JPH0324047A - Production of phenylmalonic acid monoanilide derivative and 3-phenyl-2-quinolone derivative - Google Patents
Production of phenylmalonic acid monoanilide derivative and 3-phenyl-2-quinolone derivativeInfo
- Publication number
- JPH0324047A JPH0324047A JP1160233A JP16023389A JPH0324047A JP H0324047 A JPH0324047 A JP H0324047A JP 1160233 A JP1160233 A JP 1160233A JP 16023389 A JP16023389 A JP 16023389A JP H0324047 A JPH0324047 A JP H0324047A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- derivative
- phenyl
- compound
- general formula
- 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
- ORXSOQFSAQHWSR-UHFFFAOYSA-N 3-phenyl-1h-quinolin-2-one Chemical class O=C1NC2=CC=CC=C2C=C1C1=CC=CC=C1 ORXSOQFSAQHWSR-UHFFFAOYSA-N 0.000 title claims abstract description 9
- 238000004519 manufacturing process Methods 0.000 title claims description 18
- RRIYMQRUQFUKPL-UHFFFAOYSA-N 3-anilino-3-oxo-2-phenylpropanoic acid Chemical class C=1C=CC=CC=1C(C(=O)O)C(=O)NC1=CC=CC=C1 RRIYMQRUQFUKPL-UHFFFAOYSA-N 0.000 title claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 11
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 8
- SYUQQUMHOZQROL-UHFFFAOYSA-N trimethylsilyl dihydrogen phosphite Chemical compound C[Si](C)(C)OP(O)O SYUQQUMHOZQROL-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims 5
- 238000006798 ring closing metathesis reaction Methods 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 19
- 239000003814 drug Substances 0.000 abstract description 6
- 208000001132 Osteoporosis Diseases 0.000 abstract description 5
- 125000004185 ester group Chemical group 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract description 2
- 230000011164 ossification Effects 0.000 abstract description 2
- 230000001737 promoting effect Effects 0.000 abstract description 2
- WWYDYZMNFQIYPT-UHFFFAOYSA-N ru78191 Chemical compound OC(=O)C(C(O)=O)C1=CC=CC=C1 WWYDYZMNFQIYPT-UHFFFAOYSA-N 0.000 abstract description 2
- 238000009833 condensation Methods 0.000 abstract 2
- 230000005494 condensation Effects 0.000 abstract 2
- 125000000217 alkyl group Chemical group 0.000 abstract 1
- 125000002490 anilino group Chemical class [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 230000001747 exhibiting effect Effects 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 abstract 1
- 238000007363 ring formation reaction Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000013078 crystal Substances 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- -1 phenylmalonic acid ester Chemical class 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- IEVKGWFWALGWGF-UHFFFAOYSA-N methyl 2-(2,4-dimethoxyphenyl)acetate Chemical compound COC(=O)CC1=CC=C(OC)C=C1OC IEVKGWFWALGWGF-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 229920000137 polyphosphoric acid Polymers 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- ZFXFMGARFHRTTO-UHFFFAOYSA-N 2-(2,4-dimethoxyphenyl)acetic acid Chemical compound COC1=CC=C(CC(O)=O)C(OC)=C1 ZFXFMGARFHRTTO-UHFFFAOYSA-N 0.000 description 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N carbostyril Natural products C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 239000004020 conductor Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012156 elution solvent Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- NCBZRJODKRCREW-UHFFFAOYSA-N m-anisidine Chemical compound COC1=CC=CC(N)=C1 NCBZRJODKRCREW-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
Landscapes
- Quinoline Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
（式中のＸおよびＹは同じでも異なっていてもよく、水
素原子または炭素数１〜３のアルコキシ基であり、Ｚは
炭素数１〜３のアルコキシ基である）で表されるフェニ
ルマロン酸モノアニリド誘導体およびそれを用いる３−
フェニルー２−キノロン誘導体の製造方法に関するもの
である。Detailed Description of the Invention [Industrial Application Field] (X and Y in the formula may be the same or different and are a hydrogen atom or an alkoxy group having 1 to 3 carbon atoms, and Z is an alkoxy group having 1 to 3 carbon atoms. phenylmalonic acid monoanilide derivatives represented by 3) and 3-
The present invention relates to a method for producing a phenyl-2-quinolone derivative.
