14
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 13
- 239000000460 chlorine Substances 0.000 claims description 12
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 9
- 125000001188 haloalkyl group Chemical group 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 9
- 150000001340 alkali metals Chemical class 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 235000001968 nicotinic acid Nutrition 0.000 claims description 6
- 229960003512 nicotinic acid Drugs 0.000 claims description 6
- 239000011664 nicotinic acid Substances 0.000 claims description 6
- 150000004703 alkoxides Chemical class 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 230000003301 hydrolyzing effect Effects 0.000 claims description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 230000002140 halogenating effect Effects 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- RAUVGUCBJUCSKI-UHFFFAOYSA-N methyl 2-methoxy-4-methylpyridine-3-carboxylate Chemical compound COC(=O)C1=C(C)C=CN=C1OC RAUVGUCBJUCSKI-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- UXGQMOASUWTWJN-UHFFFAOYSA-N 5-chloro-2-methoxy-4-methylpyridine-3-carboxylic acid Chemical compound COC1=NC=C(Cl)C(C)=C1C(O)=O UXGQMOASUWTWJN-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 150000008282 halocarbons Chemical class 0.000 description 3
- NZVAQFVFQJGTLU-UHFFFAOYSA-N methyl 5-chloro-2-methoxy-4-methylpyridine-3-carboxylate Chemical compound COC(=O)C1=C(C)C(Cl)=CN=C1OC NZVAQFVFQJGTLU-UHFFFAOYSA-N 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000001632 sodium acetate Substances 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- RJQVQDYEBIHZKH-UHFFFAOYSA-N methyl 2-chloro-4-methylpyridine-3-carboxylate Chemical compound COC(=O)C1=C(C)C=CN=C1Cl RJQVQDYEBIHZKH-UHFFFAOYSA-N 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 description 2
- 239000011736 potassium bicarbonate Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 2
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 1
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- BZSXEZOLBIJVQK-UHFFFAOYSA-N 2-methylsulfonylbenzoic acid Chemical compound CS(=O)(=O)C1=CC=CC=C1C(O)=O BZSXEZOLBIJVQK-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 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 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- VRLDVERQJMEPIF-UHFFFAOYSA-N dbdmh Chemical compound CC1(C)N(Br)C(=O)N(Br)C1=O VRLDVERQJMEPIF-UHFFFAOYSA-N 0.000 description 1
- 229940117389 dichlorobenzene Drugs 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- ZCCWUIFQBCQSAS-UHFFFAOYSA-N ethyl 2-chloro-4-methylpyridine-3-carboxylate Chemical compound CCOC(=O)C1=C(C)C=CN=C1Cl ZCCWUIFQBCQSAS-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical compound CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
Description
本発明は、医薬又は農薬の中間体として有用なニコチン酸誘導体又はその塩の製造方法に関する。 The present invention relates to a method for producing a nicotinic acid derivative or a salt thereof useful as an intermediate for a pharmaceutical or agrochemical.
後記式（Ｉ）で表されるニコチン酸誘導体及びその製造原料である後記式(II)で表される化合物の一部は、ヨーロッパ公開特許公報第４９４７７０号記載の一般式（Ｉ）で表される化合物に包含されている。しかしながら、同公報には各化合物の具体的開示も、製造方法の記載もない。一方、後記式(III)で表される化合物の一部は、特開平６−４１１１６号第41頁及び第58〜69頁に、式(VI)の化合物として記載されている。 A part of a nicotinic acid derivative represented by the following formula (I) and a compound represented by the following formula (II) which is a raw material for the production thereof are represented by the general formula (I) described in European Patent Publication No. 494770. It is included in the compound. However, there is no specific disclosure of each compound or description of the production method in this publication. On the other hand, some of the compounds represented by the following formula (III) are described as compounds of the formula (VI) in JP-A-6-41116, pages 41 and 58-69.
従来から種々のニコチン酸誘導体の製造方法は公知であるが、特定の置換基パターンのニコチン酸誘導体を製造するのに、必ずしも効率的な方法ではない。また、後記式（Ｉ）で表されるニコチン酸誘導体又はその塩を効率的に製造する方法が希求されていた。 Conventionally, various methods for producing nicotinic acid derivatives are known, but it is not always an efficient method for producing nicotinic acid derivatives having a specific substituent pattern. Further, a method for efficiently producing a nicotinic acid derivative represented by the following formula (I) or a salt thereof has been desired.
