JPH01265072A - Benzene compound and production thereof - Google Patents
Benzene compound and production thereofInfo
- Publication number
- JPH01265072A JPH01265072A JP1025272A JP2527289A JPH01265072A JP H01265072 A JPH01265072 A JP H01265072A JP 1025272 A JP1025272 A JP 1025272A JP 2527289 A JP2527289 A JP 2527289A JP H01265072 A JPH01265072 A JP H01265072A
- Authority
- JP
- Japan
- Prior art keywords
- ring
- formula
- group
- formulas
- salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- -1 Benzene compound Chemical class 0.000 title claims abstract description 52
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 title claims abstract description 41
- 238000004519 manufacturing process Methods 0.000 title claims description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 29
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 16
- 125000004849 alkoxymethyl group Chemical group 0.000 claims abstract description 8
- 125000001424 substituent group Chemical group 0.000 claims abstract description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- 125000003172 aldehyde group Chemical group 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 239000011593 sulfur Substances 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 4
- 150000002391 heterocyclic compounds Chemical class 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000001041 indolyl group Chemical group 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- VDWLCYCWLIKWBV-UHFFFAOYSA-N 1-(benzenesulfonyl)indole Chemical group C1=CC2=CC=CC=C2N1S(=O)(=O)C1=CC=CC=C1 VDWLCYCWLIKWBV-UHFFFAOYSA-N 0.000 claims description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 2
- 230000002152 alkylating effect Effects 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 11
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 3
- 229910052760 oxygen Inorganic materials 0.000 claims 3
- 239000001301 oxygen Substances 0.000 claims 3
- 125000002971 oxazolyl group Chemical group 0.000 claims 1
- 125000000168 pyrrolyl group Chemical group 0.000 claims 1
- 239000003524 antilipemic agent Substances 0.000 abstract description 3
- 150000001299 aldehydes Chemical class 0.000 abstract description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical class C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 abstract description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 abstract description 2
- 125000001589 carboacyl group Chemical group 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 37
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 26
- 239000002904 solvent Substances 0.000 description 24
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 23
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
- 238000003756 stirring Methods 0.000 description 14
- 238000001816 cooling Methods 0.000 description 13
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 12
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 9
- 238000001035 drying Methods 0.000 description 8
- 239000013078 crystal Substances 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 6
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 5
- 239000004327 boric acid Substances 0.000 description 5
- 238000007796 conventional method Methods 0.000 description 5
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 150000007522 mineralic acids Chemical class 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- WJUFSDZVCOTFON-UHFFFAOYSA-N veratraldehyde Chemical compound COC1=CC=C(C=O)C=C1OC WJUFSDZVCOTFON-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 150000001555 benzenes Chemical class 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- VHILMKFSCRWWIJ-UHFFFAOYSA-N dimethyl acetylenedicarboxylate Chemical compound COC(=O)C#CC(=O)OC VHILMKFSCRWWIJ-UHFFFAOYSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 2
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- 229940100198 alkylating agent Drugs 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 2
- 229940077388 benzenesulfonate Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- CUWZPOJOTMQKJU-UHFFFAOYSA-N (3,4-dimethoxyphenyl)-thiophen-3-ylmethanol Chemical compound C1=C(OC)C(OC)=CC=C1C(O)C1=CSC=C1 CUWZPOJOTMQKJU-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- DAIHUVOQEVDCEO-UHFFFAOYSA-N 1-(benzenesulfonyl)-3-(dimethoxymethyl)indole Chemical compound C12=CC=CC=C2C(C(OC)OC)=CN1S(=O)(=O)C1=CC=CC=C1 DAIHUVOQEVDCEO-UHFFFAOYSA-N 0.000 description 1
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- AJDLUSUIIVLQKJ-UHFFFAOYSA-N 2-bromo-3-(dimethoxymethyl)pyridine Chemical compound COC(OC)C1=CC=CN=C1Br AJDLUSUIIVLQKJ-UHFFFAOYSA-N 0.000 description 1
- SSXDJHBUYFUCQH-UHFFFAOYSA-N 3-(dimethoxymethyl)thiophene Chemical compound COC(OC)C=1C=CSC=1 SSXDJHBUYFUCQH-UHFFFAOYSA-N 0.000 description 1
- MYSALVGMCUNOHQ-UHFFFAOYSA-N 3-[(3,4-dimethoxyphenyl)-methoxymethyl]thiophene Chemical compound C=1C=C(OC)C(OC)=CC=1C(OC)C=1C=CSC=1 MYSALVGMCUNOHQ-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- KBTMGSMZIKLAHN-UHFFFAOYSA-N 4-bromo-1,2-dimethoxybenzene Chemical compound COC1=CC=C(Br)C=C1OC KBTMGSMZIKLAHN-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical group C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- QVXGWMYYSCNCOS-UHFFFAOYSA-N [(3,4-dimethoxyphenyl)-(3-formylthiophen-2-yl)methyl] acetate Chemical compound C1=C(OC)C(OC)=CC=C1C(OC(C)=O)C1=C(C=O)C=CS1 QVXGWMYYSCNCOS-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- UMYLPQAGFBCXML-UHFFFAOYSA-N diethyl 9-(benzenesulfonyl)-1-(3,4-dimethoxyphenyl)-4-hydroxycarbazole-2,3-dicarboxylate Chemical compound CCOC(=O)C=1C(C(=O)OCC)=C(O)C=2C3=CC=CC=C3N(S(=O)(=O)C=3C=CC=CC=3)C=2C=1C1=CC=C(OC)C(OC)=C1 UMYLPQAGFBCXML-UHFFFAOYSA-N 0.000 description 1
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- CNUDBTRUORMMPA-UHFFFAOYSA-N formylthiophene Chemical compound O=CC1=CC=CS1 CNUDBTRUORMMPA-UHFFFAOYSA-N 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 150000004671 saturated fatty acids Chemical class 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical class CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pyridine Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pyrrole Compounds (AREA)
- Indole Compounds (AREA)
- Quinoline Compounds (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は種々の医薬化合物の新規合成中間体及びその製
法に関する。DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to novel synthetic intermediates for various pharmaceutical compounds and methods for producing the same.
（発明の構成及び効果）
本発明は次式で示される新規ベンゼン化合物及びその塩
、並びにその製法に関する。(Structure and Effects of the Invention) The present invention relates to a novel benzene compound represented by the following formula, a salt thereof, and a method for producing the same.
