JP6268093B2 - Process for producing fused heterocyclic derivative and production intermediate thereof - Google Patents
Process for producing fused heterocyclic derivative and production intermediate thereof Download PDFInfo
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- JP6268093B2 JP6268093B2 JP2014535565A JP2014535565A JP6268093B2 JP 6268093 B2 JP6268093 B2 JP 6268093B2 JP 2014535565 A JP2014535565 A JP 2014535565A JP 2014535565 A JP2014535565 A JP 2014535565A JP 6268093 B2 JP6268093 B2 JP 6268093B2
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- 238000004519 manufacturing process Methods 0.000 title claims description 32
- 238000000034 method Methods 0.000 title claims description 23
- 125000000623 heterocyclic group Chemical group 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims description 79
- 150000003839 salts Chemical class 0.000 claims description 47
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- 239000002904 solvent Substances 0.000 claims description 25
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 21
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 14
- 239000012046 mixed solvent Substances 0.000 claims description 12
- 239000004381 Choline salt Substances 0.000 claims description 6
- 235000019417 choline salt Nutrition 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- 150000007529 inorganic bases Chemical class 0.000 claims description 6
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims description 6
- 150000003248 quinolines Chemical class 0.000 claims description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- 150000004292 cyclic ethers Chemical class 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 150000002825 nitriles Chemical class 0.000 claims description 5
- 239000001763 2-hydroxyethyl(trimethyl)azanium Substances 0.000 claims description 4
- 235000019743 Choline chloride Nutrition 0.000 claims description 4
- SGMZJAMFUVOLNK-UHFFFAOYSA-M choline chloride Chemical compound [Cl-].C[N+](C)(C)CCO SGMZJAMFUVOLNK-UHFFFAOYSA-M 0.000 claims description 4
- 229960003178 choline chloride Drugs 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- DQKGOGJIOHUEGK-UHFFFAOYSA-M hydron;2-hydroxyethyl(trimethyl)azanium;carbonate Chemical compound OC([O-])=O.C[N+](C)(C)CCO DQKGOGJIOHUEGK-UHFFFAOYSA-M 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- HMBHAQMOBKLWRX-UHFFFAOYSA-N 2,3-dihydro-1,4-benzodioxine-3-carboxylic acid Chemical compound C1=CC=C2OC(C(=O)O)COC2=C1 HMBHAQMOBKLWRX-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 150000004703 alkoxides Chemical class 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 229940075419 choline hydroxide Drugs 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- OKDQKPLMQBXTNH-UHFFFAOYSA-N n,n-dimethyl-2h-pyridin-1-amine Chemical compound CN(C)N1CC=CC=C1 OKDQKPLMQBXTNH-UHFFFAOYSA-N 0.000 claims 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 239000011541 reaction mixture Substances 0.000 description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 22
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- 239000000725 suspension Substances 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 17
- 239000013078 crystal Substances 0.000 description 16
- -1 ethyl acetate Chemical compound 0.000 description 14
- 238000001914 filtration Methods 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
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- 239000010410 layer Substances 0.000 description 7
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
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- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
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- 239000012267 brine Substances 0.000 description 5
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 238000000634 powder X-ray diffraction Methods 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
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- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
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- 150000007522 mineralic acids Chemical class 0.000 description 4
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- 238000001816 cooling Methods 0.000 description 3
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 3
- 229910017604 nitric acid Inorganic materials 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 3
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- 235000011181 potassium carbonates Nutrition 0.000 description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
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- CLVGARLNAPOYQB-UHFFFAOYSA-N 5-[(2,3-difluoro-6-methoxyphenyl)methoxy]-2-fluoro-4-methoxyaniline Chemical compound COC1=CC=C(F)C(F)=C1COC1=CC(N)=C(F)C=C1OC CLVGARLNAPOYQB-UHFFFAOYSA-N 0.000 description 2
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- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- OIMDPMCIWWMTIO-UHFFFAOYSA-N CC(C(=O)O)S.O=C1C(C(SC1)C(=O)OC)C(=O)OC Chemical compound CC(C(=O)O)S.O=C1C(C(SC1)C(=O)OC)C(=O)OC OIMDPMCIWWMTIO-UHFFFAOYSA-N 0.000 description 1
- 241000206601 Carnobacterium mobile Species 0.000 description 1
- GLIWTUMSMHSEIX-UHFFFAOYSA-N FC1=C(C=C(C(=C1)OC)OCC1=C(C(=CC=C1OC)F)F)NC(NC=1C(=C(SC1)C(=O)O)C(=O)O)=O.N1=CN=CC(=C1)C(=O)OC Chemical compound FC1=C(C=C(C(=C1)OC)OCC1=C(C(=CC=C1OC)F)F)NC(NC=1C(=C(SC1)C(=O)O)C(=O)O)=O.N1=CN=CC(=C1)C(=O)OC GLIWTUMSMHSEIX-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-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
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 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
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- QEXVWAYOEUYCLE-UHFFFAOYSA-N O(C1=CC=CC=C1)C(=O)NC=1C(=C(SC1)C(=O)O)C(=O)O Chemical compound O(C1=CC=CC=C1)C(=O)NC=1C(=C(SC1)C(=O)O)C(=O)O QEXVWAYOEUYCLE-UHFFFAOYSA-N 0.000 description 1
- NDTKVAXBJDSQDC-UHFFFAOYSA-N O=C1C(C(SC1)C(=O)OC)C(=O)OC.[Na] Chemical compound O=C1C(C(SC1)C(=O)OC)C(=O)OC.[Na] NDTKVAXBJDSQDC-UHFFFAOYSA-N 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- RETIFGMAGNDLAN-UHFFFAOYSA-N [4,5-bis(methoxycarbonyl)thiophen-3-yl]azanium;chloride Chemical compound Cl.COC(=O)C=1SC=C(N)C=1C(=O)OC RETIFGMAGNDLAN-UHFFFAOYSA-N 0.000 description 1
- DIHZVXAYGJFKMH-UHFFFAOYSA-N [Na].FC1=C(C(=C(C=C1)OC)COC1=C(C=C(C=C1)F)OC)F Chemical compound [Na].FC1=C(C(=C(C=C1)OC)COC1=C(C=C(C=C1)F)OC)F DIHZVXAYGJFKMH-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 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
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- BMEYAMNXPSFVFQ-UHFFFAOYSA-N dimethyl 4-oxothiolane-2,3-dicarboxylate Chemical compound COC(=O)C1SCC(=O)C1C(=O)OC BMEYAMNXPSFVFQ-UHFFFAOYSA-N 0.000 description 1
- LDCRTTXIJACKKU-ARJAWSKDSA-N dimethyl maleate Chemical compound COC(=O)\C=C/C(=O)OC LDCRTTXIJACKKU-ARJAWSKDSA-N 0.000 description 1
- CGDDISBFSPJVPK-UHFFFAOYSA-N dimethyl thiophene-2,3-dicarboxylate Chemical compound COC(=O)C=1C=CSC=1C(=O)OC CGDDISBFSPJVPK-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 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
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([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
- 159000000003 magnesium salts Chemical class 0.000 description 1
- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000001028 reflection method Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical compound [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- UJJLJRQIPMGXEZ-UHFFFAOYSA-N tetrahydro-2-furoic acid Chemical compound OC(=O)C1CCCO1 UJJLJRQIPMGXEZ-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 208000010579 uterine corpus leiomyoma Diseases 0.000 description 1
- 201000007954 uterine fibroid Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A61P13/08—Drugs for disorders of the urinary system of the prostate
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P15/18—Feminine contraceptives
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- A—HUMAN NECESSITIES
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- A61P17/10—Anti-acne agents
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- A—HUMAN NECESSITIES
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Description
本発明は、医薬品として有用な縮合複素環誘導体の新規製造方法およびその製造中間体に関する。 The present invention relates to a novel process for producing a fused heterocyclic derivative useful as a pharmaceutical product and a production intermediate thereof.