本発明者らは、前述の問題点を解決すべく検討した結果、後記式(III)で表される化合物又はその塩を出発物質とした後記式（Ｉ）で表されるニコチン酸誘導体又はその塩の製造方法を見出し、本発明を完成した。即ち、本発明は、式（Ｉ）： As a result of studying to solve the above-mentioned problems, the present inventors have determined that a nicotinic acid derivative represented by the following formula (I) or a nicotinic acid derivative represented by the following formula (I) or a salt thereof represented by the following formula (III) or a salt thereof: A method for producing a salt was found and the present invention was completed. That is, the present invention relates to the formula (I):
（式中、Ｘ1及びＸ2は各々独立に、水素原子、ハロゲン原子、アルキル基、アルコキシ基、ハロアルキル基及びハロアルコキシ基であり；Ｒはアルキル基であり；Halは塩素原子又は臭素原子である）で表されるニコチン酸誘導体又はその塩の製造方法であって、式（II）： Wherein X 1 and X 2 are each independently a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a haloalkyl group or a haloalkoxy group; R is an alkyl group; Hal is a chlorine atom or a bromine atom A nicotinic acid derivative represented by the formula (II):
（式中、Ｘ1、Ｘ2及びＲは前述の通りである）で表される化合物又はその塩と、塩素原子又は臭素原子を含むハロゲン化剤とを反応させることを特徴とする前記ニコチン酸誘導体又はその塩の製造方法に関する。また、本発明は、
(i)式(III)：
(Wherein X 1 , X 2 and R are as defined above) or a salt thereof and a halogenating agent containing a chlorine atom or a bromine atom are reacted with the nicotinic acid The present invention relates to a method for producing a derivative or a salt thereof. The present invention also provides:
(i) Formula (III):
（式中、Ｘ1及びＸ2は各々独立に、水素原子、ハロゲン原子、アルキル基、アルコキシ基、ハロアルキル基及びハロアルコキシ基であり；Ｒ’はアルキル基であり；Hal’はフッ素原子、塩素原子又は臭素原子である）で表される化合物又はその塩と、式(IV)：ＲＯ-Ｍ（式中、Ｒはアルキル基であり、Ｍはアルカリ金属原子である）で表されるアルカリ金属アルコキシドとを反応させ、前記式（II）の化合物又はその塩を製造する第一段階、並びに(ii)第一段階で得た式(II)の化合物又はその塩と、塩素原子又は臭素原子を含むハロゲン化剤とを反応させ、前記式（Ｉ）のニコチン酸誘導体又はその塩を製造する第二段階から構成されることを特徴とする前記式（Ｉ）のニコチン酸誘導体又はその塩の製造方法に関する。さらに、本発明は、式（Ｉ）： Wherein X 1 and X 2 are each independently a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a haloalkyl group or a haloalkoxy group; R ′ is an alkyl group; Hal ′ is a fluorine atom, chlorine An alkali metal represented by formula (IV): RO-M (wherein R is an alkyl group and M is an alkali metal atom) A first step of producing a compound of the formula (II) or a salt thereof by reacting with an alkoxide, and (ii) a compound of the formula (II) or a salt thereof obtained in the first step and a chlorine atom or a bromine atom. Production of a nicotinic acid derivative of the formula (I) or a salt thereof, comprising a second step of producing a nicotinic acid derivative of the formula (I) or a salt thereof by reacting with a halogenating agent comprising Regarding the method. Furthermore, the present invention provides a compound of formula (I):
式（Ｉ）、式(II)、式(III) 及び式(Ｖ)中のＸ1及びＸ2で表されるハロゲン原子、ハロアルキル基及びハロアルコキシ基中のハロゲン部分としては、フッ素、塩素、臭素及びヨウ素が挙げられ、望ましくはフッ素、塩素及び臭素が挙げられる。 In the formula (I), the formula (II), the formula (III) and the formula (V), the halogen atom represented by X 1 and X 2 , the haloalkyl group, and the halogen moiety in the haloalkoxy group include fluorine, chlorine, Bromine and iodine are preferable, and fluorine, chlorine and bromine are preferable.