（但し、Ｒ１及びＲ２は、Ｒ１がアルデヒド基もしくは
ジ低級アルコキシメチル基であり、ＲＺが水素原子、低
級アルキル基もしくは低級アルカノイル基であるか、又
はＲ１とＲｔとが互いに結合して低級アルコキシメチレ
ン基を形成していることを表し、Ｒ３及びＲ４は低級ア
ルキル基、環Ａは置換基を有するか又は有しない含硫も
しくは含窒素複素環を表す。）
本発明のベンゼン化合物（１）は、医薬化合物の合成中
間体として有用な化合物であり、例えば、抗脂血剤とし
て有用な各種ビフェニル誘導体〔特願昭６２−２９４７
３６号〕を製造するための合成中間体として用いること
ができる。(However, in R1 and R2, R1 is an aldehyde group or a di-lower alkoxymethyl group, RZ is a hydrogen atom, a lower alkyl group, or a lower alkanoyl group, or R1 and Rt are bonded to each other to form a lower alkoxymethylene group. R3 and R4 represent a lower alkyl group, and Ring A represents a sulfur-containing or nitrogen-containing heterocycle with or without a substituent.) The benzene compound (1) of the present invention is Compounds useful as intermediates for the synthesis of pharmaceutical compounds, such as various biphenyl derivatives useful as antilipidemic agents [Patent Application No. 62-2947]
No. 36] can be used as a synthetic intermediate for producing.
本発明のベンゼン化合物の具体例としては、−儀式（Ｉ
）において、環Ａが低級アルキル基で置換されていても
よいフェニルスルホニル基を置換基として有するか又は
有しない含硫もしくは含窒素複素環（例えば、チオフェ
ン環、ビロール環、イミダゾール環、ピリジン環、ピリ
ミジン環、インドール環、キノリン環、チアゾール環、
オキサゾール環）である化合物をあげることができる。Specific examples of the benzene compound of the present invention include -ritual (I)
), in which ring A has or does not have a phenylsulfonyl group optionally substituted with a lower alkyl group as a substituent (for example, a thiophene ring, a virol ring, an imidazole ring, a pyridine ring, Pyrimidine ring, indole ring, quinoline ring, thiazole ring,
Oxazole ring).
このうち、好ましい化合物は、環Ａがチオフェン環、ピ
リジン環、インドール環又はＮ−フェニルスルホニルイ
ンドール環である化合物である。Among these, preferred compounds are those in which ring A is a thiophene ring, a pyridine ring, an indole ring, or an N-phenylsulfonylindole ring.
本発明によれば、ベンゼン化合物（１）のうち（但し、
Ｒ１はアルデヒド基又はジ低級アルコキシメチル基、Ｒ
２１は水素原子、低級アルキル基又は低級アルカノイル
基を表し、Ｒ３、Ｒ４及び環Ａは前記と同一意味を有す
る。）
で示されるベンゼン化合物は、−Ｃ式
（但し、Ｒ５は低級アルキル基、Ｘｌは水素原子又はハ
ロゲン原子を表し、環Ａは前記と同一意味を有する。）
で示されるアセタール化合物又はその塩と、−ａ式
（但し、Ｒ３及びＲ４は前記と同一意味を有する。）で
示されるアルデヒド化合物とを反応させて−ｅ式
（但し、Ｒ３−Ｒ５及び環Ａは前記と同一意味を有する
。）
で示されるベンゼン化合物を得、所望により、そのジ低
級アルコキシメチル基を加水分解してアルデヒド基とす
るか、及び／又はその水酸基を常法によりアルキル化又
はアルカノイル化して製造することができる。According to the present invention, among the benzene compounds (1) (however,
R1 is an aldehyde group or a di-lower alkoxymethyl group, R
21 represents a hydrogen atom, a lower alkyl group or a lower alkanoyl group, and R3, R4 and ring A have the same meanings as above. ) The benzene compound represented by the formula -C (wherein, R5 is a lower alkyl group, Xl represents a hydrogen atom or a halogen atom, and ring A has the same meaning as above) is an acetal compound or a salt thereof. , by reacting with an aldehyde compound represented by formula -a (however, R3 and R4 have the same meanings as above) to form -e formula (however, R3-R5 and ring A have the same meanings as above). It can be produced by obtaining a benzene compound represented by the formula and, if desired, hydrolyzing its di-lower alkoxymethyl group to form an aldehyde group, and/or alkylating or alkanoylating its hydroxyl group by a conventional method.
或いは、ベンゼン化合物（１）のうち、一般式（但し、
Ｒ２２は低級アルキル基を表し、Ｒゴ、Ｒ４及び環Ａは
前記と同一意味を有する。）で示されるベンゼン化合物
は一般式
（但し、環Ａは前記と同一意味を有する。）で示される
複素環アルデヒド化合物又はその塩と、−儀式
（但し、Ｘ２はハロゲン原子を表し、Ｒ３及びＲ４は前
記と同一意味を有する。）
で示されるアルコ：トシベンゼン化合物とを反応させ、
かくして得られる一段式
（但し、Ｒ４，３１４及び環Ａは前記と同一意味を有す
る。）
で示される複素環化合物の水酸基を常法により、低級ア
ルキル化した後、ジ低級アルキルボルムアミドと反応さ
せて製造することもできる。Alternatively, among the benzene compounds (1), the general formula (however,
R22 represents a lower alkyl group, and R, R4 and ring A have the same meanings as above. ) The benzene compound represented by the general formula (however, ring A has the same meaning as above) or its salt, and the formula (however, X2 represents a halogen atom, R3 and R4 has the same meaning as above.) is reacted with an alco:tosibenzene compound represented by
The hydroxyl group of the heterocyclic compound thus obtained is represented by the one-step formula (wherein R4,314 and ring A have the same meanings as above) by a conventional method, and then reacted with di-lower alkylborumamide. It can also be manufactured by
一方、ベンゼン化合物（１）のうち、−儀式（但し、Ｒ
８は低級アルキル基を表し、Ｒ’ 、Ｒ’及び環Ａは前
記と同一意味を有する。）で示されるベンゼン化合物は
、Ｒ１がジ低級アルコキシメチル基、Ｒ２＋が水素原子
であるベンゼン化合物（１−ａ）の分子内閉環反応によ
り製造することができる。On the other hand, among the benzene compounds (1), -ceremony (however, R
8 represents a lower alkyl group, and R', R' and ring A have the same meanings as above. The benzene compound represented by ) can be produced by intramolecular ring-closing reaction of a benzene compound (1-a) in which R1 is a di-lower alkoxymethyl group and R2+ is a hydrogen atom.
