JPWO2013047751A1 - Method for producing 3,4-dihydroisoquinoline derivative - Google Patents
Method for producing 3,4-dihydroisoquinoline derivative Download PDFInfo
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- JPWO2013047751A1 JPWO2013047751A1 JP2013536428A JP2013536428A JPWO2013047751A1 JP WO2013047751 A1 JPWO2013047751 A1 JP WO2013047751A1 JP 2013536428 A JP2013536428 A JP 2013536428A JP 2013536428 A JP2013536428 A JP 2013536428A JP WO2013047751 A1 JPWO2013047751 A1 JP WO2013047751A1
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 12
- NKSZCPBUWGZONP-UHFFFAOYSA-N 3,4-dihydroisoquinoline Chemical class C1=CC=C2C=NCCC2=C1 NKSZCPBUWGZONP-UHFFFAOYSA-N 0.000 title abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 54
- 239000002253 acid Substances 0.000 claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims description 31
- 125000004432 carbon atom Chemical group C* 0.000 claims description 15
- 239000004215 Carbon black (E152) Substances 0.000 claims description 13
- 229930195733 hydrocarbon Natural products 0.000 claims description 13
- 150000002430 hydrocarbons Chemical class 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 abstract description 51
- 238000000034 method Methods 0.000 abstract description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
- -1 alkyl nitrile Chemical class 0.000 description 33
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 30
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 27
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 14
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 5
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical class OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 4
- HFNOAVXTUXLYNM-UHFFFAOYSA-N 1,3,3-trimethyl-4h-isoquinoline Chemical compound C1=CC=C2C(C)=NC(C)(C)CC2=C1 HFNOAVXTUXLYNM-UHFFFAOYSA-N 0.000 description 3
- RIWRBSMFKVOJMN-UHFFFAOYSA-N 2-methyl-1-phenylpropan-2-ol Chemical compound CC(C)(O)CC1=CC=CC=C1 RIWRBSMFKVOJMN-UHFFFAOYSA-N 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 2
- 125000005926 1,2-dimethylbutyloxy group Chemical group 0.000 description 2
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 2
- 125000005924 2-methylpentyloxy group Chemical group 0.000 description 2
- 125000005925 3-methylpentyloxy group Chemical group 0.000 description 2
- 125000000439 4-methylpentoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000012670 alkaline solution Substances 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 239000013065 commercial product Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 description 2
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- QWTDNUCVQCZILF-UHFFFAOYSA-N isopentane Chemical compound CCC(C)C QWTDNUCVQCZILF-UHFFFAOYSA-N 0.000 description 2
- 125000005921 isopentoxy group Chemical group 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000005484 neopentoxy group Chemical group 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 150000003460 sulfonic acids Chemical class 0.000 description 2
- HIFJUMGIHIZEPX-UHFFFAOYSA-N sulfuric acid;sulfur trioxide Chemical compound O=S(=O)=O.OS(O)(=O)=O HIFJUMGIHIZEPX-UHFFFAOYSA-N 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 0 *C(*)(C1)N=C(*)c2c1cccc2 Chemical compound *C(*)(C1)N=C(*)c2c1cccc2 0.000 description 1
- 125000005918 1,2-dimethylbutyl group Chemical group 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
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- MNNZINNZIQVULG-UHFFFAOYSA-N 2-chloroethylbenzene Chemical class ClCCC1=CC=CC=C1 MNNZINNZIQVULG-UHFFFAOYSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-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
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 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
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 229940117389 dichlorobenzene Drugs 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003759 ester based solvent Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 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
- 238000011835 investigation Methods 0.000 description 1
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 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
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 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
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 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
- 230000003472 neutralizing effect Effects 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 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
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 230000035484 reaction time Effects 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
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 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
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
- C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
Abstract
３，４−ジヒドロイソキノリン誘導体を、工業的に有利に製造する方法を提供することである。一般式（１）で表される３，４−ジヒドロイソキノリン誘導体の製造方法であって、一般式（２）で表される化合物と、一般式（３）で表される化合物を、炭化水素系溶媒中もしくは無溶媒にて、酸の存在下で反応する方法。It is to provide a method for producing a 3,4-dihydroisoquinoline derivative industrially advantageously. A method for producing a 3,4-dihydroisoquinoline derivative represented by the general formula (1), wherein a compound represented by the general formula (2) and a compound represented by the general formula (3) A method of reacting in the presence of an acid in a solvent or without solvent.
Description
本発明は、３，４−ジヒドロイソキノリン誘導体の製造方法に関する。 The present invention relates to a method for producing a 3,4-dihydroisoquinoline derivative.
３，４−ジヒドロイソキノリン誘導体は、様々な分野の重要な製造中間体となりうることが知られている。例えば、該誘導体の一つである１，３，３−トリメチル−３，４−ジヒドロイソキノリンは、特許文献１、特許文献２には医療用薬剤の製造中間体として、また、特許文献３には洗濯用洗剤組成物の製造中間体として記載されている。そのため、３，４−ジヒドロイソキノリン誘導体を効率的に製造できる方法は非常に重要である。 It is known that 3,4-dihydroisoquinoline derivatives can be important production intermediates in various fields. For example, 1,3,3-trimethyl-3,4-dihydroisoquinoline, which is one of the derivatives, is disclosed in Patent Document 1 and Patent Document 2 as an intermediate for producing a pharmaceutical agent, and in Patent Document 3 It is described as a manufacturing intermediate for laundry detergent compositions. Therefore, a method capable of efficiently producing a 3,4-dihydroisoquinoline derivative is very important.