式（Ｉ）、式(II)、式(III)及び式(Ｖ)中に含まれるアルキル部分としては、例えばＣ1-6アルキル（例えばメチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｔ−ブチル等）が挙げられる。 Examples of the alkyl moiety contained in the formula (I), formula (II), formula (III) and formula (V) include C 1-6 alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- Butyl etc.).
式（Ｉ）、式(II)、式(III)及び式(Ｖ)中に含まれるアルコキシ部分としては、例えばＣ1-6アルコキシ（例えばメトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｔ−ブトキシ等）が挙げられる。 Examples of the alkoxy moiety contained in formula (I), formula (II), formula (III) and formula (V) include C 1-6 alkoxy (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t -Butoxy and the like).
式（Ｉ）、式(II)、式(III)及び式(Ｖ)の化合物は、酸性物質とともに塩を形成してもよく、例えば塩酸塩、臭化水素酸塩、リン酸塩、硫酸塩又は硝酸塩のような無機酸塩；酢酸塩；ｐ−トルエンスルホン酸塩；メタンスルホン酸塩又はプロパンスルホン酸塩のような有機酸塩を形成することができる。また、式(Ｖ)の化合物は、アルカリ金属塩又はアルカリ土類金属塩を形成してもよく、例えばナトリウム塩、カリウム塩、マグネシウム塩、カルシウム塩などを形成することができる。 The compounds of formula (I), formula (II), formula (III) and formula (V) may form salts with acidic substances, for example hydrochlorides, hydrobromides, phosphates, sulfates Or an inorganic acid salt such as nitrate; acetate; p-toluenesulfonate; organic acid salt such as methanesulfonate or propanesulfonate can be formed. Further, the compound of the formula (V) may form an alkali metal salt or an alkaline earth metal salt, for example, a sodium salt, potassium salt, magnesium salt, calcium salt, or the like.
以下に本発明に係わるニコチン酸誘導体又はその塩の製造方法につき反応フローを示し詳述する。式（Ｉ）のニコチン酸誘導体又はその塩は、式（II）の化合物又はその塩と塩素原子又は臭素原子を含むハロゲン化剤とを反応することにより製造されるが、下記フローに示した二段階の反応によって製造すると効率的である。 The reaction flow is shown and explained in detail below for the method for producing a nicotinic acid derivative or salt thereof according to the present invention. The nicotinic acid derivative of the formula (I) or a salt thereof is produced by reacting the compound of the formula (II) or a salt thereof with a halogenating agent containing a chlorine atom or a bromine atom. It is efficient to produce by a step reaction.
式(III)の化合物又はその塩と、式(IV)で表されるアルカリ金属アルコキシドとを反応させ、前記式（II）の化合物又はその塩を製造する第一段階の反応は、溶媒の存在下、0〜150℃の反応温度、0.1〜24時間の反応時間で行われるのが望ましい。また、式(III)の化合物中のＲ’で表されるアルキル基と、式(IV)で表されるアルカリ金属アルコキシド中のＲで表されるアルキル基は同一の置換基であっても、異なった置換基であってもよい。本反応は減圧下で実施することもできる。 The reaction in the first step for producing the compound of the formula (II) or a salt thereof by reacting the compound of the formula (III) or a salt thereof with the alkali metal alkoxide represented by the formula (IV) is carried out in the presence of a solvent. The reaction is preferably performed at a reaction temperature of 0 to 150 ° C. and a reaction time of 0.1 to 24 hours. Further, the alkyl group represented by R ′ in the compound of formula (III) and the alkyl group represented by R in the alkali metal alkoxide represented by formula (IV) may be the same substituent, Different substituents may be used. This reaction can also be carried out under reduced pressure.
第一段階の反応で使用される式(IV)のアルカリ金属アルコキシドとしては、ナトリウムメトキシド、ナトリウムエトキシド、カリウムメトキシド等が挙げられるが、その中でもナトリウムメトキシドを使用するのが望ましい。アルカリ金属アルコキシドは式(III)の化合物又はその塩1モルに対して1.0〜5.0モルの割合で使用されるのが、望ましい。 Examples of the alkali metal alkoxide of the formula (IV) used in the first stage reaction include sodium methoxide, sodium ethoxide, potassium methoxide, etc. Among them, sodium methoxide is preferably used. The alkali metal alkoxide is desirably used in a ratio of 1.0 to 5.0 moles per mole of the compound of the formula (III) or a salt thereof.