アセタール化合物（ＩＩ）又はその塩とアルデヒド化合
物（ＩＩＩ）との反応は、アルキルリチウムの存在下で
実施することができる。アルキルリチウムとしては、低
級アルキルリチウムを用いるのが好ましい。反応は適当
な溶媒中で実施するのが好ましく、溶媒としては、慣用
の有機溶媒をいずれも使用することができ、例えば、テ
トラヒドロフラン、エーテル、ジオキサン、ヘキサン、
トルエン、キシレン等をいずれも好適に用いることがで
きる。アセタール化合物（■）は、Ｘｌが水素原子又は
ハロゲン原子である化合物をいずれも用いることができ
るが、とりわけｘｌが水素原子又は臭素原子である化合
物を用いるのが好ましい。また、環Ａが含窒素複素環式
基である場合、アセタール化合物（ＩＩ）は、例えば、
無機酸付加塩（例えば、臭化水素酸塩、硫酸塩）、有機
酸イ］加塩（例えば、酢酸塩、シュウ酸塩、メタンスル
ボン酸塩、ベンゼンスルボン酸塩、トルエンスルホン酸
塩）等として反応に供することもできる。The reaction between the acetal compound (II) or its salt and the aldehyde compound (III) can be carried out in the presence of an alkyllithium. As the alkyllithium, it is preferable to use lower alkyllithium. The reaction is preferably carried out in a suitable solvent, and any conventional organic solvent can be used, for example, tetrahydrofuran, ether, dioxane, hexane,
Any of toluene, xylene, etc. can be suitably used. As the acetal compound (■), any compound in which Xl is a hydrogen atom or a halogen atom can be used, but it is particularly preferable to use a compound in which xl is a hydrogen atom or a bromine atom. Further, when ring A is a nitrogen-containing heterocyclic group, the acetal compound (II) is, for example,
Reacts as inorganic acid addition salts (e.g. hydrobromide, sulfate), organic acid addition salts (e.g. acetate, oxalate, methanesulfonate, benzenesulfonate, toluenesulfonate), etc. It can also be served.
反応に際しては、必要に応じ、塩基（例えば、ＮＮ ｌ
−テトラメチルエチレンジアミン）を共存させてもよい
。本反応は、例えば、冷却〜室温で好適に実施すること
ができる。During the reaction, a base (for example, NN l
-tetramethylethylenediamine) may also coexist. This reaction can be suitably carried out, for example, between cooling and room temperature.
ベンゼン化合物（１−ｂ）の加水分解は、アセタール加
水分解の常法に従い、酸処理により実施することができ
る。酸としては、例えば、ギ酸、酢酸、トリフルオロ酢
酸、メタンスルホン酸、トルエンスルホン酸の如き有機
酸、及びホウ酸、塩酸、硫酸、臭化水素酸の如き無機酸
をいずれも好適に用いることができる０反応は例えば、
トルエンの如き適当な溶媒中で実施するのが好ましく、
室温付近で好適に進行する。Hydrolysis of the benzene compound (1-b) can be carried out by acid treatment according to a conventional method for acetal hydrolysis. As the acid, for example, organic acids such as formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, and toluenesulfonic acid, and inorganic acids such as boric acid, hydrochloric acid, sulfuric acid, and hydrobromic acid can be suitably used. For example, the possible 0 reactions are:
Preferably carried out in a suitable solvent such as toluene,
It progresses suitably around room temperature.
また、生成物のアルキル化又はアルカノイル化反応も、
常法に従って実施することができる。例えば、アルキル
化剤としては、低級アルキルハライドを、アルカノイル
化剤としては、低級飽和脂肪酸の反応性誘導体（例えば
、酸ハライド、酸無水物、活性エステル、混合酸無水物
）を用い、脱酸剤の存在下で好適に実施することができ
る。In addition, the alkylation or alkanoylation reaction of the product can also be
It can be carried out according to conventional methods. For example, a lower alkyl halide is used as the alkylating agent, a reactive derivative of a lower saturated fatty acid (e.g., acid halide, acid anhydride, active ester, mixed acid anhydride) is used as the alkanoylating agent, and a deoxidizing agent is used as the alkylating agent. It can be suitably carried out in the presence of.
脱酸剤としては、例えば、トリエチルアミン、リチウム
ジイソプロピルアミドを適宜用いることができる。反応
は、例えば、テトラヒドロフランの如き適当な溶媒中、
室温付近で好適に進行し、必要に応じて触媒量の４−ジ
メチルアミノピリジンを共存させてもよい。As the deoxidizer, for example, triethylamine or lithium diisopropylamide can be used as appropriate. The reaction may be carried out in a suitable solvent such as, for example, tetrahydrofuran.
The reaction proceeds preferably at around room temperature, and if necessary, a catalytic amount of 4-dimethylaminopyridine may be present.
複素環アルデヒド化合物（ｒＶ）又はその塩とアルコキ
シベンゼン化合物（Ｖ）との反応は、前記化合物（ＩＩ
）と（ＩＩＩ）の反応と同様の条件下で実施することが
できる。その際、アルコキシベンゼン化合物（Ｖ）とし
ては、Ｘ２が塩素原子、臭素原子又はヨウ素原子である
化合物を用いるのが好ましく、また環Ａが含窒素複素環
である場合、複素環アルデヒド化合物（ｒＶ）はアセタ
ール化合物（ＩＩ）と同様の無機酸又は有機酸付加塩と
して反応に供することもできる。The reaction between the heterocyclic aldehyde compound (rV) or a salt thereof and the alkoxybenzene compound (V) is performed using the compound (II).
) and (III) under similar conditions. In this case, as the alkoxybenzene compound (V), it is preferable to use a compound in which X2 is a chlorine atom, a bromine atom, or an iodine atom, and when ring A is a nitrogen-containing heterocycle, a heterocyclic aldehyde compound (rV) can also be subjected to the reaction as an inorganic acid or organic acid addition salt similar to acetal compound (II).
更に、複素環化合物（Ｖｌ）のアルキル化反応は前記と
同様、アルキル化反応の常法に従って実施することがで
き、また、続くジ低級アルキルボルムアミドとの反応も
、前記化合物（■）と（ＩＩＩ）の反応と同様の条件下
で実施することができる。Furthermore, the alkylation reaction of the heterocyclic compound (Vl) can be carried out according to the conventional method for alkylation reactions as described above, and the subsequent reaction with di-lower alkylborumamide can also be carried out when the compound (■) and ( It can be carried out under the same conditions as reaction III).