式(A):
前記化合物(A)は、
式(B−1):
Formula (B-1):
しかしながら、トリホスゲンは、毒性が強いホスゲンが生成することがあるため、取り扱いに注意が必要であり、工業的に使用する場合には特殊な設備が必要になる。また、操作性の面から、複数の溶媒の使用、減圧濃縮、多数の分液操作等を行うことは、工業的に煩雑である。更に、カラムクロマトグラフィーを用いていること、全体の収率などの点から化合物(A)またはその塩を工業的に製造するには問題がある。これらのことから、化合物(A)またはその塩の工業的製造に優れた方法の確立が望まれていた。 However, since triphosgene may produce highly toxic phosgene, it must be handled with care, and special equipment is required for industrial use. In terms of operability, it is industrially complicated to use a plurality of solvents, concentrate under reduced pressure, perform a large number of liquid separation operations, and the like. Furthermore, there is a problem in industrially producing the compound (A) or a salt thereof from the viewpoints of using column chromatography and the overall yield. From these things, establishment of the method excellent in industrial manufacture of a compound (A) or its salt was desired.
本発明の目的は、従来の縮合複素環誘導体の製造方法と比べ、工業的により優れた製造方法およびその製造中間体を提供することである。 An object of the present invention is to provide an industrially superior production method and production intermediates compared to conventional methods for producing a condensed heterocyclic derivative.
本発明者等は、上記課題を解決すべく鋭意研究を重ねた結果、一般式(D):
すなわち、本発明は、As a result of intensive studies to solve the above-mentioned problems, the present inventors have obtained general formula (D):
That is, the present invention
(1)式(A):
工程1:
一般式(B):
工程2:
一般式(D)で表される化合物を、式(E):
工程3:
一般式(F)で表される化合物を分子内環化およびR2を加水分解することにより、式(A)で表される化合物を製造する工程;および
工程4:
必要に応じて、式(A)で表される化合物をその塩へ変換する工程;(1) Formula (A):
Step 1:
Formula (B):
Step 2:
The compound represented by the general formula (D) is represented by the formula (E):
Step 3:
A step of producing a compound represented by the formula (A) by intramolecular cyclization of the compound represented by the general formula (F) and hydrolysis of R 2 ; and step 4:
If necessary, a step of converting the compound represented by the formula (A) into a salt thereof;
(2)R1およびR2がメチル基またはエチル基であり、R3が水素原子であり、Xが塩素原子である、(1)記載の製造方法;
(3)工程2が塩基の存在下で行われる、(1)または(2)記載の製造方法;
(4)塩基がN,N−ジメチルアミノピリジン、トリエチルアミンからなる群から選択されるものである、(3)記載の製造方法;
(5)工程3が塩基の存在下で行われる、(1)または(2)記載の製造方法;
(6)塩基が水酸化リチウム及びナトリウムメトキシドからなる群から選択されるものである、(5)記載の製造方法;
(7)式(A)で表される化合物の塩がコリン塩である、(1)から(6)記載の製造方法;
(8)コリン塩への変換に用いられる試薬が水酸化コリン、重炭酸コリン、塩化コリンおよび酢酸コリンからなる群から選択されるものである、(7)記載の製造方法;
(9)一般式(D):
(10)R1およびR2がメチル基またはエチル基であり、R3が水素原子である、(9)記載の化合物;等を提供するものである。(2) The production method according to (1), wherein R 1 and R 2 are a methyl group or an ethyl group, R 3 is a hydrogen atom, and X is a chlorine atom;
(3) The production method according to (1) or (2), wherein step 2 is performed in the presence of a base;
(4) The production method according to (3), wherein the base is selected from the group consisting of N, N-dimethylaminopyridine and triethylamine;
(5) The production method according to (1) or (2), wherein step 3 is performed in the presence of a base;
(6) The production method according to (5), wherein the base is selected from the group consisting of lithium hydroxide and sodium methoxide;
(7) The production method according to (1) to (6), wherein the salt of the compound represented by the formula (A) is a choline salt;
(8) The production method according to (7), wherein the reagent used for the conversion to a choline salt is selected from the group consisting of choline hydroxide, choline bicarbonate, choline chloride and choline acetate;
(9) General formula (D):
(10) The compound according to (9), wherein R 1 and R 2 are a methyl group or an ethyl group, and R 3 is a hydrogen atom;
本発明において以下の用語は、特に断らない限り、以下の意味を有する。 In the present invention, the following terms have the following meanings unless otherwise specified.
ハロゲン原子とは、フッ素原子、塩素原子、臭素原子、ヨウ素原子をいう。 A halogen atom means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
C1-6アルキル基とは、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、sec−ブチル基、tert−ブチル基、ペンチル基、イソペンチル基、ネオペンチル基、tert−ペンチル基、1−メチルブチル基、2−メチルブチル基、ヘキシル基等の炭素数1〜6の直鎖状または枝分かれ状のアルキル基をいう。R1およびR2においては、同一であることが好ましい。C 1-6 alkyl group means methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group. , 1-methylbutyl group, 2-methylbutyl group, hexyl group and the like, which are linear or branched alkyl groups having 1 to 6 carbon atoms. R 1 and R 2 are preferably the same.
以下、本発明の具体的製造方法を例示する。
(工程1)
化合物(B)またはその塩を、溶媒中、塩基存在下、化合物(C)と反応させることにより、化合物(D)を製造することができる。溶媒としては、例えば、ジクロロメタン等のハロゲン系溶媒、テトラヒドロフラン、2−メチルテトラヒドロフラン、テトラヒドロピラン等の環状エーテル類、 N,N−ジメチルホルムアミド等のアミド系溶媒、トルエン等の芳香族炭化水素系溶媒、 アセトニトリル等のニトリル系溶媒、酢酸エチル等のエステル系溶媒等またはそれらの混合溶媒およびそれらと水の混合溶媒等が挙げられ、好ましくは、テトラヒドロフランと水との混合溶媒等が挙げられる。塩基としては、トリエチルアミン、ピリジン等の有機塩基類、炭酸水素ナトリウム、炭酸水素カリウム、炭酸セシウム、炭酸ナトリウムまたは炭酸カリウム等の無機塩基類が挙げられ、好ましくは、トリエチルアミン、炭酸水素ナトリウム、または炭酸カリウムが挙げられる。塩基の当量は塩の中和及び反応で生ずる酸の中和ができる当量分あれば良い。(C)の当量は(B)に対して0.8〜1.1当量用いることができ、好ましくは1.0当量用いる。反応温度は通常0〜30℃であり、反応時間は使用する原料物質や溶媒、反応温度などにより異なるが、通常0.5〜3時間である。化合物(B)の塩としては、無機酸との塩、有機酸との塩、酸性アミノ酸との塩等が挙げられる。無機酸との塩の例としては、例えば塩酸、臭化水素酸、硝酸、硫酸、リン酸等との塩が挙げられる。有機酸との塩の例としては、例えばギ酸、酢酸、トリフルオロ酢酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、リンゴ酸、メタンスルホン酸、ベンゼンスルホン酸、p−トルエンスルホン酸等との塩が挙げられる。酸性アミノ酸との塩の例としては、例えばアスパラギン酸、グルタミン酸等との塩が挙げられる。これらの塩の中で、塩酸、メタンスルホン酸との塩が好ましい。前記スキーム1で用いられる化合物(C)は市販品を用いるか、既知の方法若しくはそれに準ずる方法に従い、製造することができる。化合物(D)は、次の工程を行う前に単離しても良いが、単離せず次の工程でそれを使用することもできる。(Process 1)
Compound (D) can be produced by reacting compound (B) or a salt thereof with compound (C) in the presence of a base in a solvent. Examples of the solvent include halogen solvents such as dichloromethane, cyclic ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, and tetrahydropyran, amide solvents such as N, N-dimethylformamide, aromatic hydrocarbon solvents such as toluene, A nitrile solvent such as acetonitrile, an ester solvent such as ethyl acetate, or a mixed solvent thereof and a mixed solvent thereof and water are preferable, and a mixed solvent of tetrahydrofuran and water is preferable. Examples of the base include organic bases such as triethylamine and pyridine, and inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate, sodium carbonate, and potassium carbonate, preferably triethylamine, sodium hydrogen carbonate, or potassium carbonate Is mentioned. The equivalent of the base may be an equivalent amount capable of neutralizing the salt and neutralizing the acid generated by the reaction. The equivalent of (C) can be used in an amount of 0.8 to 1.1 equivalents relative to (B), preferably 1.0 equivalent. The reaction temperature is usually from 0 to 30 ° C., and the reaction time is usually from 0.5 to 3 hours, although it varies depending on the raw material used, the solvent, the reaction temperature and the like. Examples of the salt of the compound (B) include a salt with an inorganic acid, a salt with an organic acid, a salt with an acidic amino acid, and the like. Examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluene. And salts with sulfonic acid and the like. Examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Among these salts, salts with hydrochloric acid and methanesulfonic acid are preferable. Compound (C) used in Scheme 1 may be a commercially available product, or can be produced according to a known method or a method analogous thereto. Compound (D) may be isolated before the next step, but it can also be used in the next step without isolation.