従来の技術を調査すると、（１）フェネチルクロリド誘導体とアセトニトリルを四塩化スズの存在下で反応する方法（非特許文献１）、（２）硫酸および酢酸を装入したアセトニトリルにフェネチルアルコール誘導体を加えて、３日間に亘り反応させた後に、さらに環化する方法（特許文献３）、（３）ベンゼン溶媒中、硫酸の存在下でシアノ酢酸エチルとフェネチルアルコール誘導体を反応させる方法（特許文献１）、（４）ベンゼン溶媒中、硫酸の存在下でアセトニトリルとフェネチルアルコール誘導体を反応させる方法（特許文献２）等が開示されている。 As a result of investigating conventional techniques, (1) a method in which phenethyl chloride derivative and acetonitrile are reacted in the presence of tin tetrachloride (Non-patent Document 1), (2) phenethyl alcohol derivative is added to acetonitrile charged with sulfuric acid and acetic acid. (3) A method of reacting ethyl cyanoacetate with a phenethyl alcohol derivative in the presence of sulfuric acid in a benzene solvent (Patent Document 1). (4) A method of reacting acetonitrile and a phenethyl alcohol derivative in a benzene solvent in the presence of sulfuric acid (Patent Document 2) and the like are disclosed.
しかしながら、これらの方法は以下に示す問題点が挙げられる。（１）の方法は、廃棄上問題となる遷移金属を使用する。（２）の方法は、反応時間が著しく長い上に、２工程を必要とする。（３）の方法は、収率が未記載であるので詳細は不明だが、シアノ酢酸エチルのエトシキカルボニル基を除去する必要があるために原子効率が良くない。（４）の方法は、遷移金属も使用することなく１工程で目的物が得られる上に、出発原料の原子効率も優れた方法であるが収率が低い。 However, these methods have the following problems. The method (1) uses a transition metal that causes a problem in disposal. The method (2) requires a very long reaction time and two steps. The details of method (3) are unknown because the yield is not described, but the atomic efficiency is not good because it is necessary to remove the ethylcarbonyl group of ethyl cyanoacetate. The method (4) is a method in which the target product can be obtained in one step without using a transition metal and the atomic efficiency of the starting material is excellent, but the yield is low.
以上から判るように、３，４−ジヒドロイソキノリン誘導体は有用な製造中間体であるにも拘わらず、従来技術では工業的規模で満足に提供できる方法は皆無である。 As can be seen from the above, although 3,4-dihydroisoquinoline derivatives are useful production intermediates, there is no method that can be satisfactorily provided on an industrial scale in the prior art.
本発明の課題は、３，４−ジヒドロイソキノリン誘導体に関して、工業的に有利な製造方法を提供することである。 An object of the present invention is to provide an industrially advantageous production method for 3,4-dihydroisoquinoline derivatives.
前記課題を克服すべく鋭意検討を行った結果、フェネチルアルコール誘導体とアルキルニトリル誘導体とを、溶媒を使用することなく酸の存在下で反応させることによって、目的とする３，４−ジヒドロイソキノリン誘導体を収率よく製造できることが判った。さらに検討を進めると、炭化水素系溶媒中で反応を行うことで、従来のベンゼン溶媒を使用する反応よりも、収率よく目的物を得ることを見出した。溶媒存在下での反応は、反応の際に生じる発熱を制御しやいため、大量スケールでの生産に適している。 As a result of intensive studies to overcome the above problems, the desired 3,4-dihydroisoquinoline derivative is obtained by reacting a phenethyl alcohol derivative and an alkyl nitrile derivative in the presence of an acid without using a solvent. It was found that it can be produced with good yield. Further investigations have revealed that the target product can be obtained in a higher yield than the reaction using a conventional benzene solvent by carrying out the reaction in a hydrocarbon solvent. The reaction in the presence of a solvent is suitable for production on a large scale because it is easy to control the heat generated during the reaction.
以上、本発明の方法は、収率において優れるだけではなく、ベンゼンのような環境適合性のない溶媒の使用を回避できる上に操作性も簡便であるので、前記課題を解決する有効な手段である。こうして、本発明を完成するに至った。 As described above, the method of the present invention not only excels in yield, but also avoids the use of non-environmentally compatible solvents such as benzene and is easy to operate, so it is an effective means for solving the above problems. is there. Thus, the present invention has been completed.
即ち、本発明は、
［１］
一般式（１）
一般式（２）
［２］
ｎ＝０である、［１］に記載の製造方法である。That is, the present invention
[1]
General formula (1)
General formula (2)
[2]
The manufacturing method according to [1], wherein n = 0.
本発明によって、環境適合性のない溶媒の使用を回避し、簡便な操作で目的とする３，４−ジヒドロイソキノリン誘導体を高収率で製造できる。そのため、本発明は工業的な製造方法として適している。 According to the present invention, the intended 3,4-dihydroisoquinoline derivative can be produced in a high yield by a simple operation while avoiding the use of a solvent that is not environmentally compatible. Therefore, the present invention is suitable as an industrial manufacturing method.