一方、Ｒ”がジ低級アルコキシメチル基、Ｒ”が水素原
子である化合物（Ｉ−ａ）の分子内閉環反応は、ホウ酸
で処理することにより嚢施することができる。反応は、
例えば、トルエン、キシレンの°如き有機溶媒中、加熱
下、とりわけ溶媒の還流温度付近で好適に進行する。On the other hand, the intramolecular ring-closing reaction of compound (I-a) in which R'' is a di-lower alkoxymethyl group and R'' is a hydrogen atom can be carried out by treatment with boric acid. The reaction is
For example, the reaction is preferably carried out in an organic solvent such as toluene or xylene under heating, particularly around the reflux temperature of the solvent.
こうして得られる目的化合物（Ｉ）において、化合物（
１−ａ）〜（Ｉ−ｃ）には、α位の不斉炭素原子に基づ
く、２種の異性体が、また、化合物（１−ｄ）にはジヒ
ドロフラン環２位及び５位の不斉炭素原子に基づく、４
種のジアステレオマーが存在するが、本発明の目的化合
物（１）は、これらいずれも包含するものである。また
、本発明の目的化合物（１）は、環Ａが含窒素複素環で
ある場合及びＲ１が水素原子である場合、塩としても得
ることができ、かかる塩の具体例としては、例えば、環
Ａが置換基を有するか又は有しない含窒素複素環である
場合、無機酸付加塩（例えば、臭化水素酸塩、硫酸塩）
及び有機酸付加塩（例えば、酢酸塩、シュウ酸塩、メタ
ンスルホン酸塩、ベンゼンスルホン酸塩、トルエンスル
ホン酸塩）を、また、Ｒ２が水素原子である場合、アル
カリ金属塩（例えば、ナトリウム塩、カリウム塩）、ア
ルカリ土類金属塩（例えば、カルシウム塩）、第４級ア
ンモニウム塩（例えば、テトラエチルアンモニウム塩、
テトラエチルアンモニウム塩）等があげられる。In the target compound (I) thus obtained, the compound (
1-a) to (I-c) have two types of isomers based on the asymmetric carbon atom at the α-position, and compound (1-d) has unisomers at the 2- and 5-positions of the dihydrofuran ring. Based on the same carbon atom, 4
Although there are various diastereomers, the target compound (1) of the present invention includes all of these. Furthermore, the object compound (1) of the present invention can be obtained as a salt when ring A is a nitrogen-containing heterocycle and when R1 is a hydrogen atom, and specific examples of such salts include, for example, ring When A is a nitrogen-containing heterocycle with or without substituents, an inorganic acid addition salt (e.g., hydrobromide, sulfate)
and organic acid addition salts (e.g. acetate, oxalate, methanesulfonate, benzenesulfonate, toluenesulfonate), and when R2 is a hydrogen atom, alkali metal salts (e.g. sodium salt). , potassium salts), alkaline earth metal salts (e.g. calcium salts), quaternary ammonium salts (e.g. tetraethylammonium salts,
(tetraethylammonium salt), etc.
上記方法により得られる本発明の目的化合物（Ｉ）及び
その塩は、各種医薬化合物の合成中間体として有用な化
合物であり、例えば、ベンゼン化合物（１）又はその塩
と一般式
％式％（）
（但し、Ｒ６及びＲ″Ｉは前記と同一意味を有する。）
で示されるアセチレン化合物とを、無溶媒又は適当な溶
媒中、有機酸（例えば、酢酸、トリフルオロ酢酸、ｐ）
ルエンスルホン酸）の存在下で反応させることにより、
抗脂血剤として優れた緒特性を有する一般式
（但し、Ｒ６は水素原子又は低級アルコキシカルボニル
基％ Ｒ’は低級アルコキシカルボニル基を表し、Ｒ３
、Ｒ４及び環Ａは前記と同一意味を有する。）
で示されるビフェニル誘導体（特願昭６２−２９４７３
６号）に導くことができる。The object compound (I) of the present invention and its salt obtained by the above method are useful compounds as intermediates for the synthesis of various pharmaceutical compounds, for example, benzene compound (1) or its salt and the general formula % formula % () (However, R6 and R″I have the same meaning as above.)
The acetylene compound represented by
By reacting in the presence of luenesulfonic acid),
The general formula has excellent properties as an antilipemic agent (where R6 is a hydrogen atom or a lower alkoxycarbonyl group, R' is a lower alkoxycarbonyl group, and R3
, R4 and ring A have the same meanings as above. ) (Patent application No. 62-29473)
No. 6).
実施例 １
（１）３−ジメトキシメチルチオフェン１０．０ｇのテ
トラヒドロフラン１００ｍｆｆ１溶液に、ＩＷ押押下−
７０〜−５０°Ｃで１．５５Ｍｎ−ブチルリチウムのヘ
キサン溶液４５ｍ１を約１０置火して加える。混液を−
７０〜−６０゛Ｃで３０分間攪拌後、更に３．４−ジメ
トキシベンズアルデヒド１０．５ｇのテトラヒドロフラ
ン５０ｍ１溶液を−７０〜−５０℃で約１０置火して加
える。同温にて３０分間（児拌後、反応液を水３００
ｍｆｌに注ぎ、更に酢酸エチル５００ ｍｌを加えて振
とう後、有機層を分取する。該有機層を乾燥後、溶媒を
留去し、残香をシリカゲルカラム〔溶媒：ヘキサンー酢
酸エチル（２：１））で精製し、溶出液から溶媒をを減
圧留去して２−（α−ヒドロキシ−３，４−ジメトキシ
ベンジル）−３−ジメトキシメチルチオフェン１８ｇを
シラツブとして得る。Example 1 (1) IW was pressed into a solution of 10.0 g of 3-dimethoxymethylthiophene in 100 mff1 of tetrahydrofuran.
Add 45 ml of a hexane solution of 1.55 M n-butyllithium at 70 to -50° C. for about 10 minutes. Mixed liquid -
After stirring at 70 to -60°C for 30 minutes, a solution of 10.5 g of 3,4-dimethoxybenzaldehyde in 50 ml of tetrahydrofuran was added at -70 to -50°C for about 10 minutes. 30 minutes at the same temperature (after stirring, dilute the reaction solution with 300% water
After adding 500 ml of ethyl acetate and shaking, the organic layer was separated. After drying the organic layer, the solvent was distilled off, the residual aroma was purified using a silica gel column [solvent: hexane-ethyl acetate (2:1)], and the solvent was distilled off from the eluate under reduced pressure to obtain 2-(α-hydroxy 18 g of -3,4-dimethoxybenzyl)-3-dimethoxymethylthiophene are obtained as silica.