(工程2)
化合物(D)を、溶媒中、塩基存在下または非存在下、化合物(E)またはその塩と反応させることにより、化合物(F)を製造することができる。溶媒としては、例えば、テトラヒドロフラン、2−メチルテトラヒドロフラン、テトラヒドロピラン等の環状エーテル類、N,N−ジメチルホルムアミド等のアミド系溶媒、トルエン等の芳香族炭化水素系溶媒、アセトニトリル等のニトリル系溶媒、酢酸エチル等のエステル系溶媒またはそれらの混合溶媒およびそれらと水の混合溶媒等が挙げられ、好ましくは、テトラヒドロフランと水との混合溶媒等が挙げられる。塩基としてはN,N−ジメチルアミノピリジン、トリエチルアミン、N−メチルピロリジン、N−メチルモルホリン、ジイソプロピルエチルアミン等の有機塩基類が挙げられ、好ましくは、N,N−ジメチルアミノピリジン、トリエチルアミン等が挙げられる。塩基の当量は化合物(E)に対して0.1〜2.0当量用いることができ、好ましくは0.1〜0.5当量用いる(ただし、化合物(E)の塩を用いる場合は、その中和に必要な塩基が更に必要である)。反応温度は室温〜60℃であり、反応時間は使用する原料物質や溶媒、反応温度などにより異なるが、通常1〜24時間である。化合物(E)の塩としては、無機酸との塩、有機酸との塩、酸性アミノ酸との塩等が挙げられる。無機酸との塩の例としては、例えば塩酸、臭化水素酸、硝酸、硫酸、リン酸等との塩が挙げられる。有機酸との塩の例としては、例えばギ酸、酢酸、トリフルオロ酢酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、リンゴ酸、メタンスルホン酸、ベンゼンスルホン酸、p−トルエンスルホン酸等との塩が挙げられる。酸性アミノ酸との塩の例としては、例えばアスパラギン酸、グルタミン酸等との塩が挙げられる。化合物(F)は、次の工程を行う前に単離しても良いが、単離せず次の工程でそれを使用することもできる。(Process 2)
Compound (F) can be produced by reacting compound (D) with compound (E) or a salt thereof in a solvent in the presence or absence of a base. Examples of the solvent include cyclic ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, amide solvents such as N, N-dimethylformamide, aromatic hydrocarbon solvents such as toluene, nitrile solvents such as acetonitrile, An ester solvent such as ethyl acetate or a mixed solvent thereof and a mixed solvent thereof with water, and the like are preferable, and a mixed solvent of tetrahydrofuran and water is preferable. Examples of the base include organic bases such as N, N-dimethylaminopyridine, triethylamine, N-methylpyrrolidine, N-methylmorpholine, diisopropylethylamine, and preferably N, N-dimethylaminopyridine, triethylamine and the like. . The equivalent of the base can be used in an amount of 0.1 to 2.0 equivalents relative to the compound (E), preferably 0.1 to 0.5 equivalents (provided that when a salt of the compound (E) is used, Further base necessary for neutralization is required). The reaction temperature is from room temperature to 60 ° C., and the reaction time is usually from 1 to 24 hours, although it varies depending on the raw material used, solvent, reaction temperature and the like. Examples of the salt of compound (E) include a salt with an inorganic acid, a salt with an organic acid, a salt with an acidic amino acid, and the like. Examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluene. And salts with sulfonic acid and the like. Examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Compound (F) may be isolated before the next step, but it can also be used in the next step without isolation.
(工程3)
本工程の分子内環化および加水分解反応は、同時または別々に行うことができる。
(工程3−1)
前記化合物(F)を、溶媒中、塩基の存在下、分子内環化および加水分解反応に付すことにより、化合物(A)を製造することができる。溶媒としては、例えば、テトラヒドロフラン、2−メチルテトラヒドロフラン、テトラヒドロピラン等の環状エーテル類、メタノール、エタノール、2−プロパノール等の低級アルコール、N,N−ジメチルホルムアミド等のアミド系溶媒、アセトニトリル等のニトリル系溶媒等またはそれらの混合溶媒と水との混合溶媒等が挙げられ、テトラヒドロフラン/メタノール/水の混合溶媒が好ましい。塩基としては水酸化ナトリウム、水酸化カリウム、水酸化リチウム、水素化ナトリウム等の無機塩基類、またはナトリウムメトキシド、カリウム−tert−ブトキシド等の金属アルコキシドが挙げられ、好ましくは、水酸化リチウム、ナトリウムメトキシド等が挙げられる。塩基の当量は化合物(F)に対して3.0〜6.0当量用いることができ、好ましくは4.0〜4.5当量用いる。反応温度は通常0〜20℃であり、反応時間は使用する原料物質や溶媒、反応温度などにより異なるが、通常1〜10時間である。
(工程3−2)
化合物(G)を単離する場合、化合物(F)を溶媒中、塩基の存在下、分子内環化反応に付すことにより、化合物(G)を製造することができる。溶媒としては、例えば、テトラヒドロフラン、2−メチルテトラヒドロフラン、テトラヒドロピラン等の環状エーテル類、メタノール、エタノール、2−プロパノール等の低級アルコール、N、N−ジメチルホルムアミド等のアミド系溶媒、アセトニトリル等のニトリル系溶媒等またはそれらの混合溶媒等が挙げられ、テトラヒドロフラン/メタノールの混合溶媒が好ましい。塩基としては水酸化ナトリウム、水酸化カリウム、水酸化リチウムまたは水素化ナトリウム等の無機塩基類、ナトリウムメトキシド、カリウム−tert−ブトキシド等の金属アルコキシドが挙げられ、水酸化リチウム、ナトリウムメトキシド等が好ましい。塩基の当量は化合物(F)に対して0.1〜1.5当量用いることができ、好ましくは1.0〜1.1当量用いる。反応温度は通常0〜20℃であり、反応時間は使用する原料物質や溶媒、反応温度などにより異なるが、通常1〜10時間である。
(工程3−3)
本工程の加水分解反応は、上記工程3−1と同様の方法若しくはそれに準じた方法により行うことができる。(Process 3)
The intramolecular cyclization and hydrolysis reaction in this step can be performed simultaneously or separately.
(Step 3-1)
Compound (A) can be produced by subjecting compound (F) to intramolecular cyclization and hydrolysis in the presence of a base in a solvent. Examples of the solvent include cyclic ethers such as tetrahydrofuran, 2-methyltetrahydrofuran and tetrahydropyran, lower alcohols such as methanol, ethanol and 2-propanol, amide solvents such as N, N-dimethylformamide, and nitriles such as acetonitrile. Examples thereof include a solvent and the like or a mixed solvent of a mixed solvent thereof and water, and a mixed solvent of tetrahydrofuran / methanol / water is preferable. Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide and sodium hydride, and metal alkoxides such as sodium methoxide and potassium tert-butoxide, preferably lithium hydroxide and sodium And methoxide. The base can be used in an amount of 3.0 to 6.0 equivalents, preferably 4.0 to 4.5 equivalents, relative to compound (F). The reaction temperature is usually 0 to 20 ° C., and the reaction time is usually 1 to 10 hours, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.
