JPH0480021B2 - - Google Patents
Info
- Publication number
- JPH0480021B2 JPH0480021B2 JP16420987A JP16420987A JPH0480021B2 JP H0480021 B2 JPH0480021 B2 JP H0480021B2 JP 16420987 A JP16420987 A JP 16420987A JP 16420987 A JP16420987 A JP 16420987A JP H0480021 B2 JPH0480021 B2 JP H0480021B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- reaction
- solvent
- hours
- carried out
- 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.)
- Expired
Links
- -1 diphenylthioether compound Chemical class 0.000 claims description 27
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 description 26
- 238000006243 chemical reaction Methods 0.000 description 23
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 239000002904 solvent Substances 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 9
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- PEYVWBGHBCDXRT-UHFFFAOYSA-N N1=NNC2=CN=NC2=C1 Chemical class N1=NNC2=CN=NC2=C1 PEYVWBGHBCDXRT-UHFFFAOYSA-N 0.000 description 4
- 229910000019 calcium carbonate Inorganic materials 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-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
- 239000002255 antigout agent Substances 0.000 description 3
- 229960002708 antigout preparations Drugs 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229910001873 dinitrogen Inorganic materials 0.000 description 3
- 230000002140 halogenating effect Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-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
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-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
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- LTYMSROWYAPPGB-UHFFFAOYSA-N diphenyl sulfide Chemical class C=1C=CC=CC=1SC1=CC=CC=C1 LTYMSROWYAPPGB-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- ZNASTXYIFMYILW-UHFFFAOYSA-N (4-formyl-2-methoxyphenyl) methanesulfonate Chemical compound COC1=CC(C=O)=CC=C1OS(C)(=O)=O ZNASTXYIFMYILW-UHFFFAOYSA-N 0.000 description 1
- ZIIBHDDDVWRCGF-UHFFFAOYSA-N (4-formyl-3-methylphenyl) methanesulfonate Chemical compound CC1=CC(OS(C)(=O)=O)=CC=C1C=O ZIIBHDDDVWRCGF-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- BAKYASSDAXQKKY-UHFFFAOYSA-N 4-Hydroxy-3-methylbenzaldehyde Chemical compound CC1=CC(C=O)=CC=C1O BAKYASSDAXQKKY-UHFFFAOYSA-N 0.000 description 1
- 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 150000003935 benzaldehydes Chemical class 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 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
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- CDHICTNQMQYRSM-UHFFFAOYSA-N di(propan-2-yl)alumane Chemical compound CC(C)[AlH]C(C)C CDHICTNQMQYRSM-UHFFFAOYSA-N 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 238000010438 heat treatment Methods 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
- 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 1
- 239000011261 inert gas Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-M periodate Chemical class [O-]I(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-M 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- DJEHXEMURTVAOE-UHFFFAOYSA-M potassium bisulfite Chemical compound [K+].OS([O-])=O DJEHXEMURTVAOE-UHFFFAOYSA-M 0.000 description 1
- 229940099427 potassium bisulfite Drugs 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 235000010259 potassium hydrogen sulphite Nutrition 0.000 description 1
- FJVZDOGVDJCCCR-UHFFFAOYSA-M potassium periodate Chemical compound [K+].[O-]I(=O)(=O)=O FJVZDOGVDJCCCR-UHFFFAOYSA-M 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- DUIOPKIIICUYRZ-UHFFFAOYSA-N semicarbazide Chemical compound NNC(N)=O DUIOPKIIICUYRZ-UHFFFAOYSA-N 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 150000003458 sulfonic acid derivatives Chemical class 0.000 description 1
- 239000000725 suspension 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【発明の詳細な説明】
産業上の利用分野
本発明は新規なジフエニルチオエーテル化合物
に関する。本発明の化合物は、抗痛風剤として有
用な新規ピラゾロトリアジン誘導体の合成中間体
として極めて有用な化合物である。DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to novel diphenylthioether compounds. The compound of the present invention is an extremely useful compound as a synthetic intermediate for a new pyrazolotriazine derivative useful as an anti-gout agent.