（２）上記（１）の生成物１．０ｇのトルエン溶液にホ
ウ酸１．９ｇを加え、加熱還流する。冷却後、反応液よ
り溶媒を減圧留去し、残香に酢酸エチルを加え洗浄、乾
燥後、溶媒を減圧留去し、シリカゲルカラムで精製して
、２−（α−ヒドロキシ−３，４−ジメトキシベンジル
）−３−チオフェンカルボアルデヒド４７０ｍｇを無色
結晶として得る。(2) Add 1.9 g of boric acid to a toluene solution of 1.0 g of the product obtained in (1) above, and heat to reflux. After cooling, the solvent was distilled off from the reaction solution under reduced pressure, and the residual aroma was washed with ethyl acetate. After drying, the solvent was distilled off under reduced pressure, and purified with a silica gel column to obtain 2-(α-hydroxy-3,4-dimethoxy). 470 mg of benzyl)-3-thiophenecarbaldehyde are obtained as colorless crystals.
（３）上記（２）の生成物１．５ｇ、無水酢酸６６１
ｍｇ、４−ジメチルアミノピリジン２０１Ｔ１ｇのテト
ラヒドロフラン溶液に氷水冷下、トリエチルアミン８１
８ｍｇのテトラヒドロフラン溶液を加え、撹拌する０反
応液にメタノールを加え、溶媒を減圧留去する。残香に
酢酸エチルを加え、飽和重炭酸水素ナトリウム水溶液で
洗浄、乾燥後、溶媒を減圧留去し、シリカゲルカラムで
精製して、２−（α−アセトキシ−３，４−ジメトキシ
ベンジル）−３−チオフェンカルボアルデヒド１．７ｇ
を無色結晶として得る。(3) 1.5 g of the product from (2) above, 661 g of acetic anhydride
To a solution of 201 T1 g of 4-dimethylaminopyridine in tetrahydrofuran was added 81 mg of triethylamine under ice-water cooling.
8 mg of tetrahydrofuran solution is added and methanol is added to the stirred reaction mixture, and the solvent is distilled off under reduced pressure. Ethyl acetate was added to the residual aroma, washed with saturated aqueous sodium bicarbonate solution, dried, the solvent was distilled off under reduced pressure, and purified with a silica gel column to give 2-(α-acetoxy-3,4-dimethoxybenzyl)-3- Thiophenecarbaldehyde 1.7g
is obtained as colorless crystals.
Ｍ、 ｐ、 ９１〜９２ °Ｃ（酢酸エチル−ヘキ
サンから再結晶）
実施例 ２
対応原料化合物を実施例１と同様に処理して２−（αニ
アモトキシ−３，４−ジエトキシベンジル）−３−チオ
フェンカルボアルデヒドを得る。M, p, 91-92 °C (recrystallized from ethyl acetate-hexane) Example 2 The corresponding raw material compound was treated in the same manner as in Example 1 to obtain 2-(α-niamotoxy-3,4-diethoxybenzyl)-3. -obtain thiophene carbaldehyde.
Ｍ、ｐ、６８°Ｃ
実施例 ３
（１）４−ブロモベラトロール１０．８５ｇのテトラヒ
ドロフラン溶液に、冷却下、２．５Ｍｎ−ブチルリチウ
ムのヘキサン溶液２４ｍ１を滴下し、撹拌後、３−チオ
フェンカルボアルデヒド５．６１ｇを加えて撹拌し、室
温にもどす。水を加え、酢酸エチル抽出し、乾燥後、溶
媒を減圧留去して、３−（α−ヒドロキシ−３，４−ジ
メトキシベンジル）チオフェンを得る。該化合物のジメ
チルホルムアミド溶液に水素化ナトリウム２．８ｇを加
え、室温で撹拌し、さらにヨウ化メチル４．１ｍｆｌを
加えて撹拌する。少量の水を加えたのち、溶媒を減圧留
去し、残香に水を加え、酢酸エチル抽出し、抽出液を乾
燥後、溶媒を減圧留去する。残香をシリカゲルカラムで
精製して、３−（α−メトキシ−３，４−ジメトキシベ
ンジル）チオフェン１０．５ｇを得る。M, p, 68°C Example 3 (1) 24 ml of a hexane solution of 2.5M n-butyllithium was added dropwise to a solution of 10.85 g of 4-bromoveratrol in tetrahydrofuran under cooling, and after stirring, 3-thiophenecarbo Add 5.61 g of aldehyde, stir, and return to room temperature. Water is added, extracted with ethyl acetate, and after drying, the solvent is distilled off under reduced pressure to obtain 3-(α-hydroxy-3,4-dimethoxybenzyl)thiophene. 2.8 g of sodium hydride is added to a dimethylformamide solution of the compound, and the mixture is stirred at room temperature, and then 4.1 mfl of methyl iodide is added and stirred. After adding a small amount of water, the solvent is distilled off under reduced pressure, water is added to the residual aroma, extracted with ethyl acetate, and after drying the extract, the solvent is distilled off under reduced pressure. The residual aroma is purified using a silica gel column to obtain 10.5 g of 3-(α-methoxy-3,4-dimethoxybenzyl)thiophene.
（２）上記（１）の生成物４．１０ｇのテトラヒドロフ
ラン溶液に、冷却下、２．５Ｍｎ−ブチルリチウムのヘ
キサン溶液６．８１ｄを滴下し、撹拌したのち、Ｎ、Ｎ
−ジメチルホルムアミド１．２５ｇを加えて撹拌する。(2) To a tetrahydrofuran solution of 4.10 g of the product of (1) above, 6.81 d of a hexane solution of 2.5 M n-butyllithium was added dropwise under cooling, and after stirring, N,N
- Add 1.25 g of dimethylformamide and stir.
反応液を室温にもどしたのち、水を加え、酢酸エチル抽
出し、抽出液を乾燥後、溶媒を減圧留去する。残香をシ
リカゲルカラムで精製して、３−（α−メトキシ−３，
４−ジメトキシベンジル）−２−チオフェンカルボアル
デヒド３．８１ｇを得る。After the reaction solution was returned to room temperature, water was added and extracted with ethyl acetate. After drying the extract, the solvent was distilled off under reduced pressure. The residual aroma was purified using a silica gel column to obtain 3-(α-methoxy-3,
3.81 g of 4-dimethoxybenzyl)-2-thiophenecarbaldehyde are obtained.