以下、本発明を実施するための形態について詳細に説明する。 Hereinafter, embodiments for carrying out the present invention will be described in detail.
一般式（１）中のＲ１およびＲ２における置換されてもよい炭素数１〜６のアルキル基での置換基とは、ハロゲン原子および炭素数１〜６のアルコキシ基を表す。ハロゲン原子は、フッ素、塩素、臭素、よう素である。炭素数１〜６のアルコキシ基は、メトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、ブチロキシ基、イソブチロキシ基、ｓ−ブチロキシ基、ｔ−ブチロキシ基、ペントキシ基、イソペントキシ基、２−メチルブチロキシ基、ネオペントキシ基、１−エチルプロポキシ基、ヘキシルオキシ基、４−メチルペントキシ基、３−メチルペントキシ基、２−メチルペントキシ基、１−メチルペントキシ基、３，３−ジメチルブチロキシ基、２，２−ジメチルブチロキシ基、１，１−ジメチルブチロキシ基、１，２−ジメチルブチロキシ基、１，３−ジメチルブチロキシ基、２，３−ジメチルブチロキシ基、２−エチルブチロキシ基のような直鎖又は分岐のアルコキシ基を表す。好適には炭素数１〜４のアルコキシ基であり、さらに好ましくは、メトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基である。置換基の数は特に限定されることはなく、各置換基は、同一もしくは異なっていても良い。 The substituent in the C1-C6 alkyl group which may be substituted in R1 and R2 in General formula (1) represents a halogen atom and a C1-C6 alkoxy group. The halogen atom is fluorine, chlorine, bromine or iodine. The alkoxy group having 1 to 6 carbon atoms is a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butyroxy group, an isobutoxy group, an s-butoxy group, a t-butyroxy group, a pentoxy group, an isopentoxy group, or 2-methylbutyroxy. Group, neopentoxy group, 1-ethylpropoxy group, hexyloxy group, 4-methylpentoxy group, 3-methylpentoxy group, 2-methylpentoxy group, 1-methylpentoxy group, 3,3-dimethylbutoxy Group, 2,2-dimethylbutoxy group, 1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 1,3-dimethylbutoxy group, 2,3-dimethylbutyroxy group, 2-ethyl A linear or branched alkoxy group such as a butyroxy group is represented. Preferred is an alkoxy group having 1 to 4 carbon atoms, and more preferred are a methoxy group, an ethoxy group, a propoxy group, and an isopropoxy group. The number of substituents is not particularly limited, and each substituent may be the same or different.
一般式（１）中のＲ１およびＲ２における置換されてもよい炭素数１〜６のアルキル基でのアルキル基とは、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、ｓ−ブチル基、ｔ−ブチル基、ペンチル基、イソペンチル基、２−メチルブチル基、ネオペンチル基、１−エチルプロピル基、ヘキシル基、４−メチルペンチル基、３−メチルペンチル基、２−メチルペンチル基、１−メチルペンチル基、３，３−ジメチルブチル基、２，２−ジメチルブチル基、１，１−ジメチルブチル基、１，２−ジメチルブチル基、１，３−ジメチルブチル基、２，３−ジメチルブチル基、２−エチルブチル基のような直鎖又は分岐のアルキル基を表す。好ましくは、炭素数１〜３のアルキル基であり、さらに好ましくは、メチル基またはエチル基である。 The alkyl group in the alkyl group having 1 to 6 carbon atoms which may be substituted in R1 and R2 in the general formula (1) is a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, s -Butyl group, t-butyl group, pentyl group, isopentyl group, 2-methylbutyl group, neopentyl group, 1-ethylpropyl group, hexyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3- A linear or branched alkyl group such as dimethylbutyl group and 2-ethylbutyl group is represented. Preferably, it is a C1-C3 alkyl group, More preferably, it is a methyl group or an ethyl group.
一般式（１）中のＸにおけるハロゲン原子とは、フッ素、塩素、臭素、よう素である。 The halogen atom in X in the general formula (1) is fluorine, chlorine, bromine or iodine.
一般式（１）中のＸにおける置換されてもよい炭素数１〜６のアルキル基とは、一般式（１）中のＲ１およびＲ２における置換されてもよい炭素数１〜６のアルキル基と同義である。 The alkyl group having 1 to 6 carbon atoms which may be substituted in X in the general formula (1) is an alkyl group having 1 to 6 carbon atoms which may be substituted in R1 and R2 in the general formula (1). It is synonymous.
一般式（１）中のＸにおける置換されてよい炭素数１〜６のアルコキシ基での置換基とは、ハロゲン原子であり、フッ素、塩素、臭素、よう素である。置換基の数は特に限定されることはなく、各置換基は、同一もしくは異なっていても良い。 The substituent in the C1-C6 alkoxy group which may be substituted in X in General formula (1) is a halogen atom, and is a fluorine, chlorine, bromine, and iodine. The number of substituents is not particularly limited, and each substituent may be the same or different.