(Step 3-2)
When isolating compound (G), compound (G) can be produced by subjecting compound (F) to an intramolecular cyclization reaction in a solvent in the presence of a base. Examples of the solvent include cyclic ethers such as tetrahydrofuran, 2-methyltetrahydrofuran and tetrahydropyran, lower alcohols such as methanol, ethanol and 2-propanol, amide solvents such as N and N-dimethylformamide, and nitriles such as acetonitrile. Examples thereof include a solvent and the like or a mixed solvent thereof, and a mixed solvent of tetrahydrofuran / methanol is preferable. Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide or sodium hydride, metal alkoxides such as sodium methoxide and potassium tert-butoxide, and lithium hydroxide and sodium methoxide. preferable. 0.1-1.5 equivalent can be used for the equivalent of a base with respect to a compound (F), Preferably 1.0-1.1 equivalent is used. The reaction temperature is usually 0 to 20 ° C., and the reaction time is usually 1 to 10 hours, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.
(Step 3-3)
The hydrolysis reaction in this step can be performed by the same method as in step 3-1 or a method analogous thereto.
(工程4)
化合物(A)は常法により、その塩とすることができる。このような塩としては、例えば、ナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩等の無機塩、トリエチルアミン、ジイソプロピルアミン、N,N’−ジベンジルエチレンジアミン、エタノールアミン、(2−ヒドロキシエチル)トリメチルアンモニウム(以下、コリンと称す)、N−メチルグルカミン、アルギニン、リシン等の有機塩基との付加塩が挙げられ、コリン塩が好ましい。コリン塩への変換に用いられる試薬としては、例えば、水酸化コリン、重炭酸コリン、塩化コリンおよび酢酸コリンが挙げられる。(Process 4)
Compound (A) can be converted to a salt thereof by a conventional method. Examples of such salts include inorganic salts such as sodium salts, potassium salts, calcium salts, and magnesium salts, triethylamine, diisopropylamine, N, N′-dibenzylethylenediamine, ethanolamine, and (2-hydroxyethyl) trimethylammonium. (Hereinafter referred to as choline), addition salts with organic bases such as N-methylglucamine, arginine, lysine and the like, and choline salts are preferred. Examples of the reagent used for conversion to the choline salt include choline hydroxide, choline bicarbonate, choline chloride and choline acetate.
ここで、前記スキーム1で用いられる化合物(B)及びその塩は、市販品を用いるか、a)〜c)に記載された方法または参考例に記載の方法若しくはそれに準じた方法により製造することができる。
a) 特開昭64−29373
b) Synthetic Communications, 32, 2565(2002)
c) Synthesis, 200(1977)Here, the compound (B) and the salt thereof used in the above-mentioned scheme 1 are commercially available, or manufactured by the method described in a) to c), the method described in Reference Examples, or a method analogous thereto. Can do.
a) JP-A 64-29373
b) Synthetic Communications, 32, 2565 (2002)
c) Synthesis, 200 (1977)
また、前記スキーム1で用いられる化合物(E)またはその塩は、特許文献1に記載された方法または参考例に記載の方法若しくはそれに準じた方法により製造することができる。 The compound (E) or a salt thereof used in the scheme 1 can be produced by the method described in Patent Document 1, the method described in Reference Examples, or a method analogous thereto.
本明細書中の製造工程において得られる化合物には、その水和物または溶媒和物も含まれ、そのいずれも用いることができる。さらに、本明細書中の製造工程において得られる化合物は、互変異性体及び/または幾何異性体が存在することがあるが、そのいずれの異性体も用いることができ、また、その混合物も用いることができる。 The compound obtained in the production process in the present specification includes hydrates or solvates thereof, and any of them can be used. Furthermore, the compounds obtained in the production process in the present specification may have tautomers and / or geometric isomers, any of which can be used, and also a mixture thereof. be able to.
本発明の製造方法により、製造中間体である前記化合物(D)を経由することにより、医薬品として有用な化合物(A)またはその塩を、高収率且つ高純度で得ることができる。 According to the production method of the present invention, the compound (A) or a salt thereof useful as a pharmaceutical product can be obtained with high yield and high purity through the compound (D) which is a production intermediate.
本発明の内容を以下の実施例により更に詳細に説明するが、本発明はその内容に限定されるものではない。 The content of the present invention will be described in more detail with reference to the following examples, but the present invention is not limited to the content.
参考例1
4−オキソチオラン−2,3−ジカルボン酸ジメチル
メチルチオグリコレート(15.0g)、テトラヒドロフラン(45g)、ピペリジン(0.361g)の反応混合物に室温でマレイン酸ジメチル(21.4g)のテトラヒドロフラン(30g)溶液を加えた。反応混合物に窒素雰囲気下、55℃で20%ナトリウムメトキシドのメタノール溶液(43g)を加えた。反応混合物を還流下で3時間撹拌した。反応混合物に45〜50℃でジイソプロピルエーテル(105g)及び酢酸(0.85g)を加えた後、冷却した。懸濁液をろ過し、4−オキソチオラン−2,3−ジカルボン酸ジメチルのナトリウム塩の湿結晶(43.3g)を得た。この湿結晶を室温で85%りん酸(9.8g)、水(20g)及び酢酸エチル(150g)の混合物に加え、水層を除去した。得られた有機層を10%塩水で洗浄後、無水硫酸マグネシウムで乾燥した。乾燥剤をろ去後、ろ液を減圧濃縮し、表題化合物(22.7g)を得た。Reference example 1
Dimethyl 4-oxothiolane-2,3-dicarboxylate methylthioglycolate (15.0 g), tetrahydrofuran (45 g), piperidine (0.361 g) in a reaction mixture at room temperature with dimethyl maleate (21.4 g) in tetrahydrofuran (30 g) The solution was added. To the reaction mixture was added 20% sodium methoxide in methanol (43 g) at 55 ° C. under a nitrogen atmosphere. The reaction mixture was stirred at reflux for 3 hours. Diisopropyl ether (105 g) and acetic acid (0.85 g) were added to the reaction mixture at 45 to 50 ° C., and then cooled. The suspension was filtered to obtain wet crystals of sodium dimethyl 4-oxothiolane-2,3-dicarboxylate (43.3 g). The wet crystals were added to a mixture of 85% phosphoric acid (9.8 g), water (20 g) and ethyl acetate (150 g) at room temperature, and the aqueous layer was removed. The obtained organic layer was washed with 10% brine and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (22.7 g).
参考例2
4−(ヒドロキシイミノ)チオラン−2,3−ジカルボン酸ジメチル
4−オキソチオラン−2,3−ジカルボン酸ジメチル(10.0g)、ピリジン(5.44g)、ヒドロキシルアミン塩酸塩(3.34g)の混合物を50℃で1時間撹拌した。反応混合物に室温で酢酸エチル及び7%リン酸水溶液を加え、水層を除去した。得られた有機層を5%重曹水及び10%塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥した。乾燥剤をろ去後、ろ液を減圧濃縮し、表題化合物(10.4g)を得た。Reference example 2
Dimethyl 4- (hydroxyimino) thiolane-2,3-dicarboxylate Mixture of dimethyl 4-oxothiolane-2,3-dicarboxylate (10.0 g), pyridine (5.44 g), hydroxylamine hydrochloride (3.34 g) Was stirred at 50 ° C. for 1 hour. Ethyl acetate and 7% aqueous phosphoric acid solution were added to the reaction mixture at room temperature, and the aqueous layer was removed. The obtained organic layer was washed with 5% sodium bicarbonate water and 10% brine. The organic layer was dried over anhydrous sodium sulfate. After removing the desiccant by filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (10.4 g).
参考例3
4−アミノチオフェン−2,3−ジカルボン酸ジメチル 塩酸塩
4−(ヒドロキシイミノ)チオラン−2,3−ジカルボン酸ジメチル(10.4g)の酢酸(32g)溶液に4N−塩化水素/酢酸エチル溶液(120g)を室温で加えた。反応混合物を室温で8時間撹拌した。懸濁液をろ過後、得られた固体を乾燥し、表題化合物(9.42g)を得た。Reference example 3
4-Aminothiophene-2,3-dicarboxylate dimethyl hydrochloride 4- (hydroxyimino) thiolane-2,3-dicarboxylate (10.4 g) in acetic acid (32 g) solution in 4N-hydrogen chloride / ethyl acetate solution ( 120 g) was added at room temperature. The reaction mixture was stirred at room temperature for 8 hours. After filtering the suspension, the obtained solid was dried to obtain the title compound (9.42 g).