第一段階の反応で使用される溶媒としては、反応に関与しないものであれば特に限定はなく、例えばベンゼン、トルエン、キシレン等の芳香族炭化水素、ヘキサン、シクロへキサン等の脂肪族炭化水素、塩化メチレン、1,2-ジクロロエタン等のハロゲン化炭化水素、メタノール、エタノール等のアルコール類、テトラヒドロフラン、1,2-ジメトキシエタン等のエーテル類、N,N-ジメチルホルムアミド、ジメチルスルホキシド等の非プロトン性極性溶媒等が挙げられるが、その中でもアルコール類を使用するのが望ましい。 The solvent used in the first stage reaction is not particularly limited as long as it does not participate in the reaction. For example, aromatic hydrocarbons such as benzene, toluene and xylene, and aliphatic hydrocarbons such as hexane and cyclohexane. , Halogenated hydrocarbons such as methylene chloride and 1,2-dichloroethane, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and 1,2-dimethoxyethane, non-protons such as N, N-dimethylformamide and dimethyl sulfoxide Among them, it is desirable to use alcohols.
式（II）の化合物又はその塩と、塩素原子又は臭素原子を含むハロゲン化剤とを反応させて、前記式（Ｉ）のニコチン酸誘導体又はその塩を製造する第二段階の反応は、塩基及び溶媒の存在下、0〜150℃の反応温度、0.1〜24時間の反応時間で行われるのが望ましい。本反応は減圧下で実施することもできる。 The reaction in the second step of producing a nicotinic acid derivative of the formula (I) or a salt thereof by reacting a compound of the formula (II) or a salt thereof with a halogenating agent containing a chlorine atom or a bromine atom is a base. And in the presence of a solvent, the reaction temperature is preferably 0 to 150 ° C. and the reaction time is 0.1 to 24 hours. This reaction can also be carried out under reduced pressure.
第二段階の反応で使用される塩素原子又は臭素原子を含むハロゲン化剤としては、通常の塩素化、臭素化に用いるものであれば特に限定はなく、例えば塩素、臭素、塩化スルフリル、次亜塩素酸ナトリウム、N-クロロコハク酸イミド、N-ブロモコハク酸イミド、1,3-ジクロロ-5,5-ジメチルヒダントイン、1,3-ジブロモ-5,5-ジメチルヒダントイン等が挙げられるが、その中でも塩素又は臭素を使用するのが望ましい。当該ハロゲン化剤は、式（II）の化合物1モルに対して1.0〜5.0モルの割合で使用されるのが望ましい。 The halogenating agent containing a chlorine atom or bromine atom used in the second stage reaction is not particularly limited as long as it is used for ordinary chlorination and bromination. For example, chlorine, bromine, sulfuryl chloride, hypochlorous acid, Examples include sodium chlorate, N-chlorosuccinimide, N-bromosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin, and 1,3-dibromo-5,5-dimethylhydantoin. Or it is desirable to use bromine. The halogenating agent is preferably used in a proportion of 1.0 to 5.0 mol per 1 mol of the compound of formula (II).
第二段階の反応で使用される塩基としては、例えば、水酸化ナトリウム、水酸化カリウム等のアルカリ金属の水酸化物；炭酸ナトリウム、炭酸カリウム等のアルカリ金属の炭酸塩；酢酸ナトリウム、酢酸カリウム等のアルカリ金属の酢酸塩；炭酸水素ナトリウム、炭酸水素カリウム等のアルカリ金属の炭酸水素塩；ピリジン、トリエチルアミン等のアミン類等が挙げられるが、その中でも酢酸ナトリウムを使用するのが望ましい。塩基は、式（II）の化合物1モルに対して0.1〜5.0モルの割合で使用されるのが望ましい。 Examples of the base used in the second stage reaction include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; sodium acetate and potassium acetate. Alkali metal acetates such as sodium hydrogen carbonate and potassium hydrogen carbonate; amines such as pyridine and triethylamine are preferable, among which sodium acetate is preferably used. The base is preferably used in a proportion of 0.1 to 5.0 moles per mole of the compound of formula (II).