一般式（１）中のＸにおける置換されてよい炭素数１〜６のアルコキシ基でのアルコシ基とは、メトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、ブチロキシ基、イソブチロキシ基、ｓ−ブチロキシ基、ｔ−ブチロキシ基、ペントキシ基、イソペントキシ基、２−メチルブチロキシ基、ネオペントキシ基、１−エチルプロポキシ基、ヘキシルオキシ基、４−メチルペントキシ基、３−メチルペントキシ基、２−メチルペントキシ基、１−メチルペントキシ基、３，３−ジメチルブチロキシ基、２，２−ジメチルブチロキシ基、１，１−ジメチルブチロキシ基、１，２−ジメチルブチロキシ基、１，３−ジメチルブチロキシ基、２，３−ジメチルブチロキシ基、２−エチルブチロキシ基のような直鎖又は分岐のアルコキシ基を表す。好適には炭素数１〜４のアルコキシ基であり、さらに好ましくは、メトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基である。 The alkoxy group in the alkoxy group having 1 to 6 carbon atoms which may be substituted in X in the general formula (1) is a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butyroxy group, an isobutyroxy group, or s-butyroxy. Group, t-butoxy group, pentoxy group, isopentoxy group, 2-methylbutoxy group, neopentoxy group, 1-ethylpropoxy group, hexyloxy group, 4-methylpentoxy group, 3-methylpentoxy group, 2-methyl Pentoxy group, 1-methylpentoxy group, 3,3-dimethylbutoxy group, 2,2-dimethylbutoxy group, 1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 1,3 -Represents a straight-chain or branched alkoxy group such as a dimethylbutyroxy group, a 2,3-dimethylbutyroxy group, or a 2-ethylbutyroxy group. Preferred is an alkoxy group having 1 to 4 carbon atoms, and more preferred are a methoxy group, an ethoxy group, a propoxy group, and an isopropoxy group.
一般式（１）中のＲ３における炭素数１〜３のアルキル基とは、メチル基、エチル基、プロピル基、およびイソプロピル基である。 The C1-C3 alkyl group in R3 in General formula (1) is a methyl group, an ethyl group, a propyl group, and an isopropyl group.
一般式（１）中のｎは０〜４の整数である。 N in General formula (1) is an integer of 0-4.
一般式（１）中のｎが２以上のときは、Ｘは同一もしくは異なっていてもよい。 When n in the general formula (1) is 2 or more, Xs may be the same or different.
一般式（２）中のＲ１、Ｒ２、Ｘおよびｎは、一般式（１）と同義である。 R1, R2, X and n in the general formula (2) have the same meaning as in the general formula (1).
一般式（２）で表される化合物に関して、例えば、１，１−ジメチル−２−フェニルエタノールは、市販品として入手できる。 Regarding the compound represented by the general formula (2), for example, 1,1-dimethyl-2-phenylethanol can be obtained as a commercial product.
一般式（３）中のＲ３は、一般式（１）と同義である。 R3 in the general formula (3) has the same meaning as in the general formula (1).
一般式（３）で表される化合物に関して、例えば、アセトニトリルは、市販品として入手できる。 Regarding the compound represented by the general formula (3), for example, acetonitrile can be obtained as a commercial product.
一般式（１）で表される化合物は、一般式（２）で表される化合物と一般式（３）で表される化合物を、炭化水素系溶媒中もしくは無溶媒にて、酸の存在下で反応させて得ることができる。 The compound represented by the general formula (1) is obtained by combining the compound represented by the general formula (2) and the compound represented by the general formula (3) in a hydrocarbon solvent or without solvent in the presence of an acid. It can obtain by making it react.
反応に使用する炭化水素系溶媒とは、ペンタン、ヘキサン、ヘプタン、オクタン、２−メチルブタン、イソヘキサン、シクロヘキサン、メチルシクロヘキサン等の炭素と水素から構成される直鎖状、分岐状および環状の溶媒や、ジクロロメタン、ジクロロエタン、クロロホルム、四塩化炭素等の塩素、炭素および水素から構成される溶媒を表す。好ましくは、炭素と水素から構成される直鎖状および環状の溶媒と、塩素、炭素および水素から構成される溶媒であり、さらに好ましくは、ヘキサン、ペプタン、シクロヘキサン、メチルシクロヘキサン、ジクロロエタンである。また、これらの溶媒は、単独もしくは２種類以上を任意の割合で混合することができる。 The hydrocarbon solvent used for the reaction is a linear, branched or cyclic solvent composed of carbon and hydrogen such as pentane, hexane, heptane, octane, 2-methylbutane, isohexane, cyclohexane, methylcyclohexane, A solvent composed of chlorine, carbon and hydrogen such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride. Preferred are linear and cyclic solvents composed of carbon and hydrogen, and solvents composed of chlorine, carbon and hydrogen, and more preferred are hexane, peptane, cyclohexane, methylcyclohexane and dichloroethane. These solvents can be used alone or in combination of two or more at any ratio.
本反応は無溶媒でも実施可能であるが、炭化水素系溶媒を使用する際には、通常、一般式（２）で表される化合物に対して、２０重量倍以下が好ましい。 This reaction can be carried out without a solvent, but when a hydrocarbon solvent is used, it is usually preferably 20 times by weight or less with respect to the compound represented by the general formula (2).
使用する酸は、反応が進行する限りにおいて特に限定されることはないが、スルホン酸類が好ましい。スルホン酸類としては、トリフルオロメタンスルホン酸、硫酸が例示され、好ましくは、硫酸である。 The acid to be used is not particularly limited as long as the reaction proceeds, but sulfonic acids are preferred. Examples of the sulfonic acids include trifluoromethanesulfonic acid and sulfuric acid, and sulfuric acid is preferable.