発明の構成および効果
本発明のジフエニルチオエーテル化合物は下記
一般式
[式中、R1は低級アルキル基または低級アルコ
キシ基を示す]
で表される化合物である。Structure and Effects of the Invention The diphenylthioether compound of the present invention has the following general formula: [In the formula, R 1 represents a lower alkyl group or a lower alkoxy group] This is a compound represented by the following formula.
本明細書において、低級アルキル基とは、例え
ば、メチル、エチル、プロピル、イソプロピル、
ブチル、t−ブチル、ペンチル、ヘキシルなどの
直鎖または分枝鎖状のアルキル基が含まれる。ま
た低級アルコキシ基としては、例えば、メトキ
シ、エトキシ、プロポキシ、イソプロポキシ、ブ
トキシ、t−ブトキシ、ペンチルオキシ、ヘキシ
ルオキシなどの直鎖または分枝鎖状のアルコキシ
基が含まれる。 In this specification, lower alkyl groups include, for example, methyl, ethyl, propyl, isopropyl,
Straight chain or branched alkyl groups such as butyl, t-butyl, pentyl, hexyl and the like are included. Examples of the lower alkoxy group include linear or branched alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentyloxy, and hexyloxy.
また低級アルキル基を置換基として有すること
のあるフエニル基としては、例えば、フエニル、
2−メチルフエニル、3−メチルフエニル、4−
メチルフエニル、4−エチルフエニル、3−(1
−プロピル)フエニル、4−(1−ブチル)フエ
ニル、4−(t−ブチル)フエニル、4−(1−ペ
ンチル)フエニル、4−(1−ヘキシル)フエニ
ルなどが含まれる。 Furthermore, phenyl groups that may have lower alkyl groups as substituents include, for example, phenyl,
2-methylphenyl, 3-methylphenyl, 4-
Methylphenyl, 4-ethylphenyl, 3-(1
-propyl)phenyl, 4-(1-butyl)phenyl, 4-(t-butyl)phenyl, 4-(1-pentyl)phenyl, 4-(1-hexyl)phenyl, and the like.
本発明の化合物は種々の方法により製造され、
例えば下記反応式−1で示される方法で製造され
る。 The compounds of the present invention can be produced by various methods,
For example, it is produced by the method shown in Reaction Formula-1 below.
[式中、R1は前記に同じ、R2は低級アルキル基
または置換基として低級アルキル基を有すること
のあるフエニル基を示す。]
上記反応は、不活性溶媒中で、一般式(2)で表さ
れるベンズアルデヒド誘導体に少なくとも等モル
量程度、好ましくは1〜3倍モル量程度のチオフ
エノールを100〜200℃、好ましくは130〜160℃に
て1〜100時間程度、好ましくは2〜70時間程度
反応させることにより実施される。 [In the formula, R 1 is the same as above, and R 2 represents a lower alkyl group or a phenyl group that may have a lower alkyl group as a substituent. ] The above reaction is carried out by adding thiophenol in an inert solvent at 100 to 200°C, preferably at 130°C, at least about an equimolar amount, preferably about 1 to 3 times the molar amount, to the benzaldehyde derivative represented by general formula (2). The reaction is carried out at ~160°C for about 1 to 100 hours, preferably about 2 to 70 hours.
本発明で使用される不活性溶媒としては、反応
に悪影響を与えないものであればいずも使用で
き、例えば、N,N−ジメチルホルムアミド
(DMF)、ジメチルスルホキシド(DMSO)、ア
セトニトリル、N,N−ジメチルアセトアミド、
ヘキサメチルリン酸トリアミド(HMPA)など
を例示することができる。中でもN,N−ジメチ
ルホルムアミド(DMF)、ヘキサメチルリン酸ト
リアミド(HMPA)が好ましい。上記溶媒は単
独で用いてもよく、また2種以上を混合して使用
することもできる。 As the inert solvent used in the present invention, any solvent can be used as long as it does not adversely affect the reaction. For example, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, N,N- -dimethylacetamide,
Examples include hexamethylphosphoric acid triamide (HMPA). Among them, N,N-dimethylformamide (DMF) and hexamethylphosphoric acid triamide (HMPA) are preferred. The above solvents may be used alone or in combination of two or more.