実施例 ４
（１）２−ブロモ−３−ジメトキシメチルピリジン１１
．６ｇのテトラヒドロフラン溶液に撹拌冷却下、１．５
５Ｍｎ−ブチルリチウムのヘキサン溶液３２．６ｍｌを
加える。混液を冷却下撹拌後、該混液に３．４−ジメト
キシベンズアルデヒド８゜３ｇのテトラヒドロフラン溶
液を加える。撹拌後、反応液を水に注ぎ、さらに酢酸エ
チルを加え有機層を分取する。該有機層を洗浄、乾燥後
、溶媒を減圧留去し、残香をシリカゲルカラムで精製し
て、２−（α−ヒドロキシ−３，４−メトキシベンジル
）−３−ジメトキシメチルピリジン８．４ｇを黄色結晶
として得る。Example 4 (1) 2-bromo-3-dimethoxymethylpyridine 11
．． Add 1.5 to 6 g of tetrahydrofuran solution under stirring and cooling.
Add 32.6 ml of a hexane solution of 5M n-butyllithium. After stirring the mixture under cooling, a solution of 8.3 g of 3,4-dimethoxybenzaldehyde in tetrahydrofuran was added to the mixture. After stirring, the reaction solution is poured into water, ethyl acetate is added, and the organic layer is separated. After washing and drying the organic layer, the solvent was distilled off under reduced pressure, and the residual aroma was purified using a silica gel column to obtain 8.4 g of 2-(α-hydroxy-3,4-methoxybenzyl)-3-dimethoxymethylpyridine in a yellow color. Obtained as crystals.
Ｍ、ｐ、９１〜９２ °Ｃ（酢酸エチル−ヘキサンか
ら再結晶）
（２）上記（１）の生成物１１ｇをトルエンに加熱溶解
し、ホウ酸３２ｇを加えて加熱還流する。反応液を冷却
後、溶媒を減圧留去する。残香に酢酸エチルを加え、水
洗、乾燥後、溶媒を減圧留去し、シリカゲルカラムで精
製して、３−（３，４−ジメトキシフェニル）−１−メ
トキシ−Ｉ Ｈ，３Ｈ−ピリジノ（２，３−ｃ）フラン
６．５ｇを淡褐色シラツブとして得る。M, p, 91-92°C (recrystallized from ethyl acetate-hexane) (2) 11 g of the product from (1) above is dissolved in toluene by heating, 32 g of boric acid is added, and the mixture is heated to reflux. After cooling the reaction solution, the solvent is distilled off under reduced pressure. Ethyl acetate was added to the residual aroma, washed with water, dried, the solvent was distilled off under reduced pressure, and purified with a silica gel column to obtain 3-(3,4-dimethoxyphenyl)-1-methoxy-I H,3H-pyridino(2, 3-c) Obtain 6.5 g of furan as a pale brown syrup.
実施例 ５
（１）１−フェニルスルホニル−３−ジメトキシメチル
インドール１９ｇとＮ、Ｎ、Ｎ’、Ｎ’、−テトラメチ
ルエチレンジアミン６．５ｇのテトラヒドロフラン溶液
に撹拌冷却下、１．５５Ｍｎ−ブチルリチウムのヘキサ
ン溶液４０ｍを加える。混液を室温で撹拌後、再び冷却
下にて３．４−ジメトキシベンズアルデヒド９．３ｇの
テトラヒドロフラン溶液を加え、室温で撹拌後、反応液
を水に注ぎ、酢酸エチル抽出する。抽出液を乾燥後、溶
媒を減圧留去し、シリカゲルカラムで精製して、ｌ−フ
ェニルスルホニル−２−（α−ヒドロキシ−３，４−ジ
メトキシベンジル）−３−ジメトキシメチルインドール
１７ｇをシラツブとして得る。Example 5 (1) 1.55M n-butyllithium was added to a tetrahydrofuran solution of 19 g of 1-phenylsulfonyl-3-dimethoxymethylindole and 6.5 g of N,N,N',N',-tetramethylethylenediamine under stirring and cooling. Add 40ml of hexane solution. After stirring the mixture at room temperature, a solution of 9.3 g of 3.4-dimethoxybenzaldehyde in tetrahydrofuran was added under cooling again, and after stirring at room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. After drying the extract, the solvent is distilled off under reduced pressure and purified with a silica gel column to obtain 17 g of l-phenylsulfonyl-2-(α-hydroxy-3,4-dimethoxybenzyl)-3-dimethoxymethylindole as a silica lump. .
（２）上記（１）の生成物０．５ｇのトルエン溶液にホ
ウ酸０，６ｇを加えて加熱還流する。反応液を冷却後、
溶媒を減圧留去する。残香に酢酸エチルを加え水洗、乾
燥後、溶媒を減圧留去し、シリカゲルカラムで精製して
、３−（３，４−ジメトキシフェニル）−１−メトキシ
−４−フェニルスルホニル−ＩＨ，３Ｈ−インド０ （
２，３−ｃ）フラン３７０■を淡黄色結晶として得る。(2) Add 0.6 g of boric acid to a toluene solution of 0.5 g of the product obtained in (1) above and heat to reflux. After cooling the reaction solution,
The solvent is removed under reduced pressure. After adding ethyl acetate to the residual aroma, washing with water, and drying, the solvent was distilled off under reduced pressure and purified with a silica gel column to obtain 3-(3,4-dimethoxyphenyl)-1-methoxy-4-phenylsulfonyl-IH,3H-indo. 0 (
2,3-c) 370 cm of furan is obtained as pale yellow crystals.
Ｍ、ｐ、１３１〜１３２°Ｃ
参考例１
２−（α−アセトキシ−３，４−ジメトキシベンジル）
−３−チオフェンカルボアルデヒド１゜５ｇ及びアセチ
レンジカルボン酸ジメチルエステル１．８ｇのベンゼン
溶液にトリフルオロ酢酸を加え、加熱還流する。反応液
から溶媒を留去し、残香をシリカゲルカラムで精製して
４−ヒドロキシ−５，６−ビス（メトキシカルボニル）
−７−（３，４−ジメトキシフェニル）ベンゾ（ｂ）チ
オフェン３５０■を無色結晶として得る。M, p, 131-132°C Reference example 1 2-(α-acetoxy-3,4-dimethoxybenzyl)
Trifluoroacetic acid is added to a benzene solution containing 1.5 g of -3-thiophenecarbaldehyde and 1.8 g of acetylene dicarboxylic acid dimethyl ester, and the mixture is heated to reflux. The solvent was distilled off from the reaction solution, and the residual aroma was purified using a silica gel column to obtain 4-hydroxy-5,6-bis(methoxycarbonyl).
350 μm of -7-(3,4-dimethoxyphenyl)benzo(b)thiophene is obtained as colorless crystals.
該結晶を酢酸エチル−ヘキサンから再結晶して無色プリ
ズムを得る。The crystals are recrystallized from ethyl acetate-hexane to obtain colorless prisms.