第二段階の反応で使用される溶媒としては、反応に関与しないものであれば特に限定はなく、例えばクロロベンゼン、ジクロロベンゼン等の芳香族炭化水素；ヘキサン、シクロへキサン等の脂肪族炭化水素；塩化メチレン、1,2-ジクロロエタン等のハロゲン化炭化水素；テトラヒドロフラン、1,2-ジメトキシエタン等のエーテル類；酢酸等のカルボン酸類、酢酸メチル、酢酸エチル等のエステル類；アセトニトリル、プロピオニトリル等のニトリル類；N,N-ジメチルホルムアミド、ジメチルスルホキシド等の非プロトン性極性溶媒等が挙げられるが、その中でもエステル類を使用するのが望ましい。 The solvent used in the second-stage reaction is not particularly limited as long as it does not participate in the reaction. For example, aromatic hydrocarbons such as chlorobenzene and dichlorobenzene; aliphatic hydrocarbons such as hexane and cyclohexane; Halogenated hydrocarbons such as methylene chloride and 1,2-dichloroethane; Ethers such as tetrahydrofuran and 1,2-dimethoxyethane; Carboxylic acids such as acetic acid; Esters such as methyl acetate and ethyl acetate; Acetonitrile, propionitrile, etc. Aprotic polar solvents such as N, N-dimethylformamide and dimethyl sulfoxide, among which nitriles are preferably used.
前記した式(Ｉ)の化合物又はその塩を加水分解して式(Ｖ)の化合物又はその塩を製造する反応は、塩基の存在下、水または水を含む溶媒中で、0〜150℃の反応温度、0.1〜24時間の反応時間で行われるのが望ましい。本反応は減圧下で実施することもできる。
加水分解反応で使用される塩基としては、例えば、水酸化ナトリウム、水酸化カリウム等のアルカリ金属の水酸化物；水酸化マグネシウム、水酸化カルシウム等のアルカリ土類金属の水酸化物；炭酸ナトリウム、炭酸カリウム等のアルカリ金属の炭酸塩；炭酸マグネシウム、炭酸カルシウム等のアルカリ土類金属の炭酸塩、炭酸水素ナトリウム、炭酸水素カリウム等のアルカリ金属の炭酸水素塩等が挙げられるが、その中でも水酸化ナトリウムを使用するのが望ましい。塩基は、式(Ｉ)の化合物又はその塩1モルに対して1モル以上使用されるのが望ましい。
加水分解反応で使用される溶媒としては、反応に関与しないものであれば特に限定はなく、例えばベンゼン、トルエン、キシレン等の芳香族炭化水素；ヘキサン、シクロヘキサン等の脂肪族炭化水素、塩化メチレン、1,2-ジクロロエタン等のハロゲン化炭化水素；メタノール、エタノール等のアルコール類；テトラヒドロフラン、1,2-ジメトキシエタン等のエーテル類、アセトニトリル、プロピオニトリル等のニトリル類；N,N-ジメチルホルムアミド、ジメチルスルホキシド等の非プロトン性極性溶媒等が挙げられるが、加水分解反応は水または水を含むアルコール中で行なうのが望ましい。
加水分解反応終了後、式(Ｖ)の化合物はアルカリ金属塩又はアルカリ土類金属塩を形成するため、塩酸、硫酸等の鉱酸で中和処理することにより、式(Ｖ)の化合物を得ることができる。また、中和処理なしに、式(Ｖ)の化合物のアルカリ金属塩又はアルカリ土類金属塩を単離することもできる。
The reaction for producing the compound of formula (V) or a salt thereof by hydrolyzing the compound of formula (I) or a salt thereof described above is carried out at 0 to 150 ° C. in water or a solvent containing water in the presence of a base. The reaction is preferably carried out at a reaction temperature of 0.1 to 24 hours. This reaction can also be carried out under reduced pressure.
Examples of the base used in the hydrolysis reaction include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide; sodium carbonate, Examples include alkali metal carbonates such as potassium carbonate; alkaline earth metal carbonates such as magnesium carbonate and calcium carbonate; and alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate. It is desirable to use sodium. The base is preferably used in an amount of 1 mol or more per 1 mol of the compound of the formula (I) or a salt thereof.