上記反応が進行するに従つて、スルホン酸誘導
体が生成するため、上記溶媒中には、水酸化ナト
リウム、水酸化カリウムなどのアルカリ金属水酸
化物、炭酸ナトリウム、炭酸カリウム、炭酸カル
シウムなどのアルカリ金属あるいはアルカリ土類
金属の炭酸塩などの無機塩基、ピリジン、トリエ
チルアミンなどの有機塩基を存在させるのがよ
い。これら塩基のうちピリジンあるいは炭酸カル
シウムを用いる場合には、一般式(1)で表されるジ
フエニルチオエーテル化合物が高収率で得られる
ため特に好ましい。上記塩基も単独で使用しても
よく、あるいは2種以上を混合して使用すること
もできる。 As the above reaction progresses, sulfonic acid derivatives are produced, so the solvent contains alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and alkali metals such as sodium carbonate, potassium carbonate, and calcium carbonate. Alternatively, it is preferable to include an inorganic base such as an alkaline earth metal carbonate, or an organic base such as pyridine or triethylamine. Among these bases, it is particularly preferable to use pyridine or calcium carbonate because the diphenylthioether compound represented by general formula (1) can be obtained in high yield. The above bases may be used alone or in combination of two or more.
また上記反応は、好ましくは、窒素ガス、アル
ゴンガスなどの不活性ガスの気流下において実施
するのがよい。上記方法により製造されるジフエ
ニルチオエーテル化合物は、通常の精製方法によ
り精製でき、例えば、以下の方法により精製する
ことができる。 Further, the above reaction is preferably carried out under a stream of an inert gas such as nitrogen gas or argon gas. The diphenylthioether compound produced by the above method can be purified by a conventional purification method, for example, by the following method.
すなわち、ジフエニルチオエーテル化合物に対
して少なくとも等モル量の亜硫酸水素ナトリウ
ム、亜硫酸水素カリウムなどの亜硫酸水素アルカ
リ金属塩を含有する水溶液に、該ジフエニルチオ
エーテル化合物を溶解し、その水溶液をベンゼ
ン、トルエン、ジエチルエーテル等の有機溶媒で
洗浄後、炭酸カリウムどの塩基でPHを弱アルカリ
性とし、酢酸エチル、ジエチルエーテル、トルエ
ン、ベンゼンなどの有機溶媒で抽出することによ
り高純度のジフエニルチオエーテルが得られる。 That is, the diphenylthioether compound is dissolved in an aqueous solution containing an alkali metal salt of bisulfite such as sodium bisulfite or potassium bisulfite in an amount equivalent to at least an equimolar amount to the diphenylthioether compound, and the aqueous solution is dissolved in benzene, toluene, After washing with an organic solvent such as diethyl ether, the pH is made slightly alkaline with a base such as potassium carbonate, and highly purified diphenylthioether is obtained by extraction with an organic solvent such as ethyl acetate, diethyl ether, toluene, or benzene.
本発明のジフエニルチオエーテル化合物は抗痛
風剤として有用な後記式(8)および(9)で示されるピ
ラゾロトリアジン誘導体の合成中間体として有用
である。 The diphenylthioether compound of the present invention is useful as a synthetic intermediate for pyrazolotriazine derivatives represented by formulas (8) and (9) below, which are useful as anti-gout agents.
本発明の化合物から該ピラゾロトリアジン誘導
体を製造するには、例えば下記反応式−2に示さ
れる方法が採用される。 In order to produce the pyrazolotriazine derivative from the compound of the present invention, for example, the method shown in Reaction Formula 2 below is employed.