参考例4
4−アミノチオフェン−2,3−ジカルボン酸ジメチル メタンスルホン酸塩
メタンスルホン酸(80.0g)の酢酸エチル(900g)溶液に4−(ヒドロキシイミノ)チオラン−2,3−ジカルボン酸ジメチル(97.1g)の酢酸エチル(500g)溶液を65〜75℃で加えた。反応混合物を同温で2時間撹拌した。45〜50℃でメチルイソブチルケトン(100g)を加え、室温まで冷却した。懸濁液をろ過後、得られた固体を乾燥し、表題化合物(102g)を得た。Reference example 4
4-Aminothiophene-2,3-dicarboxylic acid dimethyl methanesulfonate To a solution of methanesulfonic acid (80.0 g) in ethyl acetate (900 g), dimethyl 4- (hydroxyimino) thiolane-2,3-dicarboxylate (97. 1 g) of ethyl acetate (500 g) was added at 65-75 ° C. The reaction mixture was stirred at the same temperature for 2 hours. Methyl isobutyl ketone (100 g) was added at 45-50 ° C. and cooled to room temperature. After filtering the suspension, the obtained solid was dried to obtain the title compound (102 g).
参考例5
1,2−ジフルオロ−3−[(4−フルオロ−2−メトキシフェノキシ)メチル]−4−メトキシベンゼン
2,3−ジフルオロ−6−メトキシベンズアルデヒド(150g)のトルエン(900g)溶液に水素化ホウ素ナトリウム(13.2g)の0.1N−水酸化ナトリウム水溶液(180g)を35〜39℃で加えた。反応混合物を同温で5時間撹拌した。反応混合物を室温まで冷却後、水層を除去した。得られた有機層を20%塩水で洗浄し、2,3−ジフルオロ−6−メトキシベンジルアルコールのトルエン溶液を得た。この溶液に室温で濃塩酸(610g)を加えた。反応混合物を38〜43℃で5時間撹拌した。反応混合物を室温まで冷却後、水層を除去した。得られた有機層を水、20%塩水で洗浄し、3−(クロロメチル)−1,2−ジフルオロ−4−メトキシベンゼンのトルエン溶液を得た。この溶液に室温で4−フルオロ−2−メトキシフェノール(125g)、テトラブチルアンモニウムブロミド(56.2g)を加えた。反応混合物に60〜63℃で25%水酸化ナトリウム水溶液(170g)を加え、同温で4時間撹拌した。反応混合物に水を加え、水層を除去した。得られた有機層を水で洗浄し、減圧濃縮した。残渣を2−プロパノールに溶解し、水を加えた。懸濁液をろ過後、得られた固体を乾燥し、表題化合物(232g)を得た。Reference Example 5
1,2-difluoro-3-[(4-fluoro-2-methoxyphenoxy) methyl] -4-methoxybenzene sodium borohydride in a solution of 2,3-difluoro-6-methoxybenzaldehyde (150 g) in toluene (900 g) (13.2 g) of 0.1 N aqueous sodium hydroxide (180 g) was added at 35-39 ° C. The reaction mixture was stirred at the same temperature for 5 hours. After cooling the reaction mixture to room temperature, the aqueous layer was removed. The obtained organic layer was washed with 20% brine to obtain a toluene solution of 2,3-difluoro-6-methoxybenzyl alcohol. To this solution was added concentrated hydrochloric acid (610 g) at room temperature. The reaction mixture was stirred at 38-43 ° C. for 5 hours. After cooling the reaction mixture to room temperature, the aqueous layer was removed. The obtained organic layer was washed with water and 20% brine to obtain a toluene solution of 3- (chloromethyl) -1,2-difluoro-4-methoxybenzene. 4-Fluoro-2-methoxyphenol (125 g) and tetrabutylammonium bromide (56.2 g) were added to this solution at room temperature. A 25% aqueous sodium hydroxide solution (170 g) was added to the reaction mixture at 60 to 63 ° C., and the mixture was stirred at the same temperature for 4 hours. Water was added to the reaction mixture and the aqueous layer was removed. The obtained organic layer was washed with water and concentrated under reduced pressure. The residue was dissolved in 2-propanol and water was added. After filtering the suspension, the obtained solid was dried to obtain the title compound (232 g).
参考例6
1,2−ジフルオロ−3−[(4−フルオロ−2−メトキシ−5−ニトロフェノキシ)メチル]−4−メトキシベンゼン
1,2−ジフルオロ−3−[(4−フルオロ−2−メトキシフェノキシ)メチル]−4−メトキシベンゼン(158g)の酢酸(1200g)溶液に60%硝酸(72.2g)を59〜62℃で加え、同温で2時間撹拌した。懸濁液に15〜19℃で水(1200g)を加え、同温で1時間撹拌した。懸濁液をろ過後、得られた固体を水で洗浄し、表題化合物の湿結晶(190g、Net量168g)を得た。Reference Example 6
1,2-difluoro-3-[(4-fluoro-2-methoxy-5-nitrophenoxy) methyl] -4-methoxybenzene 1,2-difluoro-3-[(4-fluoro-2-methoxyphenoxy) methyl ] To a solution of 4-methoxybenzene (158 g) in acetic acid (1200 g) was added 60% nitric acid (72.2 g) at 59-62 ° C., and the mixture was stirred at the same temperature for 2 hours. Water (1200 g) was added to the suspension at 15 to 19 ° C., and the mixture was stirred at the same temperature for 1 hour. After filtering the suspension, the obtained solid was washed with water to obtain wet crystals of the title compound (190 g, Net amount 168 g).
参考例7
2−フルオロ−5−[(2,3−ジフルオロ−6−メトキシフェニル)メトキシ]−4−メトキシアニリン
ラネーニッケル (2.5g) 、酢酸エチル (180g) 、1,2−ジフルオロ−3−[(4−フルオロ−2−メトキシ−5−ニトロフェノキシ)メチル]−4−メトキシベンゼンの湿結晶(10.9g、Net量10.0g) の反応混合物を水素雰囲気下室温にて4時間撹拌した。触媒をろ去し、ろ液を減圧濃縮した。残渣をメタノールで溶解し、水を加えた。懸濁液をろ過後、得られた固体を乾燥し、表題化合物(7.97g) を得た。Reference Example 7
2-fluoro-5-[(2,3-difluoro-6-methoxyphenyl) methoxy] -4-methoxyaniline Raney nickel (2.5 g), ethyl acetate (180 g), 1,2-difluoro-3-[(4 -Fluoro-2-methoxy-5-nitrophenoxy) methyl] -4-methoxybenzene wet crystal (10.9 g, Net amount 10.0 g) was stirred at room temperature under hydrogen atmosphere for 4 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved with methanol and water was added. After filtering the suspension, the obtained solid was dried to obtain the title compound (7.97 g).
実施例1
4−(フェノキシカルボニルアミノ)チオフェン−2,3−ジカルボン酸ジメチル
炭酸カリウム(17.1g)、水(90g)、テトラヒドロフラン(150g)および4−アミノチオフェン−2,3−ジカルボン酸ジメチル 塩酸塩(30.0g)の反応混合物に6〜13℃でクロロギ酸フェニル(18.6g)を加えた。反応混合物を12〜13℃で30分間撹拌後、水層を除去した。得られた有機層にtert−ブチルメチルエーテルを加え、20%塩水で洗浄した。得られた有機層を減圧濃縮した。残渣をジイソプロピルエーテルで溶解し、n−ヘキサンを加えた。懸濁液をろ過後、得られた固体を乾燥し、表題化合物(37.0g)を得た。
1H-NMR (DMSO-d6) δ ppm: 3.82 (3H, s), 3.82 (3H, s), 7.13-7.30 (3H, m), 7.40-7.46 (2H, m), 7.80 (1H, s), 10.24 (1H, s)Example 1
4- (phenoxycarbonylamino) thiophene-2,3-dicarboxylic acid dimethyl potassium carbonate (17.1 g), water (90 g), tetrahydrofuran (150 g) and 4-aminothiophene-2,3-dicarboxylic acid dimethyl hydrochloride (30 0.06) to the reaction mixture was added phenyl chloroformate (18.6 g) at 6-13 ° C. After stirring the reaction mixture at 12-13 ° C. for 30 minutes, the aqueous layer was removed. To the obtained organic layer, tert-butyl methyl ether was added and washed with 20% brine. The obtained organic layer was concentrated under reduced pressure. The residue was dissolved with diisopropyl ether, and n-hexane was added. After filtering the suspension, the obtained solid was dried to obtain the title compound (37.0 g).