The solvent used in the hydrolysis reaction is not particularly limited as long as it does not participate in the reaction. For example, aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and cyclohexane, methylene chloride, Halogenated hydrocarbons such as 1,2-dichloroethane; alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and 1,2-dimethoxyethane; nitriles such as acetonitrile and propionitrile; N, N-dimethylformamide; Examples thereof include aprotic polar solvents such as dimethyl sulfoxide, but the hydrolysis reaction is preferably carried out in water or an alcohol containing water.
After completion of the hydrolysis reaction, the compound of the formula (V) forms an alkali metal salt or an alkaline earth metal salt. Thus, the compound of the formula (V) is obtained by neutralizing with a mineral acid such as hydrochloric acid or sulfuric acid. be able to. Further, the alkali metal salt or alkaline earth metal salt of the compound of the formula (V) can be isolated without neutralization treatment.
前記式（Ｖ）の化合物又はその塩を製造する方法においては、適宜、前記した式（Ｉ）のニコチン酸誘導体又はその塩の製造方法とを組み合わせることができる。その実施態様を以下に記載する。
（１）式(II)：
In the method for producing the compound of the formula (V) or a salt thereof, the method for producing the nicotinic acid derivative of the formula (I) or a salt thereof can be appropriately combined. The embodiment is described below.
(1) Formula (II):
（式中、Ｘ1、Ｘ2及びＲは前述の通りである）で表される化合物又はその塩と、ハロゲン化剤とを反応させ、式（Ｉ）： (Wherein, X 1 , X 2 and R are as defined above) or a salt thereof and a halogenating agent are reacted to form a compound represented by formula (I):
（式中、Ｘ1、Ｘ2、及びＲは前述の通りであり；Halは塩素原子又は臭素原子である）で表されるニコチン酸誘導体又はその塩を得、このものを加水分解して式（Ｖ）： (Wherein X 1 , X 2 , and R are as described above; Hal is a chlorine atom or a bromine atom) to obtain a nicotinic acid derivative or a salt thereof, which is hydrolyzed to obtain a formula (V):
（式中、Ｘ1、Ｘ2、Ｒ及びHalは前述の通りである）で表されるニコチン酸又はその塩を製造する方法。
（２）(i)式(III)：
(Wherein, X 1 , X 2 , R and Hal are as described above), and a method for producing nicotinic acid or a salt thereof.
(2) (i) Formula (III):
（式中、Ｘ1及びＸ2は各々独立に、水素原子、ハロゲン原子、アルキル基、アルコキシ基、ハロアルキル基及びハロアルコキシ基であり；Ｒ’はアルキル基であり；Hal’はフッ素原子、塩素原子又は臭素原子である）で表される化合物又はその塩と、式(IV)：ＲＯ-Ｍ（式中、Ｒはアルキル基であり、Ｍはアルカリ金属原子である）で表されるアルカリ金属アルコキシドとを反応させ、式（II）： Wherein X 1 and X 2 are each independently a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a haloalkyl group or a haloalkoxy group; R ′ is an alkyl group; Hal ′ is a fluorine atom, chlorine An alkali metal represented by formula (IV): RO-M (wherein R is an alkyl group and M is an alkali metal atom) Reaction with an alkoxide gives the formula (II):
（式中、Ｘ1、Ｘ2及びＲは前述の通りである）で表される化合物又はその塩を製造する第一段階、
(ii)第一段階で得られた式(II)の化合物とハロゲン化剤とを反応させ、式（Ｉ）：
Wherein X 1 , X 2 and R are as defined above, or a first step for producing a salt thereof,
(ii) reacting the compound of formula (II) obtained in the first step with a halogenating agent to give formula (I):
（式中、Ｘ1、Ｘ2、及びＲは前述の通りであり；Halは塩素原子又は臭素原子である）で表されるニコチン酸誘導体又はその塩を製造する第二段階並びに
(iii)第二段階で得た式（Ｉ）の化合物又はその塩を加水分解して、式（Ｖ）：
(Wherein, X 1 , X 2 and R are as defined above; Hal is a chlorine atom or a bromine atom)
(iii) Hydrolyzing the compound of formula (I) or a salt thereof obtained in the second step to obtain a compound of formula (V):
（式中、Ｘ1、Ｘ2、Ｒ及びHalは前述の通りである）で表されるニコチン酸又はその塩を得る第三段階より構成されることを特徴とする前記式（Ｖ）で表されるニコチン酸又はその塩を製造する方法。 (Wherein, X 1 , X 2 , R and Hal are as described above), and is constituted by the third step of obtaining nicotinic acid or a salt thereof represented by the formula (V) Of producing nicotinic acid or a salt thereof.