すなわち、本発明の化合物(1)を還元して化合物
(3)に導く。この還元反応は、該化合物(1)に水素化
リチウムアルミニウム、水素化アルミニウム、水
素化ジイソプロピルアルミニウム、水素化ジイソ
ブチルアルミニウム、水素化ホウ素リチウム、水
素化ホウ素ナトリウム、ジボランなどの水素化還
元剤を用いて常法により行なわれる。該反応は通
常溶媒中で行なわれ、溶媒としては、ジエチルエ
ーテル、テトラヒドロフラン、ジオキサン、ジグ
ライムなどのエーテル類、ヘキサン、ヘプタンな
どの脂肪族炭化水素類、ベンゼン、トルエンなど
の芳香族炭化水素類、メタノール、エタノールな
どの低級アルコール類などが挙げられる。水素化
還元剤の使用割合は、化合物(1)に対して少なくと
も0.5倍モル量、好ましくは0.6〜1.2倍モル量程度
使用するのがよい。該反応は、通常、氷冷下〜
100℃、好ましくは0〜50℃程度で行なわれ、30
分〜10時間程度で終了する。 That is, the compound (1) of the present invention is reduced to form the compound
Leads to (3). This reduction reaction is performed by using a hydrogenation reducing agent such as lithium aluminum hydride, aluminum hydride, diisopropyl aluminum hydride, diisobutyl aluminum hydride, lithium borohydride, sodium borohydride, diborane, etc. to the compound (1). It is carried out in the usual manner. The reaction is usually carried out in a solvent, and examples of the solvent include ethers such as diethyl ether, tetrahydrofuran, dioxane, and diglyme, aliphatic hydrocarbons such as hexane and heptane, aromatic hydrocarbons such as benzene and toluene, and methanol. and lower alcohols such as ethanol. The hydrogenation reducing agent is preferably used in an amount of at least 0.5 times, preferably 0.6 to 1.2 times, the amount of compound (1). The reaction is usually carried out under ice cooling.
It is carried out at 100℃, preferably about 0 to 50℃, and 30℃
It will finish in about 10 minutes to 10 hours.
得られた化合物(3)をハロゲン化剤で処理してハ
ロゲン化することにより化合物(4)に導く。該ハロ
ゲン化反応は、例えば、塩化メチレン、クロロホ
ルムなどのハロゲン化炭化水素の溶媒中、ハロゲ
ン化剤として塩化チオニル、臭化チオニルなどの
ハロゲン化チオニルを反応させることにより行な
われる。ハロゲン化剤の使用量は、化合物(3)に対
して少なくとも等モル量程度用いるのがよい。上
記反応は、好ましくは0〜50℃程度で行なわれ、
通常30分〜5時間程度で終了する。 The obtained compound (3) is treated with a halogenating agent to halogenate it, leading to compound (4). The halogenation reaction is carried out, for example, by reacting a thionyl halide such as thionyl chloride or thionyl bromide as a halogenating agent in a halogenated hydrocarbon solvent such as methylene chloride or chloroform. The amount of the halogenating agent to be used is preferably at least equimolar to compound (3). The above reaction is preferably carried out at about 0 to 50°C,
It usually takes about 30 minutes to 5 hours to complete.
ついで、得られた化合物(4)に、N,N−ジメチ
ルホルムアミド、ジメチルスルホキシドなどの非
プロトン性極性溶媒中でシアン化ナトリウム、シ
アン化カリウムなどのシアン化合物を反応させる
ことにより化合物(5)に導かれる。シアン化合物の
使用量は、化合物(4)に対して1〜1.3倍モル量程
度用いるのがよう。上記反応は、室温〜100℃付
近にて実施されるのが好ましく、通常1〜20時間
程度で終了する。 Then, compound (5) is obtained by reacting the obtained compound (4) with a cyanide compound such as sodium cyanide or potassium cyanide in an aprotic polar solvent such as N,N-dimethylformamide or dimethyl sulfoxide. . The amount of cyanide to be used is approximately 1 to 1.3 times the molar amount of compound (4). The above reaction is preferably carried out at room temperature to around 100°C and is usually completed in about 1 to 20 hours.
上記化合物(5)に、例えばベンゼン、トルエンな
どの芳香族炭化水素類の溶媒中で、少なくとも等
モル量のギ酸エステル(例えばギ酸メチル、ギ酸
エツルなど)を反応させることにより化合物(6)に
導くことができる。本反応は、通常氷冷下にて、
5〜20分程度、次に室温下4〜12時間程度行うの
が好ましい。上記反応を十分に進行させるために
ナトリウムメトキシドなどのナトリウムアルコキ
シドを上記ギ酸エステルに対して少なくとも等モ
ル量程度存在させるのが好ましい。生成する化合
物(6)は、反応終了後、反応液に水を加え、水層を
分取し、塩酸などの鉱酸によりPHを3〜4に調整
することによつて単離することができる。 Compound (6) is obtained by reacting the above compound (5) with at least an equimolar amount of formic acid ester (for example, methyl formate, ethyl formate, etc.) in an aromatic hydrocarbon solvent such as benzene or toluene. be able to. This reaction is usually carried out under ice cooling.