1 H-NMR (DMSO-d 6 ) δ ppm: 3.82 (3H, s), 3.82 (3H, s), 7.13-7.30 (3H, m), 7.40-7.46 (2H, m), 7.80 (1H, s ), 10.24 (1H, s)
実施例2
4−{3−[2−フルオロ−5−(2,3−ジフルオロ−6−メトキシベンジルオキシ)−4−メトキシフェニル]ウレイド}チオフェン−2,3−ジカルボン酸ジメチル
2−フルオロ−5−[(2,3−ジフルオロ−6−メトキシフェニル)メトキシ]−4−メトキシアニリン(7.70g)、4−(フェノキシカルボニルアミノ)チオフェン−2,3−ジカルボン酸ジメチル(8.65g)、トリエチルアミン(0.37g)、テトラヒドロフラン(80mL)の反応混合物を室温で24時間撹拌した。反応混合物を減圧濃縮した。残渣に酢酸エチルとメタノールを加えた。懸濁液をろ過後、得られた固体を乾燥し、表題化合物(12.0g)を得た。
1H-NMR (DMSO-d6) δ ppm: 3.71 (3H, s), 3.82 (3H, s), 3.83 (3H, s), 3.89 (3H, s), 5.00 (2H, d, J=1.6Hz), 6.87-6.93 (1H, m), 7.00 (1H, d, J=12.8Hz), 7.41-7.50 (1H, m), 7.75 (1H, d, J=8.0Hz), 7.94 (1H, s), 8.82 (1H, s), 8.95 (1H, s)Example 2
4- {3- [2-fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] ureido} thiophene-2,3-dicarboxylate 2-fluoro-5-[( 2,3-difluoro-6-methoxyphenyl) methoxy] -4-methoxyaniline (7.70 g), dimethyl 4- (phenoxycarbonylamino) thiophene-2,3-dicarboxylate (8.65 g), triethylamine (0. 37 g) and tetrahydrofuran (80 mL) were stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure. Ethyl acetate and methanol were added to the residue. After filtering the suspension, the obtained solid was dried to obtain the title compound (12.0 g).
1 H-NMR (DMSO-d 6 ) δ ppm: 3.71 (3H, s), 3.82 (3H, s), 3.83 (3H, s), 3.89 (3H, s), 5.00 (2H, d, J = 1.6 Hz), 6.87-6.93 (1H, m), 7.00 (1H, d, J = 12.8Hz), 7.41-7.50 (1H, m), 7.75 (1H, d, J = 8.0Hz), 7.94 (1H, s ), 8.82 (1H, s), 8.95 (1H, s)
実施例3
3−[2−フルオロ−5−(2,3−ジフルオロ−6−メトキシベンジルオキシ)−4−メトキシフェニル]−2,4−ジオキソ−1,2,3,4−テトラヒドロチエノ[3,4−d]ピリミジン−5−カルボン酸メチル
4−{3−[2−フルオロ−5−(2,3−ジフルオロ−6−メトキシベンジルオキシ)−4−メトキシフェニル]ウレイド}チオフェン−2,3−ジカルボン酸ジメチル(10.0g)のテトラヒドロフラン(40g)懸濁液に28%ナトリウムメトキシドのメタノール溶液(3.48g)を加え、室温で3時間撹拌し、酢酸(1.30g)を加えた。反応混合物を減圧濃縮した。残渣にメタノールを加え、さらに水を加えた。懸濁液をろ過後、得られた固体を乾燥し、表題化合物(8.58g)を得た。
1H-NMR (DMSO-d6) δ ppm: 3.79 (3H, s), 3.81 (3H, s), 3.84 (3H, s), 4.95 (2H, s), 6.88-6.94 (1H, m), 7.08 (1H, d, J=11.6Hz), 7.19-7.23 (2H, m), 7.44-7.53 (1H, m), 11.62 (1H, s)Example 3
3- [2-Fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4 d] methyl pyrimidine-5-carboxylate 4- {3- [2-fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] ureido} thiophene-2,3-dicarboxylic acid A methanol solution (3.48 g) of 28% sodium methoxide was added to a suspension of dimethyl (10.0 g) in tetrahydrofuran (40 g), stirred at room temperature for 3 hours, and acetic acid (1.30 g) was added. The reaction mixture was concentrated under reduced pressure. Methanol was added to the residue, and water was further added. After filtering the suspension, the obtained solid was dried to obtain the title compound (8.58 g).
1 H-NMR (DMSO-d 6 ) δ ppm: 3.79 (3H, s), 3.81 (3H, s), 3.84 (3H, s), 4.95 (2H, s), 6.88-6.94 (1H, m), 7.08 (1H, d, J = 11.6Hz), 7.19-7.23 (2H, m), 7.44-7.53 (1H, m), 11.62 (1H, s)
実施例4
4−(フェノキシカルボニルアミノ)チオフェン−2,3−ジカルボン酸ジメチル
炭酸カリウム(9.38kg)、水(49kg)、テトラヒドロフラン(82kg)、4−アミノチオフェン−2,3−ジカルボン酸ジメチル 塩酸塩(16.4kg)の反応混合物を40分間撹拌後、11〜21℃でクロロギ酸フェニル(10.1kg)を加えた。反応混合物を30分間撹拌後、水層を除去し、表題化合物のテトラヒドロフラン溶液を得た。Example 4
Dimethyl 4- (phenoxycarbonylamino) thiophene-2,3-dicarboxylate potassium carbonate (9.38 kg), water (49 kg), tetrahydrofuran (82 kg), dimethyl 4-aminothiophene-2,3-dicarboxylate hydrochloride (16 4 kg) of the reaction mixture was stirred for 40 minutes and then phenyl chloroformate (10.1 kg) was added at 11-21 ° C. The reaction mixture was stirred for 30 minutes, and then the aqueous layer was removed to obtain a tetrahydrofuran solution of the title compound.
実施例5
4−{3−[2−フルオロ−5−(2,3−ジフルオロ−6−メトキシベンジルオキシ)−4−メトキシフェニル]ウレイド}チオフェン−2,3−ジカルボン酸ジメチル
実施例4で得た4−(フェノキシカルボニルアミノ)チオフェン−2,3−ジカルボン酸ジメチルのテトラヒドロフラン溶液に2−フルオロ−5−[(2,3−ジフルオロ−6−メトキシフェニル)メトキシ]−4−メトキシアニリン(17.0kg)、テトラヒドロフラン(8.5kg)、トリエチルアミン(1.1kg)を加え、50℃で3.5時間撹拌し、表題化合物のテトラヒドロフラン溶液を得た。Example 5
4- {3- [2-fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] ureido} thiophene-2,3-dicarboxylate dimethyl 4-obtained in Example 4 To a tetrahydrofuran solution of dimethyl (phenoxycarbonylamino) thiophene-2,3-dicarboxylate, 2-fluoro-5-[(2,3-difluoro-6-methoxyphenyl) methoxy] -4-methoxyaniline (17.0 kg), Tetrahydrofuran (8.5 kg) and triethylamine (1.1 kg) were added, and the mixture was stirred at 50 ° C. for 3.5 hours to obtain a tetrahydrofuran solution of the title compound.