（３）式（Ｉ）の化合物が5-クロロ-2-メトキシ-4-メチルニコチン酸メチルであり、式(II)の化合物が、２−メトキシ−４−メチルニコチン酸メチルであり、式（Ｖ）の化合物が5-クロロ-2-メトキシ-4-メチルニコチン酸である（１）又は（２）の方法。
（４）式(III)の化合物が2-クロロ-4-メチルニコチン酸エチル又は2-クロロ-4-メチルニコチン酸メチルである（２）の方法。
(3) The compound of formula (I) is methyl 5-chloro-2-methoxy-4-methylnicotinate, the compound of formula (II) is methyl 2-methoxy-4-methylnicotinate, The method of (1) or (2), wherein the compound of V) is 5-chloro-2-methoxy-4-methylnicotinic acid.
(4) The method of (2), wherein the compound of formula (III) is ethyl 2-chloro-4-methylnicotinate or methyl 2-chloro-4-methylnicotinate.
合成例１
攪拌機、冷却器及び温度計を備えた300ml四つ口フラスコに、28％ナトリウムメチラートメタノール溶液137.8g (714 mmol)を仕込み、系内温度を50℃に保ちながら2-クロロ-4-メチルニコチン酸エチル47.5g(238mmol)のメタノール48ml溶液を滴下し、1時間攪拌した。水500ml中に反応液を投入し、ジエチルエーテルで抽出した後、減圧下蒸留して2-メトキシ-4-メチルニコチン酸メチル (沸点95℃/ 7mmHg)27ｇ(収率63%)を得た。
Synthesis example 1
A 300 ml four-necked flask equipped with a stirrer, a condenser and a thermometer was charged with 137.8 g (714 mmol) of a 28% sodium methylate methanol solution, and 2-chloro-4-methylnicotine was maintained while maintaining the system temperature at 50 ° C. A solution of ethyl acetate 47.5 g (238 mmol) in methanol 48 ml was added dropwise and stirred for 1 hour. The reaction solution was poured into 500 ml of water, extracted with diethyl ether, and distilled under reduced pressure to obtain 27 g (yield 63%) of methyl 2-methoxy-4-methylnicotinate (boiling point 95 ° C./7 mmHg).
合成例２
攪拌機、温度計、冷却管及びN2ガス導入管を備えた500ml四つ口フラスコに、N2雰囲気下、28%ナトリウムメチラートメタノール溶液203g(1.05 mol)を仕込んだ。系内温度を40℃以下に保ちながら2-クロロ-4-メチルニコチン酸メチル92.8g(0.5 mol)を約30分要して滴下した。滴下終了後、系内温度を45〜50℃に保持しながら原料の消失まで約４時間反応させた。反応を終えて減圧下系内のメタノールを約100ml蒸留除去した後、7%硫酸水溶液390gとトルエン300mlの混合溶液に攪拌下投入した。抽出、分液の後、トルエン層を0.5%炭酸水素ナトリウム水溶液150mlで洗浄した。トルエンを留去した後、減圧蒸留にて85〜92℃/5mmHgの留分2-メトキシ-4-メチルニコチン酸メチル83.3g（収率92%）を得た。
Synthesis example 2
A 500 ml four-necked flask equipped with a stirrer, a thermometer, a condenser tube and an N 2 gas introduction tube was charged with 203 g (1.05 mol) of 28% sodium methylate methanol solution in an N 2 atmosphere. While maintaining the system temperature at 40 ° C. or lower, 92.8 g (0.5 mol) of methyl 2-chloro-4-methylnicotinate was added dropwise over about 30 minutes. After completion of the dropwise addition, the reaction was continued for about 4 hours until the raw material disappeared while maintaining the system temperature at 45-50 ° C. After completion of the reaction, about 100 ml of methanol in the system was distilled off under reduced pressure, and then poured into a mixed solution of 390 g of 7% sulfuric acid aqueous solution and 300 ml of toluene with stirring. After extraction and liquid separation, the toluene layer was washed with 150 ml of 0.5% aqueous sodium hydrogen carbonate solution. After toluene was distilled off, 83.3 g of methyl 2-methoxy-4-methylnicotinate (yield 92%) having a fraction of 85 to 92 ° C./5 mmHg was obtained by distillation under reduced pressure.