市販されている硫酸は３〜５％程度の水を含有しているが、いずれの硫酸も使用することができる。実施例に記載のごとく、市販の硫酸は、含有する水分を発煙硫酸にて硫酸に変換してから、反応に使用することも可能である。 Commercially available sulfuric acid contains about 3 to 5% water, but any sulfuric acid can be used. As described in the examples, commercially available sulfuric acid can be used in the reaction after the contained water is converted to sulfuric acid with fuming sulfuric acid.
酸の使用量は、反応が進行する限りにおいて特に限定されることはないが、通常、一般式（２）で表される化合物に対して、３当量以上３０当量以下であり、好ましくは、５当量以上１５当量以下である。 The amount of the acid used is not particularly limited as long as the reaction proceeds, but is usually 3 equivalents or more and 30 equivalents or less, preferably 5 equivalents, relative to the compound represented by the general formula (2). Equivalent to 15 equivalents.
反応温度は、反応が進行する限りにおいて特に限定されることはないが、通常は０℃以上８０℃もしくは溶媒の沸点以下であり、好ましくは１０℃以上５０℃以下もしくは溶媒の沸点以下である。 The reaction temperature is not particularly limited as long as the reaction proceeds, but it is usually 0 ° C. or higher and 80 ° C. or lower than the boiling point of the solvent, preferably 10 ° C. or higher and 50 ° C. or lower or lower than the boiling point of the solvent.
炭化水素系溶媒使用時の実施形態としては、一般式（２）で表される化合物と一般式（３）で表される化合物を炭化水素系溶媒に混合したものを、炭化水素系溶媒を装入した酸に加える方法、一般式（２）で表される化合物と一般式（３）で表される化合物を炭化水素系溶媒に混合したものを酸に加える方法、一般式（２）で表される化合物と一般式（３）で表される化合物を混合したものを、炭化水素系溶媒を装入した酸に加える方法などが挙げられるが、これらに限定されるものではなく、適宜設定することができる。 As an embodiment when using a hydrocarbon solvent, a mixture of a compound represented by the general formula (2) and a compound represented by the general formula (3) in a hydrocarbon solvent is used. A method of adding to the acid, a method of adding a compound represented by the general formula (2) and a compound represented by the general formula (3) to a hydrocarbon solvent, and adding the acid to the acid, represented by the general formula (2) A method of adding a compound obtained by mixing a compound represented by formula (3) to an acid charged with a hydrocarbon-based solvent is not limited thereto, and is appropriately set. be able to.
以下に反応後処理について述べる。 The post-reaction treatment is described below.
反応終了後は、水もしくはアルカリ水溶液を加えることができる。大量の酸を使用した際には、水を加えた後にアルカリ水溶液にて中和作業をする方法が安全上好ましい。使用するアルカリ水溶液に関しては、アンモニア、水酸化カリウム、水酸化ナトリウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、炭酸水素カリウム等を水に溶解したものを使用することが可能である。中和操作後に塩が析出した場合には、水を追加して塩を溶解したり、濾過操作にて塩を除くことが可能である。 After completion of the reaction, water or an aqueous alkaline solution can be added. When a large amount of acid is used, a method of neutralizing with an aqueous alkaline solution after adding water is preferable for safety. Regarding the alkaline aqueous solution to be used, it is possible to use a solution in which ammonia, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like are dissolved in water. When salt is precipitated after the neutralization operation, water can be added to dissolve the salt, or the salt can be removed by filtration operation.
中和作業後は、分液をすることができる。反応に炭化水素系溶媒を使用した場合は、そのまま分液してもよく、また適当な溶媒を別途追加することも可能である。反応に炭化水素系溶媒を使用しなかった場合は、適当な溶媒を装入して分液操作が行える。その際の溶媒として、トルエン、キシレン、ベンゼン、クロロベンゼン、ジクロロベンゼン等のベンゼン系溶媒、酢酸エチル、酢酸イソプロピル、酢酸ブチル等のエステル系溶媒、ジエチルエーテル、ジイソプロピルエーテル、メチル−ｔ−ブチルエーテル等のエーテル系溶媒、ジクロロメタン、ジクロロエタン、クロロホルム等の含塩素炭化水素系溶媒、ヘキサン、ヘプタン、シクロヘキサン、メチルシクロヘキサン等炭化水素系溶媒等が例示され、水と相溶することのない溶媒を追加することが可能である。分液の回数は特に制限されることがなく、目的とする純度に応じて実施することができる。 After the neutralization operation, the liquid can be separated. When a hydrocarbon solvent is used in the reaction, the liquid may be separated as it is, or an appropriate solvent may be added separately. When a hydrocarbon solvent is not used in the reaction, a liquid separation operation can be performed by charging an appropriate solvent. Solvents used here include benzene solvents such as toluene, xylene, benzene, chlorobenzene, dichlorobenzene, ester solvents such as ethyl acetate, isopropyl acetate, butyl acetate, ethers such as diethyl ether, diisopropyl ether, and methyl-t-butyl ether. Solvents containing chlorine, chlorohydrocarbon solvents such as dichloromethane, dichloroethane, chloroform, etc., hydrocarbon solvents such as hexane, heptane, cyclohexane, methylcyclohexane, etc. are exemplified, and it is possible to add a solvent that is not compatible with water. It is. The number of times of liquid separation is not particularly limited, and can be carried out according to the target purity.