Ｍ、ｐ、１４７〜１４８°Ｃ
参考例２〜５
対応原料化合物を参考例１と同様に処理して下記第１表
記載の化合物を得る。（表中、Ｍｅはメチル基、Ｅｔは
エチル基を表す。以下同様。）参考例６
ジイソプロピルアミン７．０ｇのテトラヒドロフラン溶
液に冷却下、１．５５Ｍｎ−ブチルリチウムのヘキサン
溶液を加える。混液を冷却、撹拌後、３−（３，４−ジ
メトキシフェニル）−１−メトキシ−ＩＨ，３Ｈ−ピリ
ジノ（２，３−Ｃ）フラン５．０ｇのテトラヒドロフラ
ン溶液を加える。反応終了後０反応液にアセチレンジカ
ルボン酸ジメチルエステル２．７ｇ及び酢酸のテトラヒ
ドロフラン溶液を加えて撹拌する。反応液を水に注ぎ、
酢酸エチル抽出する。抽出液から溶媒を留去し、残香を
シリカゲルカラムで精製する。得られた淡褐色油状物１
．８ｇのベンゼンに溶液に、トリフルオロ酢酸を加え、
室温で撹拌する。反応液より溶媒を留去し、残香を酢酸
エチル中、飽和重炭酸水素すトリウム水溶液で中和し、
更に、エーテルで洗浄して、５−ヒドロキシ−６，７−
ビス（メトキシカルボニル）−８−（３，４−ジメトキ
シフェニル）キノリン１．３ｇを得る。M, p, 147-148°C Reference Examples 2-5 The corresponding starting compounds were treated in the same manner as in Reference Example 1 to obtain the compounds listed in Table 1 below. (In the table, Me represents a methyl group and Et represents an ethyl group. The same applies hereinafter.) Reference Example 6 A hexane solution of 1.55 M n-butyllithium is added to a tetrahydrofuran solution of 7.0 g of diisopropylamine under cooling. After cooling and stirring the mixture, a solution of 5.0 g of 3-(3,4-dimethoxyphenyl)-1-methoxy-IH,3H-pyridino(2,3-C)furan in tetrahydrofuran is added. After the reaction is completed, 2.7 g of acetylene dicarboxylic acid dimethyl ester and acetic acid in tetrahydrofuran solution are added to the reaction solution and stirred. Pour the reaction solution into water,
Extract with ethyl acetate. The solvent is distilled off from the extract, and the residual aroma is purified using a silica gel column. Obtained pale brown oil 1
．． Add trifluoroacetic acid to a solution of 8 g of benzene,
Stir at room temperature. The solvent was distilled off from the reaction solution, and the residual aroma was neutralized with a saturated aqueous solution of sodium bicarbonate in ethyl acetate.
Furthermore, washing with ether gave 5-hydroxy-6,7-
1.3 g of bis(methoxycarbonyl)-8-(3,4-dimethoxyphenyl)quinoline are obtained.
該結晶を酢酸エチル−ヘキサン混液から再結晶して、淡
褐色針状晶を得る。The crystals are recrystallized from an ethyl acetate-hexane mixture to give light brown needles.
Ｍ、ｐ、１８３〜１８４℃
参考例７
３−（３，４−ジメトキシフェニル）−１−メトキシ−
４−フェニルスルホニル−ＩＨ，３１１−インドロ（２
，３−ｃ）フラン３１．４ｇ及びアセチレンジカルボン
酸ジメチル２８．５ｇのベンゼン溶液を加熱還流する０
反応液にｐ−）ルエンスルホン酸・１水和物を加え、更
に加熱還流する。反応液から溶媒を留去し、エーテルを
加えて析出品を濾取することにより、４−ヒドロキシ−
２，３−ビス（メトキシカルボニル）−１−（３゜４−
ジメトキシフェニル）−９−フヱニルスルホニル力ルバ
ゾール２７．５ｇｔ”ｉＷる。M, p, 183-184°C Reference Example 7 3-(3,4-dimethoxyphenyl)-1-methoxy-
4-phenylsulfonyl-IH,311-indolo(2
, 3-c) A benzene solution of 31.4 g of furan and 28.5 g of dimethyl acetylenedicarboxylate is heated to reflux.
p-)luenesulfonic acid monohydrate was added to the reaction solution, and the mixture was further heated to reflux. 4-hydroxy-
2,3-bis(methoxycarbonyl)-1-(3゜4-
(dimethoxyphenyl)-9-phenylsulfonyl Rubazole 27.5 gt"iW.
Ｍ、 ｐ、１９２ 〜１９３ °Ｃ
Ｃ参考例
月応原料化合物を参考例７と同様に処理して４−ヒドロ
キシ−２，３−ビス（エトキシカルボニル）−１−（３
，４−ジメトキシフェニル）−９−フェニルスルホニル
カルバゾールヲ得る。M, p, 192 to 193 °C CReference Example The raw material compound was treated in the same manner as in Reference Example 7 to obtain 4-hydroxy-2,3-bis(ethoxycarbonyl)-1-(3
, 4-dimethoxyphenyl)-9-phenylsulfonylcarbazole is obtained.