合成例３
攪拌機、温度計、冷却管及びCl2ガス導入管を備えた500ml四つ口フラスコに、2-メトキシ-4-メチルニコチン酸メチル90.6g (0.5 mol)、酢酸エチル300ml及び酢酸ナトリウム49.2g(0.6 mol)を仕込んだ。系内温度を70℃に保持しながら塩素ガスを（導入量10g/hr）約４時間導入し、原料の消失を確認して反応を終えた。冷水700mlに反応混合物を投入して酢酸エチル200mlを加え、抽出、分液の後、酢酸エチル層を1%炭酸水素ナトリウム水溶液150mlで洗浄した。無水亡硝で乾燥後酢酸エチルを留去して目的物 5-クロロ-2-メトキシ-4-メチルニコチン酸メチルの粗結晶105.6g（粗収率98%）を得た。これをメタノールより再結晶して91.8g（融点43〜44℃）を得た。
Synthesis example 3
In a 500 ml four-necked flask equipped with a stirrer, a thermometer, a condenser tube and a Cl 2 gas introduction tube, methyl 2-methoxy-4-methylnicotinate 90.6 g (0.5 mol), ethyl acetate 300 ml and sodium acetate 49.2 g (0.6 mol). While maintaining the system temperature at 70 ° C., chlorine gas was introduced (introduction amount: 10 g / hr) for about 4 hours, and the reaction was completed after confirming the disappearance of the raw materials. The reaction mixture was poured into 700 ml of cold water, 200 ml of ethyl acetate was added, extracted and separated, and the ethyl acetate layer was washed with 150 ml of 1% aqueous sodium hydrogen carbonate solution. After drying over anhydrous anhydrous glass, ethyl acetate was distilled off to obtain 105.6 g (crude yield 98%) of crude crystals of the desired product methyl 5-chloro-2-methoxy-4-methylnicotinate. This was recrystallized from methanol to obtain 91.8 g (melting point: 43 to 44 ° C.).
合成例４
攪拌機、冷却器及び温度計を備えた1000ml四つ口フラスコに、5-クロロ-2-メトキシ-4-メチルニコチン酸メチル107.8g (0.5 mol)と10％水酸化ナトリウム水溶液 210g(0.525 mol)を仕込み、系内温度90℃で2時間攪拌した。放冷後、15％硫酸水溶液を滴下して中和結晶化した。析出した結晶を濾過した後、乾燥して5-クロロ-2-メトキシ-4-メチルニコチン酸（融点127〜129℃）99.3ｇ(収率98%)を得た。
Synthesis example 4
To a 1000 ml four-necked flask equipped with a stirrer, a condenser and a thermometer, add 107.8 g (0.5 mol) of methyl 5-chloro-2-methoxy-4-methylnicotinate and 210 g (0.525 mol) of 10% aqueous sodium hydroxide solution. The mixture was stirred and stirred at a system temperature of 90 ° C. for 2 hours. After standing to cool, 15% sulfuric acid aqueous solution was added dropwise to effect neutralization crystallization. The precipitated crystals were filtered and dried to obtain 99.3 g (yield 98%) of 5-chloro-2-methoxy-4-methylnicotinic acid (melting point 127-129 ° C.).
Claims (5)
(ii)第一段階で得られた式(II)の化合物と、塩素又は臭素とを反応させ、式（Ｉ）：
(iii)第二段階で得た式（Ｉ）の化合物を加水分解して、式（Ｖ）：
(ii) reacting the compound of formula (II) obtained in the first step with chlorine or bromine to give formula (I):
(iii) hydrolyzing the compound of formula (I) obtained in the second step to give formula (V):
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