前記で得られた化合物（１）を含む反応混合物は、硫酸ナトリウムや硫酸マグネシウム等の乾燥剤で水分を除去することができるが、この工程は必須ではない。 The reaction mixture containing the compound (1) obtained above can remove moisture with a desiccant such as sodium sulfate or magnesium sulfate, but this step is not essential.
前記で得られた化合物（１）を含む反応混合物は、溶媒を留去することが可能である。
溶媒留去して得られた化合物（１）を含む反応混合物は、目的とする純度に応じて、さらに精製することが可能である。化合物（１）で表される化合物が固体の場合には、適当な溶媒による洗浄、再沈殿あるいは再結晶を行えばよく、液体の場合は、蒸留を行うことができる。また、固体や液体のいずれも、カラムクロマトグラフィーによる精製も可能である。In the reaction mixture containing the compound (1) obtained above, the solvent can be distilled off.
The reaction mixture containing the compound (1) obtained by distilling off the solvent can be further purified according to the target purity. When the compound represented by the compound (1) is a solid, it may be washed, reprecipitated or recrystallized with an appropriate solvent, and when it is a liquid, distillation can be carried out. In addition, both solid and liquid can be purified by column chromatography.
以上のように本発明によって、３，４−ジヒドロイソキノリン誘導体を簡便な操作で効率よく製造することが可能になった。 As described above, according to the present invention, 3,4-dihydroisoquinoline derivatives can be efficiently produced by a simple operation.
以下に実施例により、本発明を更に詳細に示すが、本発明はこれらに限定されるものではない。 The present invention will be illustrated in more detail by the following examples, but the present invention is not limited thereto.
２−メチル−１−フェニルプロパン−２−オールを化合物（Ｉ）、１，３，３−トリメチル−３，４−ジヒドロイソキノリンを化合物（ＩＩ）、高速液体クロマトグラフィーをＨＰＬＣと称する。 2-methyl-1-phenylpropan-2-ol is referred to as compound (I), 1,3,3-trimethyl-3,4-dihydroisoquinoline as compound (II), and high performance liquid chromatography is referred to as HPLC.
［比較例１］国際公開第２００３／６４３８９号公報の記載例の追試
化合物（Ｉ）７．０ｇとアセトニトリル１．６２ｍｌを含むベンゼン溶液７．０ｍｌを９７％硫酸１０ｍｌに０℃で滴下した。滴下終了後、室温にて終夜撹拌を行った。得られた反応混合物をＨＰＬＣにて分析すると化合物（ＩＩ）が２．７２ｇ生成していた。国際公開第２００３／６４３８９号公報の記載によると、化合物（ＩＩ）は２．５３ｇで単離されており、該特許文献を再現できた。収率は化合物（Ｉ）基準で３３．４％、アセトニトリル基準で５０．６％であった。 7.0 ml of a benzene solution containing 7.0 g of Compound (I) and 1.62 ml of acetonitrile was added dropwise at 0 ° C. to 10 ml of 97% sulfuric acid. After completion of dropping, the mixture was stirred overnight at room temperature. Analysis of the resulting reaction mixture by HPLC revealed that 2.72 g of compound (II) was produced. According to the description in International Publication No. 2003/64389, Compound (II) was isolated in 2.53 g, and the patent document could be reproduced. The yield was 33.4% based on Compound (I) and 50.6% based on acetonitrile.
［実施例１］シクロヘキサンを溶媒とした化合物（ＩＩ）の合成
９７％硫酸２５２．４１ｇにシクロヘキサン７５ｍｌを加えて１５℃に冷却した。これに、化合物（Ｉ）５０．００ｇとアセトニトリル２３．２３ｇを含むシクロヘキサン７５ｍｌを２０℃以下に維持して４５分間かけて滴下した。滴下終了後、２０℃で２０時間撹拌した。次いで、１０℃に冷却した水３７５ｍｌに前記反応混合物を５０℃以下で滴下した。この時点で反応混合物をＨＰＬＣにて観測すると化合物（ＩＩ）が反応収率８９．９％で生成していた。２５％アンモニア水溶液を２５℃で滴下した後に、シクロヘキサン３５０ｍｌを加えて分液をした。得られた有機層を減圧下で濃縮すると化合物（ＩＩ）５２．３０ｇが純度９３．７％で得られた。収率８５．０％。 To 252.41 g of 97% sulfuric acid, 75 ml of cyclohexane was added and cooled to 15 ° C. To this, 75 ml of cyclohexane containing 50.00 g of Compound (I) and 23.23 g of acetonitrile was added dropwise over 45 minutes while maintaining at 20 ° C. or lower. After completion of dropping, the mixture was stirred at 20 ° C. for 20 hours. Next, the reaction mixture was added dropwise to 375 ml of water cooled to 10 ° C. at 50 ° C. or lower. At this point, when the reaction mixture was observed by HPLC, compound (II) was produced in a reaction yield of 89.9%. A 25% aqueous ammonia solution was dropped at 25 ° C., and 350 ml of cyclohexane was added to separate the layers. The obtained organic layer was concentrated under reduced pressure to obtain 52.30 g of Compound (II) with a purity of 93.7%. Yield 85.0%.