It is preferable to carry out the heating for about 5 to 20 minutes, and then for about 4 to 12 hours at room temperature. In order to allow the above reaction to proceed sufficiently, it is preferable that a sodium alkoxide such as sodium methoxide be present in at least an equimolar amount relative to the formic acid ester. The generated compound (6) can be isolated by adding water to the reaction solution after the reaction, separating the aqueous layer, and adjusting the pH to 3 to 4 with a mineral acid such as hydrochloric acid. .
得られた化合物(6)に、氷冷下セミカルバジド・
鉱酸塩を少なくとも等モル量程度滴下し、続いて
室温下、4〜15時間程度反応させて閉環すること
により化合物(7)を得る。この反応は、例えばメタ
ノール、エタノールなどの低級アルコール類ある
いはそれと水との混合溶媒を用いて行なわれる。
低級アルコールと水との混合割合は(1:1)〜
(10:1)程度の範囲のものを使用できる。 The obtained compound (6) was added with semicarbazide under ice cooling.
Compound (7) is obtained by dropping at least an equimolar amount of the mineral acid salt and then reacting at room temperature for about 4 to 15 hours to effect ring closure. This reaction is carried out using, for example, a lower alcohol such as methanol or ethanol, or a mixed solvent of lower alcohol and water.
The mixing ratio of lower alcohol and water is (1:1) ~
(10:1) can be used.
上記の方法で得られる化合物(7)を下記の方法に
より抗痛風剤として有用な式(8)および(9)のピラゾ
ロトリアジン誘導体に導くことができる。 Compound (7) obtained by the above method can be converted into pyrazolotriazine derivatives of formulas (8) and (9) useful as anti-gout agents by the following method.
すなわち、化合物(7)に、オルトギ酸メチル、オ
ルトギ酸エチルなどのオリトギ酸アルキルを反応
させて閉環させることにより化合物(8)が得られ
る。上記反応は、反応に悪影響を与えない溶媒を
用いて実施できるが、オルトギ酸アルキルが溶媒
として機能するため、別途溶媒を用いることは必
ずしも必要でない。該反応は化合物(7)に対してオ
ルトギ酸アルキルを15倍モル量程度用い、通常80
〜120℃にて約2〜15時間程度で終了する。 That is, compound (8) is obtained by reacting compound (7) with an alkyl orthoformate such as methyl orthoformate or ethyl orthoformate to cause ring closure. The above reaction can be carried out using a solvent that does not adversely affect the reaction, but since the alkyl orthoformate functions as a solvent, it is not necessarily necessary to use a separate solvent. The reaction uses about 15 times the molar amount of alkyl orthoformate relative to compound (7), and usually 80
The process is completed in about 2 to 15 hours at ~120°C.
得られた化合物(8)を酸化剤で常法により処理し
て酸化することにより化合物(9)に導くことができ
る。すなわち、化合物(8)に、低級アルコールと水
との混合溶媒(40:1)中で、メタ過ヨウ素酸ナ
トリウム、メタ過ヨウ素酸カリウムなどのメタ過
ヨウ素酸塩または酢酸中過酸化水素を化合物(8)に
対して約2倍モル量加え、室温にて約40時間反応
させることにより化合物(9)が得られる。 Compound (9) can be obtained by treating and oxidizing the obtained compound (8) with an oxidizing agent in a conventional manner. That is, compound (8) is added with a metaperiodate salt such as sodium metaperiodate or potassium metaperiodate, or hydrogen peroxide in acetic acid in a mixed solvent of lower alcohol and water (40:1). Compound (9) is obtained by adding about twice the molar amount of (8) and reacting at room temperature for about 40 hours.
つぎに、実施例および参考例を挙げて本発明化
合物およびその製法をさらに具体的に説明する。 Next, the compound of the present invention and the method for producing the same will be explained in more detail with reference to Examples and Reference Examples.