実施例6
3−[2−フルオロ−5−(2,3−ジフルオロ−6−メトキシベンジルオキシ)−4−メトキシフェニル]−2,4−ジオキソ−1,2,3,4−テトラヒドロチエノ[3,4−d]ピリミジン−5−カルボン酸 テトラヒドロフラン和物
実施例5で得た4−{3−[2−フルオロ−5−(2,3−ジフルオロ−6−メトキシベンジルオキシ)−4−メトキシフェニル]ウレイド}チオフェン−2,3−ジカルボン酸ジメチルのテトラヒドロフラン溶液にメタノール(41kg)と水(47kg)を加え、11〜13℃で7.3%水酸化リチウム水溶液(80.1kg)を加え、11℃で90分間撹拌した。反応混合物に9〜16℃で酢酸(11.4kg)を加え、更に29〜31℃で酢酸(13.0kg)を加えた。反応混合物に種晶を加え、同温で30分間撹拌した。懸濁液に水(34kg)を加え、30℃で40分間撹拌した。懸濁液を4〜9℃で90分間撹拌した。懸濁液をろ過後、得られた固体をメタノール(54kg)と水(68kg)の混合液で洗浄し、表題化合物の湿結晶(31.64kg、Net量(化合物(A)フリー体換算)26.7kg)を得た。
表題化合物の湿結晶の一部を外温60℃で減圧乾燥し、得られた表題化合物の乾燥結晶について1H−NMR、HPLCおよび粉末X線回折を測定した。
1H-NMR (DMSO-d6) δ ppm: 1.68-1.82 (3H, m), 3.53-3.65 (3H, m), 3.80 (3H, s),3.81 (3H, s), 4.94-4.98 (2H, m), 6.87-6.94 (1H, m), 7.13 (1H, d, J=11.2Hz), 7.25 (1H, d, J=7.2Hz), 7.39 (1H, s), 7.43-7.52 (1H, m), 11,99 (1H, s), 14.53 (1H, s)Example 6
3- [2-Fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4 d] pyrimidine-5-carboxylic acid tetrahydrofuranate 4- {3- [2-fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] ureido} obtained in Example 5 Methanol (41 kg) and water (47 kg) are added to a tetrahydrofuran solution of dimethyl thiophene-2,3-dicarboxylate, a 7.3% lithium hydroxide aqueous solution (80.1 kg) is added at 11-13 ° C., and 90 ° C. at 11 ° C. Stir for minutes. Acetic acid (11.4 kg) was added to the reaction mixture at 9 to 16 ° C., and acetic acid (13.0 kg) was further added at 29 to 31 ° C. Seed crystals were added to the reaction mixture, and the mixture was stirred at the same temperature for 30 minutes. Water (34 kg) was added to the suspension and stirred at 30 ° C. for 40 minutes. The suspension was stirred at 4-9 ° C. for 90 minutes. After the suspension was filtered, the obtained solid was washed with a mixed solution of methanol (54 kg) and water (68 kg) to give wet crystals of the title compound (31.64 kg, Net amount (compound (A) free form equivalent)) 26 0.7 kg) was obtained.
A portion of the wet crystals of the title compound was dried under reduced pressure at an external temperature of 60 ° C., and 1 H-NMR, HPLC and powder X-ray diffraction were measured on the obtained dry crystals of the title compound.
1 H-NMR (DMSO-d 6 ) δ ppm: 1.68-1.82 (3H, m), 3.53-3.65 (3H, m), 3.80 (3H, s), 3.81 (3H, s), 4.94-4.98 (2H , m), 6.87-6.94 (1H, m), 7.13 (1H, d, J = 11.2Hz), 7.25 (1H, d, J = 7.2Hz), 7.39 (1H, s), 7.43-7.52 (1H, m), 11,99 (1H, s), 14.53 (1H, s)
実施例6で得られた乾燥結晶のHPLC測定は以下の条件で測定した。
HPLC測定条件
カラム:Inertsil(登録商標)C8−3(粒子径3μm、内径3mm、長さ15cm)、GLサイエンス株式会社
カラム温度:40℃
移動相A:0.002mol/Lリン酸二水素カリウム溶液(pH3.6)
移動相B:アセトニトリル
移動相の送液:移動相Aと移動相Bの混合比を表1のように変えて濃度勾配制御する。
流量:毎分0.5mL
面積測定範囲:0.002mol/Lリン酸二水素カリウム溶液(pH3.6)/アセトニトリル混液由来のピークを除き、分析開始より65分後までとした。
化学純度(HPLC):98.5%The HPLC measurement of the dry crystals obtained in Example 6 was performed under the following conditions.
HPLC measurement condition column: Inertsil (registered trademark) C8-3 (particle diameter 3 μm, inner diameter 3 mm, length 15 cm), GL Science Inc. column temperature: 40 ° C.
Mobile phase A: 0.002 mol / L potassium dihydrogen phosphate solution (pH 3.6)
Mobile phase B: Acetonitrile mobile phase feeding: The concentration ratio is controlled by changing the mixing ratio of mobile phase A and mobile phase B as shown in Table 1.
Flow rate: 0.5 mL per minute
Area measurement range: 0.002 mol / L Potassium dihydrogen phosphate solution (pH 3.6) / acetonitrile-derived peak was excluded, and 65 minutes after the start of analysis.
Chemical purity (HPLC): 98.5%
実施例6で得られた乾燥結晶の粉末X線回折を以下の条件で測定した。
粉末X線回折装置:X’Pert Pro MPD(スペクトリス株式会社パナリティカル事業部)
反射法:CuKα線、管電圧45kV、管電流40mA
得られた回折図を図1に示し、代表的なピーク(2θ(°))を表2に示す。
粉末X線回折はデータの性質上、結晶の同一性を認定する際には、2θ値及び全体的な回折パターンが重要である。X線回折パターンにおける相対強度が、試料条件や測定条件によって変動しうることは、一般的に公知である。なお、粉末X線回折による回折パターンの2θ値は、試料条件や測定条件によって僅かに変動することがある。The powder X-ray diffraction of the dry crystal obtained in Example 6 was measured under the following conditions.
Powder X-ray diffractometer: X'Pert Pro MPD (Spectris Panalytical Division)
Reflection method: CuKα line, tube voltage 45 kV, tube current 40 mA
The obtained diffractogram is shown in FIG. 1 and typical peaks (2θ (°)) are shown in Table 2.
In powder X-ray diffraction, the 2θ value and the overall diffraction pattern are important when identifying the identity of crystals due to the nature of the data. It is generally known that the relative intensity in an X-ray diffraction pattern can vary depending on sample conditions and measurement conditions. Note that the 2θ value of the diffraction pattern by powder X-ray diffraction may slightly vary depending on the sample conditions and measurement conditions.
実施例7
3−[2−フルオロ−5−(2,3−ジフルオロ−6−メトキシベンジルオキシ)−4−メトキシフェニル]−2,4−ジオキソ−1,2,3,4−テトラヒドロチエノ[3,4−d]ピリミジン−5−カルボン酸 (2−ヒドロキシエチル)トリメチルアンモニウム
3−[2−フルオロ−5−(2,3−ジフルオロ−6−メトキシベンジルオキシ)−4−メトキシフェニル]−2,4−ジオキソ−1,2,3,4−テトラヒドロチエノ[3,4−d]ピリミジン−5−カルボン酸 テトラヒドロフラン和物の湿結晶(107.7g、Net量(化合物(A)フリー体換算)83.4g)、テトラヒドロフラン(345mL)、水(275mL)の混合物に55℃で50%重炭酸コリン水溶液(60mL)を加えた。得られた溶液をろ過し、テトラヒドロフラン(34mL)と水(31mL)の混合液を加えた。反応混合物に58℃で2−プロパノール(296mL)を加えた。反応混合物に種晶を加え、45℃で3時間撹拌した。懸濁液に同温で2−プロパノール(887mL)を加え、1時間撹拌した。懸濁液を20〜30℃で1時間撹拌し、3〜5℃で 1時間撹拌した。懸濁液をろ過後、得られた固体を乾燥し、表題化合物(89.3g)を得た。
1H-NMR (DMSO-d6) δ ppm: 3.10 (9H, s), 3.37-3.43 (2H, m), 3.78 (3H, s), 3.81 (3H, s), 3.76-3.88 (2H, m), 4.93-4.98 (2H, m), 5.53 (1H, s), 6.44 (1H, s), 6.87-6.94 (1H, m), 7.05 (1H, d, J=11.6Hz), 7.11 (1H, d, J=7.6Hz), 7.43-7.52 (1H, m), 11.15 (1H, s)Example 7
3- [2-Fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4 d] pyrimidine-5-carboxylic acid (2-hydroxyethyl) trimethylammonium 3- [2-fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] -2,4-dioxo -1,2,3,4-Tetrahydrothieno [3,4-d] pyrimidine-5-carboxylic acid Wet crystals of tetrahydrofuran hydrate (107.7 g, Net amount (compound (A) free form equivalent) 83.4 g)) , Tetrahydrofuran (345 mL) and water (275 mL) were added 50% aqueous choline bicarbonate solution (60 mL) at 55 ° C. The resulting solution was filtered and a mixture of tetrahydrofuran (34 mL) and water (31 mL) was added. To the reaction mixture was added 2-propanol (296 mL) at 58 ° C. Seed crystals were added to the reaction mixture, and the mixture was stirred at 45 ° C. for 3 hours. 2-Propanol (887 mL) was added to the suspension at the same temperature and stirred for 1 hour. The suspension was stirred at 20-30 ° C for 1 hour and stirred at 3-5 ° C for 1 hour. After filtering the suspension, the obtained solid was dried to obtain the title compound (89.3 g).