比較例から判るように、溶媒をシクロヘキサンにすることにより著しく収率が改善できた。 As can be seen from the comparative examples, the yield could be remarkably improved by using cyclohexane as the solvent.
また、得られた化合物は分析のため、５ｔｏｒｒ ８２℃で蒸留した。分析値は国際公開第２００３／６４３８９号公報と一致した。 The obtained compound was distilled at 5 torr 82 ° C. for analysis. The analysis value was consistent with International Publication No. 2003/64389.
化合物（ＩＩ）の物質データ
１Ｈ −ＮＭＲ （ＣＤＣｌ３） δ： ７．４８ （１Ｈ， ｄ， Ｊ ＝ ７．６ Ｈｚ）， ７．３５−７．３３ （１Ｈ， ｍ）， ７．２９−７．２７ （１Ｈ， ｍ）， ７．１４ （１Ｈ， ｄ， Ｊ ＝ ７．６ Ｈｚ）， ２．６９ （２Ｈ， ｓ）， ２．３７ （３Ｈ， ｓ）， １．２０ （６Ｈ， ｓ）．Substance data of compound (II)
1 H-NMR (CDCl 3 ) δ: 7.48 (1H, d, J = 7.6 Hz), 7.35-7.33 (1H, m), 7.29-7.27 (1H, m ), 7.14 (1H, d, J = 7.6 Hz), 2.69 (2H, s), 2.37 (3H, s), 1.20 (6H, s).
［実施例２］シクロヘキサンを溶媒にした化合物（ＩＩ）の合成
９５％硫酸１０３．０９ｇにシクロヘキサン３０ｍｌを加えて１５℃に冷却した。これに、化合物（Ｉ）２０．００ｇとアセトニトリル９．２９ｇを含むシクロヘキサン３０ｍｌを２０℃以下で滴下した。滴下終了後、２０℃で２０時間撹拌した。得られた反応混合物をＨＰＬＣにて観測すると化合物（ＩＩ）が反応収率８７．５％で生成していた。Example 2 Synthesis of Compound (II) Using Cyclohexane as a Solvent 30 ml of cyclohexane was added to 103.09 g of 95% sulfuric acid and cooled to 15 ° C. To this, 30 ml of cyclohexane containing 20.00 g of compound (I) and 9.29 g of acetonitrile was added dropwise at 20 ° C. or lower. After completion of dropping, the mixture was stirred at 20 ° C. for 20 hours. When the obtained reaction mixture was observed by HPLC, compound (II) was produced at a reaction yield of 87.5%.
［実施例３］シクロヘキサンを溶媒にした化合物（ＩＩ）の合成
９７％硫酸６３．８８ｇに２５％発煙硫酸３４．０６ｇを加えた後にシクロヘキサン３０ｍｌを加えて１５℃に冷却した。化合物（Ｉ）２０．００ｇとアセトニトリル９．２９ｇを含むシクロヘキサン３０ｍｌを２０℃以下で滴下した。滴下終了後、２０℃で２０時間撹拌した。得られた反応混合物をＨＰＬＣにて観測すると化合物（ＩＩ）が反応収率８４．０％で生成していた。Example 3 Synthesis of Compound (II) Using Cyclohexane as a Solvent After adding 34.06 g of 25% fuming sulfuric acid to 63.88 g of 97% sulfuric acid, 30 ml of cyclohexane was added and cooled to 15 ° C. 30 ml of cyclohexane containing 20.00 g of compound (I) and 9.29 g of acetonitrile was added dropwise at 20 ° C. or lower. After completion of dropping, the mixture was stirred at 20 ° C. for 20 hours. When the obtained reaction mixture was observed by HPLC, compound (II) was produced at a reaction yield of 84.0%.
［実施例４］メチルシクロヘキサンを溶媒にした化合物（ＩＩ）の合成
シクロヘキサンをメチルシクロヘキサンにする以外は実施例３と同様に反応を行った。得られた反応混合物をＨＰＬＣにて観測すると化合物（ＩＩ）が反応収率７８．７％で生成していた。Example 4 Synthesis of Compound (II) Using Methylcyclohexane as a Solvent The reaction was carried out in the same manner as in Example 3 except that cyclohexane was changed to methylcyclohexane. When the obtained reaction mixture was observed by HPLC, compound (II) was produced in a reaction yield of 78.7%.
［実施例５］ヘプタンを溶媒にした化合物（ＩＩ）の合成
シクロヘキサンをヘプタンにする以外は実施例３と同様に反応を行った。得られた反応混合物をＨＰＬＣにて観測すると化合物（ＩＩ）が反応収率８４．０％で生成していた。[Example 5] Synthesis of compound (II) using heptane as a solvent The reaction was carried out in the same manner as in Example 3 except that cyclohexane was changed to heptane. When the obtained reaction mixture was observed by HPLC, compound (II) was produced at a reaction yield of 84.0%.