実施例 1
3−メトキシ−4−フエニルチオベンズアルデ
ヒドの製造:
3−メトキシ−4−メチルスルホニルオキシベ
ンズアルデヒド430g(2.0M)およびピリジン
200mlのDMF1.8、HMPA200ml溶液を窒素ガ
ス気流下、130℃まで昇温し、これにチオフエノ
ール277mlを加える。更に2.5時間還流(140〜150
℃)する。冷後、NaHSO3500gの水1溶液を
加え、2時間撹拌する。反応液を分液ロートにあ
け、水5を加え、トルエン3で洗浄し、トル
エン層を水3で抽出する。水層を合わせ、トル
エン1.5で洗浄後、K2CO3500gで弱アルカリ性
とし、酢酸エチルで2回抽出(5+2)す
る。有機層を10%HCl(2)で洗浄後、水、飽
和食塩水で洗浄し、硫酸マグネシウムで乾燥す
る。溶媒を留去して目的物を淡黄色結晶として得
る。収量258g(53%)、融点57〜58℃(エーテ
ル:n−ヘキサンで再結晶)1
H−NMR(CDCl3、ppm):9.86(1H、s)、7.44
〜7.57(5H、m)、7.35(1H、d、J=1.7)、
7.24(1H、dd、J=1.7、7.9)、6.80(1H、d、
J=7.9)、3.99(3H、s)
実施例 2
3−メチル−4−フエニルチオベンズアルデヒ
ドの製造:
後記参考例で得た3−メチル−4−メチルスル
ホニルオキシベンズアルデヒド6.5g(30.3m
mol)および炭酸カルシウム4.1gのDMF30ml懸
濁液を、窒素ガス気流下、110℃まで昇温し、こ
れにチオフエノール4.2ml加え、140℃にて22時間
撹拌する。冷後、反応液をろ過し、ろ液を濃縮す
る。その残渣に亜硫酸水素ナトリウム10gの水溶
液を加え、1時間撹拌する。反応液を分液ロート
に移し、エーテルで洗浄後、水層を炭酸カリウム
10gの水溶液で弱アルカリ性とし、酢酸エチル
300mlで抽出する。有機層を水および飽和食塩水
で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を
留去する。その残渣をシリカゲルカラムクロマト
グラフイー(エーテル:ヘキサン=1:2)にて
精製し、目的とする3−メチル−4−フエニルチ
オベンズアルデヒドを無色油状物質として得る。
収量4.1g(59%)1
H−NMR(CDCl3、ppm):9.90(1H、s)、7.66
(1H、s)、7.40〜7.52(6H、m)、6.96(1H、
d、J=7.9)、2.46(3H、s)
参考例
3−メチル−4−メチルスルホニルオキシベン
ズアルデヒドの製造:
4−ハイドロキシ−3−メチルベンズアルデヒ
ド4.5g(33.1mmol)およびトリエチルアミン
5.1mlのジクロロメタン30ml溶液に、氷冷撹拌下、
メタンスルホニルクロライド2.8mlを滴下し、同
温にて1時間撹拌する。反応液を分液ロート縫津
し、水を加え、ジクロロメタン100mlで抽出する。
有機層を10%HCl水溶液、飽和食塩水で洗浄後、
硫酸ナトリウムで乾燥する。溶媒を留去して、目
的とする。3−メチル−4−メチルスルホニルオ
キシベンズアルデヒドを橙色油状物質として得
る。収量6.5g(92%)1
H−NMR(CDCl3、ppm):9.98(1H、s)、7.81
(1H、s)、7.77(1H、d、J=8.4)、7.48(1H、
d、J=8.4)、3.27(3H、s)、2.44(3H、s)Example 1 Preparation of 3-methoxy-4-phenylthiobenzaldehyde: 430 g (2.0 M) of 3-methoxy-4-methylsulfonyloxybenzaldehyde and pyridine
Heat a 200ml solution of DMF1.8 and 200ml HMPA to 130°C under a nitrogen gas stream, and add 277ml of thiophenol. Reflux for another 2.5 hours (140-150
°C). After cooling, a solution of 500 g of NaHSO 3 in 1 water is added and stirred for 2 hours. Pour the reaction solution into a separatory funnel, add 5 parts of water, wash with 3 parts of toluene, and extract the toluene layer with 3 parts of water. The aqueous layers were combined, washed with 1.5 toluene, made weakly alkaline with 500 g of K 2 CO 3 and extracted twice with ethyl acetate (5+2). The organic layer is washed with 10% HCl (2), then water and saturated brine, and dried over magnesium sulfate. The solvent is distilled off to obtain the desired product as pale yellow crystals. Yield 258g (53%), melting point 57-58°C (ether: recrystallized from n-hexane) 1H -NMR ( CDCl3 , ppm): 9.86 (1H, s), 7.44
~7.57 (5H, m), 7.35 (1H, d, J=1.7),
7.24 (1H, dd, J = 1.7, 7.9), 6.80 (1H, d,
J = 7.9), 3.99 (3H, s) Example 2 Production of 3-methyl-4-phenylthiobenzaldehyde: 6.5 g (30.3 m