Ｍ、ｐ、２０２〜２０３°ＣM, p, 202-203°C
Claims (1)
しくはジ低級アルコキシメチル基であり、Ｒ＾２が水素
原子、低級アルキル基もしくは低級アルカノイル基であ
るか、又はＲ＾１とＲ＾２とが互いに結合して低級アル
コキシメチレン基を形成していることを表し、Ｒ＾３及
びＲ＾４は低級アルキル基、環Ａは置換基を有するか又
は有しない含硫もしくは含窒素複素環を表す。） で示されるベンゼン化合物又はその塩。 ２、環Ａがフェニルスルホニル基又は低級アルキルフェ
ニルスルホニル基で置換されていてもよい、チオフェン
環、ピロール環、イミダゾール環、ピリジン環、ピリミ
ジン環、インドール環、キノリン環、チアゾール環又は
オキサゾール環である請求項１記載の化合物。 ３、環Ａがチオフェン環、ピリジン環、インドール環又
はＮ−フェニルスルホニルインドール環である請求項２
記載の化合物。 ４、一般式 ▲数式、化学式、表等があります▼ （但し、Ｒ＾５は低級アルキル基、Ｘ＾１はハロゲン原
子、環Ａは置換基を有するか又は有しない含硫もしくは
含酸素複素環を表す。） で示されるアセタール化合物又はその塩と、一般式 ▲数式、化学式、表等があります▼ （但し、Ｒ＾３及びＲ＾４は低級アルキル基を表す。）
で示されるアルデヒド化合物とを反応させて、一般式 ▲数式、化学式、表等があります▼ （但し、Ｒ＾３〜Ｒ＾５及び環Ａは前記と同一意味を有
する。） で示されるベンゼン化合物を得、所望により、そのジ低
級アルコキシメチル基を加水分解してアルデヒド基とす
るか、及び／又はその水酸基をアルキル化もしくはアル
カノイル化し、さらに必要であれば生成物を塩とするこ
とを特徴とする一般式▲数式、化学式、表等があります
▼ （但し、Ｒ＾１＾１はアルデヒド基又はジ低級アルコキ
シメチル基、Ｒ＾２＾１は水素原子、低級アルキル基又
は低級アルカノイル基を表し、Ｒ＾３、Ｒ＾４及び環Ａ
は前記と同一意味を有する。） で示されるベンゼン化合物又はその塩の製法。 ５、一般式 ▲数式、化学式、表等があります▼ （但し、環Ａは置換基を有するか又は有しない含硫もし
くは含酸素複素環を表す。） で示される複素環アルデヒド化合物又はその塩と一般式 ▲数式、化学式、表等があります▼ （但し、Ｘ＾２はハロゲン原子を表し、Ｒ＾３及びＲ＾
４は前記と同一意味を有する、）で示されるアルコキシ
ベンゼン化合物とを反応させ、かくして得られる、一般
式 ▲数式、化学式、表等があります▼ （但し、Ｒ＾３及びＲ＾４環Ａは前記と同一意味を有す
る。） で示される複素環化合物の水酸基を低級アルキル化した
後、ジ低級アルキルホルムアミドと反応させ、所望によ
り生成物を塩とすることを特徴とする、一般式 ▲数式、化学式、表等があります▼ （但し、Ｒ＾２＾２は低級アルキル基を表し、Ｒ＾３、
Ｒ＾４及び環Ａは前記と同一意味を有する。）で示され
るベンゼン化合物又はその塩の製法。 ６、一般式 ▲数式、化学式、表等があります▼ （但し、Ｒ＾３〜Ｒ＾５は低級アルキル基、環Ａは置換
基を有するか又は有しない含硫もしくは含酸素複素環を
表す。） で示されるベンゼン化合物又はその塩を分子内閉環反応
させ、所望により生成物を塩とすることを特徴とする、
一般式 ▲数式、化学式、表等があります▼ （但し、Ｒ＾３〜Ｒ＾５及び環Ａは前記と同一意味を有
する。） で示されるベンゼン化合物又はその塩の製法。[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (However, R^1 and R^2 are R^1 is an aldehyde group or di-lower alkoxymethyl group, and R^2 represents a hydrogen atom, a lower alkyl group or a lower alkanoyl group, or R^1 and R^2 combine with each other to form a lower alkoxymethylene group, and R^3 and R^4 are (a lower alkyl group, ring A represents a sulfur-containing or nitrogen-containing heterocycle with or without a substituent) or a salt thereof. 2. Ring A is a thiophene ring, pyrrole ring, imidazole ring, pyridine ring, pyrimidine ring, indole ring, quinoline ring, thiazole ring or oxazole ring, which may be substituted with a phenylsulfonyl group or a lower alkylphenylsulfonyl group. A compound according to claim 1. 3. Claim 2, wherein ring A is a thiophene ring, pyridine ring, indole ring or N-phenylsulfonylindole ring.
Compounds described. 4. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (However, R^5 is a lower alkyl group, X^1 is a halogen atom, and ring A is a sulfur-containing or oxygen-containing heterocycle with or without a substituent. ) and the general formula ▲ mathematical formula, chemical formula, table, etc. ▼ (However, R^3 and R^4 represent lower alkyl groups.)
A benzene compound represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (However, R^3 to R^5 and ring A have the same meanings as above.) and, if desired, hydrolyzing the di-lower alkoxymethyl group to give an aldehyde group, and/or alkylating or alkanoylating the hydroxyl group, and if necessary, converting the product into a salt. There are general formulas such as ▲ mathematical formulas, chemical formulas, tables, etc. R^3, R^4 and ring A
has the same meaning as above. ) A method for producing a benzene compound or a salt thereof. 5. Heterocyclic aldehyde compounds or their salts represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (However, ring A represents a sulfur-containing or oxygen-containing heterocycle with or without a substituent.) General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, X^2 represents a halogen atom, R^3 and R^
4 has the same meaning as above) is reacted with the alkoxybenzene compound represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (However, R^3 and R^4 ring A is The general formula ▲ is characterized in that the hydroxyl group of the heterocyclic compound represented by (has the same meaning as above) is lower-alkylated and then reacted with di-lower alkylformamide to optionally convert the product into a salt, There are chemical formulas, tables, etc.▼ (However, R^2^2 represents a lower alkyl group, R^3,
R^4 and ring A have the same meanings as above. ) A method for producing a benzene compound or its salt. 6. General formula ▲ There are numerical formulas, chemical formulas, tables, etc. ▼ (However, R^3 to R^5 are lower alkyl groups, and ring A represents a sulfur-containing or oxygen-containing heterocycle with or without a substituent. ) or a salt thereof is subjected to an intramolecular ring-closing reaction, and if desired, the product is converted into a salt,
A method for producing a benzene compound or its salt represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (However, R^3 to R^5 and ring A have the same meanings as above.)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1025272A JPH0737456B2 (en) | 1989-02-02 | 1989-02-02 | Benzene compound and its manufacturing method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1025272A JPH0737456B2 (en) | 1989-02-02 | 1989-02-02 | Benzene compound and its manufacturing method |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62294736A Division JPH01135766A (en) | 1987-11-20 | 1987-11-20 | Biphenyl derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01265072A true JPH01265072A (en) | 1989-10-23 |
| JPH0737456B2 JPH0737456B2 (en) | 1995-04-26 |
Family
ID=12161395
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1025272A Expired - Lifetime JPH0737456B2 (en) | 1989-02-02 | 1989-02-02 | Benzene compound and its manufacturing method |
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| Country | Link |
|---|---|
| JP (1) | JPH0737456B2 (en) |
-
1989
- 1989-02-02 JP JP1025272A patent/JPH0737456B2/en not_active Expired - Lifetime
Non-Patent Citations (5)
| Title |
|---|
| CHEM ABSTRACTS=1972 * |
| CHEM.ABSTRACTS=1968 * |
| CHEM.ABSTRACTS=1969 * |
| CHEM.ABSTRACTS=1975 * |
| CHEM.ABSTRACTS=1982 * |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0737456B2 (en) | 1995-04-26 |
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