［実施例６］無溶媒での化合物（ＩＩ）の合成
９７％硫酸６７．３１ｇを１０℃に冷却した後に、化合物（Ｉ）１０．００ｇとアセトニトリル４．１０ｇを混合したものを１５℃以下に維持して滴下した。６〜１０℃で３時間撹拌した後に、室温まで昇温して１６時間撹拌した。反応終了後、反応混合物をＨＰＬＣにて観測すると化合物（ＩＩ）が反応収率８５．６％で生成していた。[Example 6] Synthesis of compound (II) without solvent After cooling 67.31 g of 97% sulfuric acid to 10 ° C, a mixture of 10.00 g of compound (I) and 4.10 g of acetonitrile was reduced to 15 ° C or less. Maintained and dropped. After stirring at 6 to 10 ° C. for 3 hours, the mixture was warmed to room temperature and stirred for 16 hours. After completion of the reaction, the reaction mixture was observed by HPLC. Compound (II) was produced at a reaction yield of 85.6%.
［実施例７］ジクロロエタンを溶媒にした化合物（ＩＩ）の合成
９７％硫酸１０１．０ｇを装入したジクロロエタン３０ｍｌを１５℃に冷却した後に、化合物（Ｉ）２０．００ｇとアセトニトリル９．２９ｇを含むジクロロエタン３０ｍｌを２０℃以下で滴下した。滴下終了後、２０℃で２０時間撹拌した。得られた反応混合物をＨＰＬＣにて観測すると化合物（ＩＩ）が反応収率７９．０％で生成していた。Example 7 Synthesis of Compound (II) Using Dichloroethane as Solvent After 30 ml of dichloroethane charged with 101.0 g of 97% sulfuric acid was cooled to 15 ° C., it contained 20.00 g of Compound (I) and 9.29 g of acetonitrile. 30 ml of dichloroethane was added dropwise at 20 ° C. or lower. After completion of dropping, the mixture was stirred at 20 ° C. for 20 hours. When the obtained reaction mixture was observed by HPLC, compound (II) was produced at a reaction yield of 79.0%.
［参考例１］
シクロヘキサンをトルエンにする以外は実施例３と同様に反応を行った。得られた反応混合物をＨＰＬＣにて観測すると化合物（ＩＩ）が反応収率１８．０％で生成していた。トルエンのようなベンゼン系溶媒は著しく反応収率が低下することが判った。[Reference Example 1]
The reaction was performed in the same manner as in Example 3 except that cyclohexane was changed to toluene. When the obtained reaction mixture was observed by HPLC, compound (II) was produced at a reaction yield of 18.0%. It has been found that the reaction yield of a benzene solvent such as toluene is significantly reduced.
［参考例２］
シクロヘキサンをキシレンにする以外は実施例３と同様に反応を行った。得られた反応混合物をＨＰＬＣにて観測すると化合物（ＩＩ）が反応収率２０．２％で生成していた。キシレンのようなベンゼン系溶媒は著しく反応収率が低下することが判った。[Reference Example 2]
The reaction was carried out in the same manner as in Example 3 except that cyclohexane was changed to xylene. When the obtained reaction mixture was observed by HPLC, compound (II) was produced at a reaction yield of 20.2%. It has been found that the reaction yield of a benzene solvent such as xylene is significantly reduced.
本発明によると、３，４−ジヒドロイソキノリン誘導体を簡便な操作で高収率で提供することが可能になった。さらに、本発明は、環境適合性のない溶媒を回避できる上に工業的にも有利に生産できるために、産業上の利用価値は高い。 According to the present invention, it has become possible to provide a 3,4-dihydroisoquinoline derivative in a high yield by a simple operation. Furthermore, since the present invention can avoid solvents that are not environmentally compatible and can be advantageously produced industrially, it has a high industrial utility value.
Claims (2)
一般式（２）
一般式（３）
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| WO2001016275A1 (en) * | 1999-08-27 | 2001-03-08 | The Procter & Gamble Company | Fast-acting formulation components, compositions and laundry methods employing same |
| WO2003064389A1 (en) * | 2002-01-31 | 2003-08-07 | Ono Pharmaceutical Co., Ltd. | Nitrogen-containing bicyclic compounds and drugs containing the same as the active ingredient |
| WO2005070917A1 (en) * | 2004-01-23 | 2005-08-04 | Sankyo Agro Company, Limited | 3-(dihydro(tetrahydro)isoquinolin-1-yl)quinolines |
| WO2007011022A1 (en) * | 2005-07-22 | 2007-01-25 | Sankyo Agro Company, Limited | 3-(isoquinoline-1-yl)quinoline derivative |
| WO2008117061A2 (en) * | 2007-03-28 | 2008-10-02 | Sterix Limited | Tetrahydroisoquinolines as tumour growth inhibitors |
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| WO2001016275A1 (en) * | 1999-08-27 | 2001-03-08 | The Procter & Gamble Company | Fast-acting formulation components, compositions and laundry methods employing same |
| WO2003064389A1 (en) * | 2002-01-31 | 2003-08-07 | Ono Pharmaceutical Co., Ltd. | Nitrogen-containing bicyclic compounds and drugs containing the same as the active ingredient |
| WO2005070917A1 (en) * | 2004-01-23 | 2005-08-04 | Sankyo Agro Company, Limited | 3-(dihydro(tetrahydro)isoquinolin-1-yl)quinolines |
| WO2007011022A1 (en) * | 2005-07-22 | 2007-01-25 | Sankyo Agro Company, Limited | 3-(isoquinoline-1-yl)quinoline derivative |
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