A suspension of 4.1 g of calcium carbonate (mol) and 4.1 g of calcium carbonate in 30 ml of DMF is heated to 110°C under a nitrogen gas stream, 4.2 ml of thiophenol is added thereto, and the mixture is stirred at 140°C for 22 hours. After cooling, the reaction solution is filtered and the filtrate is concentrated. An aqueous solution of 10 g of sodium bisulfite is added to the residue and stirred for 1 hour. Transfer the reaction solution to a separating funnel, wash with ether, and add potassium carbonate to the aqueous layer.
Make it slightly alkaline with 10g of aqueous solution and add ethyl acetate.
Extract with 300ml. The organic layer is washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent is distilled off. The residue is purified by silica gel column chromatography (ether:hexane=1:2) to obtain the desired 3-methyl-4-phenylthiobenzaldehyde as a colorless oil.
Yield 4.1g (59%) 1H -NMR ( CDCl3 , ppm): 9.90 (1H, s), 7.66
(1H, s), 7.40-7.52 (6H, m), 6.96 (1H,
d, J=7.9), 2.46 (3H, s) Reference Example 3 Production of methyl-4-methylsulfonyloxybenzaldehyde: 4.5 g (33.1 mmol) of 4-hydroxy-3-methylbenzaldehyde and triethylamine
Add 5.1 ml of dichloromethane to 30 ml of dichloromethane solution under ice-cooling and stirring.
Add 2.8 ml of methanesulfonyl chloride dropwise and stir at the same temperature for 1 hour. Transfer the reaction solution to a separatory funnel, add water, and extract with 100 ml of dichloromethane.
After washing the organic layer with 10% HCl aqueous solution and saturated saline,
Dry with sodium sulfate. The solvent is distilled off and used as the desired product. 3-Methyl-4-methylsulfonyloxybenzaldehyde is obtained as an orange oil. Yield 6.5g (92%) 1H -NMR ( CDCl3 , ppm): 9.98 (1H, s), 7.81
(1H, s), 7.77 (1H, d, J=8.4), 7.48 (1H,
d, J=8.4), 3.27 (3H, s), 2.44 (3H, s)
Claims (1)
キシ基を示す] で表されるジフエニルチオエーテル化合物。[Claims] 1. General formula A diphenylthioether compound represented by [In the formula, R 1 represents a lower alkyl group or a lower alkoxy group].
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP16420987A JPS649971A (en) | 1987-06-30 | 1987-06-30 | Diphenyl thioether compound |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP16420987A JPS649971A (en) | 1987-06-30 | 1987-06-30 | Diphenyl thioether compound |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS649971A JPS649971A (en) | 1989-01-13 |
JPH0480021B2 true JPH0480021B2 (en) | 1992-12-17 |
Family
ID=15788737
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP16420987A Granted JPS649971A (en) | 1987-06-30 | 1987-06-30 | Diphenyl thioether compound |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS649971A (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5420128A (en) * | 1990-10-09 | 1995-05-30 | Otsuka Pharmaceutical Co., Ltd. | Pyrimidine derivatives, method of manufacturing the same, and androgen inhibitor |
-
1987
- 1987-06-30 JP JP16420987A patent/JPS649971A/en active Granted
Also Published As
Publication number | Publication date |
---|---|
JPS649971A (en) | 1989-01-13 |
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