1 H-NMR (DMSO-d 6 ) δ ppm: 3.10 (9H, s), 3.37-3.43 (2H, m), 3.78 (3H, s), 3.81 (3H, s), 3.76-3.88 (2H, m ), 4.93-4.98 (2H, m), 5.53 (1H, s), 6.44 (1H, s), 6.87-6.94 (1H, m), 7.05 (1H, d, J = 11.6Hz), 7.11 (1H, d, J = 7.6Hz), 7.43-7.52 (1H, m), 11.15 (1H, s)
実施例8
3−[2−フルオロ−5−(2,3−ジフルオロ−6−メトキシベンジルオキシ)−4−メトキシフェニル]−2,4−ジオキソ−1,2,3,4−テトラヒドロチエノ[3,4−d]ピリミジン−5−カルボン酸 (2−ヒドロキシエチル)トリメチルアンモニウム
3−[2−フルオロ−5−(2,3−ジフルオロ−6−メトキシベンジルオキシ)−4−メトキシフェニル]−2,4−ジオキソ−1,2,3,4−テトラヒドロチエノ[3,4−d]ピリミジン−5−カルボン酸 テトラヒドロフラン和物の湿結晶(11.09g、Net量(化合物(A)フリー体換算)10.0g)、メタノール(80mL)、水(10mL)、ジイソプロピルアミン(1.99g)の反応混合物を室温で10分間撹拌した。得られた溶液をろ過し、ろ液にメタノール(20mL)を加えた。反応混合物に49%酢酸コリン水溶液(7.2g)と水(10mL)の溶液を55〜60℃で加え、40〜55℃で2時間撹拌した。反応混合物を室温で1時間撹拌した後、氷冷下2時間撹拌した。懸濁液をろ過後、得られた固体を乾燥し、表題化合物(11.3g)を得た。Example 8
3- [2-Fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4 d] pyrimidine-5-carboxylic acid (2-hydroxyethyl) trimethylammonium 3- [2-fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] -2,4-dioxo -1,2,3,4-tetrahydrothieno [3,4-d] pyrimidine-5-carboxylic acid wet crystals of tetrahydrofuran hydrate (11.09 g, amount of Net (compound (A) free form equivalent) 10.0 g) , Methanol (80 mL), water (10 mL), diisopropylamine (1.99 g) was stirred at room temperature for 10 minutes. The resulting solution was filtered and methanol (20 mL) was added to the filtrate. A 49% aqueous solution of choline acetate (7.2 g) and water (10 mL) was added to the reaction mixture at 55-60 ° C., and the mixture was stirred at 40-55 ° C. for 2 hours. The reaction mixture was stirred at room temperature for 1 hour and then stirred for 2 hours under ice cooling. After filtering the suspension, the obtained solid was dried to obtain the title compound (11.3 g).
実施例9
3−[2−フルオロ−5−(2,3−ジフルオロ−6−メトキシベンジルオキシ)−4−メトキシフェニル]−2,4−ジオキソ−1,2,3,4−テトラヒドロチエノ[3,4−d]ピリミジン−5−カルボン酸 (2−ヒドロキシエチル)トリメチルアンモニウム
3−[2−フルオロ−5−(2,3−ジフルオロ−6−メトキシベンジルオキシ)−4−メトキシフェニル]−2,4−ジオキソ−1,2,3,4−テトラヒドロチエノ[3,4−d]ピリミジン−5−カルボン酸 テトラヒドロフラン和物の湿結晶(1.15g、Net量(化合物(A)フリー体換算)1.00g)、塩化コリン(0.30g)、トリエチルアミン(274μL)、テトラヒドロフラン(4.3mL)、水(4.3mL)の反応混合物を55℃で20分間撹拌し、テトラヒドロフラン(430μL)、水(380μL)、2−プロパノール(3.5mL)を加えた。反応混合物に45℃で種晶を加え、40〜45℃で2−プロパノール(9.6mL)を加えた。反応混合物を0℃で4時間撹拌した。懸濁液をろ過後、得られた固体を乾燥し、表題化合物(0.90g)を得た。Example 9
3- [2-Fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4 d] pyrimidine-5-carboxylic acid (2-hydroxyethyl) trimethylammonium 3- [2-fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] -2,4-dioxo -1,2,3,4-tetrahydrothieno [3,4-d] pyrimidine-5-carboxylic acid wet crystals of tetrahydrofuran hydrate (1.15 g, amount of Net (compound (A) free form equivalent) 1.00 g) , Choline chloride (0.30 g), triethylamine (274 μL), tetrahydrofuran (4.3 mL), and water (4.3 mL) were stirred at 55 ° C. for 20 minutes. Hydrofuran (430 μL), water (380 μL) and 2-propanol (3.5 mL) were added. Seed crystals were added to the reaction mixture at 45 ° C., and 2-propanol (9.6 mL) was added at 40 to 45 ° C. The reaction mixture was stirred at 0 ° C. for 4 hours. After filtering the suspension, the obtained solid was dried to obtain the title compound (0.90 g).
例えば、実施例4から6の操作を行うことにより、化合物(A)を収率97%、化学純度(HPLC)98.5%で得ることができる。このように、前記化合物(D)を経由する一連の製造方法は、医薬品として有用な化合物(A)またはその塩を、高収率且つ高純度で製造できるため、工業的製造方法として極めて有用であることがわかる。 For example, by performing the operations of Examples 4 to 6, compound (A) can be obtained in a yield of 97% and chemical purity (HPLC) of 98.5%. As described above, the series of production methods via the compound (D) is extremely useful as an industrial production method because the compound (A) or a salt thereof useful as a pharmaceutical can be produced with high yield and high purity. I know that there is.
本発明により、前立腺肥大症、子宮筋腫、子宮内膜症、子宮線維腫、思春期早発症、無月経症、月経前症候群、月経困難症、多嚢胞性卵巣症候群、紅斑性狼瘡、多毛症、小人症、睡眠障害、ニキビ、禿頭症、アルツハイマー病、不妊症、過敏性腸症候群、前立腺癌、子宮癌、卵巣癌、乳癌、下垂体腫瘍等の性ホルモン依存性疾患等の予防もしくは治療剤、生殖調節剤、避妊薬、排卵誘発剤又は性ホルモン依存性癌術後再発予防剤等などとして有用な縮合複素環誘導体またはその塩を高収率且つ高純度で製造することができる。 According to the present invention, prostatic hypertrophy, uterine fibroids, endometriosis, uterine fibroma, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, polycystic ovary syndrome, lupus erythematosus, hirsutism, Preventive or therapeutic agent for sex hormone dependent diseases such as dwarfism, sleep disorder, acne, baldness, Alzheimer's disease, infertility, irritable bowel syndrome, prostate cancer, uterine cancer, ovarian cancer, breast cancer, pituitary tumor In addition, a fused heterocyclic derivative or a salt thereof useful as a reproductive regulator, a contraceptive, an ovulation inducer, a sex hormone dependent cancer postoperative recurrence preventive agent, or the like can be produced with high yield and high purity.
Claims (12)
工程1:
一般式(B):
工程2:
一般式(D)で表される化合物を、式(E):
工程3:
一般式(F)で表される化合物を分子内環化およびR2を加水分解することにより、式(A)で表される化合物を製造する工程;および
工程4:
必要に応じて、式(A)で表される化合物をその塩へ変換する工程。Formula (A):
Step 1:
Formula (B):
Step 2:
The compound represented by the general formula (D) is represented by the formula (E):
Step 3:
A step of producing a compound represented by the formula (A) by intramolecular cyclization of the compound represented by the general formula (F) and hydrolysis of R 2 ; and step 4:
A step of converting the compound represented by the formula (A) into a salt thereof as necessary.
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