さらに詳しく言えば、本発明は医薬品またはその製造中
間体として有用な前記一般式（１）で表される化合物お
よびそれを用いて、骨形或促進作用を示し、骨粗壓症治
療剤として有用な、一般式（式中のＸ，ＹおよびＺは前
記と同じ意味をもつ）で表サれる３−フエニル−２−キ
ノロン誘導体を製造する方法に関するものである。More specifically, the present invention provides a compound represented by the general formula (1) that is useful as a pharmaceutical or an intermediate for its production, and a compound that exhibits a bone formation promoting effect using the same and is useful as a therapeutic agent for osteoporosis. The present invention relates to a method for producing a 3-phenyl-2-quinolone derivative represented by the general formula (X, Y and Z have the same meanings as above).
本発明の前記一般式（１）の化合物から得られる前記一
般式（ＩＩ）で表される３−フェニル−２−キノロン誘
導体は、骨吸収抑制作用を有し、骨粗透症治療剤として
有用であることが知られている（特開昭６３−２９５５
６１号）。The 3-phenyl-2-quinolone derivative represented by the general formula (II) obtained from the compound of the general formula (1) of the present invention has a bone resorption inhibitory effect and is useful as a therapeutic agent for osteoporosis. It is known that
No. 61).
これまで、前記一般式（Ｉｔ）で表される３−フ二二ル
−２−キノロン誘導体の製造方法として、式で表される
ｍ−アニンジンと式
で表されるフエニルマロン酸エステル誘導体とをジフエ
ニルエーテル中加熱還流して、式で表される化合物を製
造する方法が知られている〔ジャーナル オブ ヘテロ
サイクリツク ケミス ト リ ー （Ｊ， Ｈｅ
ｔｅｒｏｃｙｃｌｉｃ Ｃｈｅｍ，） 、 ２１
巻、 １９８４年、７３７〜７３９ページ〕。Until now, as a method for producing the 3-phenyl-2-quinolone derivative represented by the general formula (It), m-aningine represented by the formula and a phenylmalonic acid ester derivative represented by the formula A method for producing a compound represented by the formula by heating under reflux in enyl ether is known [Journal of Heterocyclic Chemistry (J, He
terocyclic Chem,), 21
Vol., 1984, pp. 737-739].
本発明の目的は、医薬品またはその製造中間体として有
用な前記一般式（Ｉ）で表されるフエニルマロン酸モノ
アニリド誘導体およびそれヲ用イて骨粗壓症治療剤とし
て有用な前記一般式（ＩＩ）で表される３−フェニルー
２−キノロン誘導体を効率的に製造する方法を提供する
ことである。The object of the present invention is to provide phenylmalonic acid monoanilide derivatives represented by the general formula (I) useful as pharmaceuticals or intermediates for the production thereof, and the phenylmalonic acid monoanilide derivatives represented by the general formula (II) useful as therapeutic agents for osteoporosis. An object of the present invention is to provide a method for efficiently producing a 3-phenyl-2-quinolone derivative represented by:
これまで、一般式（ｎ）で表される３−フェニル−２−
キノロン誘導体を合戊する方法として、上述したように
前記式（Ｉ［［）で表されるｍ−アニンジンと前記式（
ＩＶ）で表されるフェニルマロン酸エステル誘導体とを
反応させる方法が知られている。Until now, 3-phenyl-2- represented by general formula (n)
As described above, as a method for combining quinolone derivatives, m-aningine represented by the formula (I[[) and the formula (
A method of reacting with a phenylmalonic acid ester derivative represented by IV) is known.
しかしながら、この反応は２６０℃以上という高温の加
熱条件を必要とするため、より緩和な条件で製造できる
方法の開発が望まれていた。However, since this reaction requires heating conditions at a high temperature of 260° C. or higher, there has been a desire to develop a method that allows production under milder conditions.
本発明者らは、これらの問題を解決すべく鋭意検討した
結果、ある種のフエニルマロン酸モノアニリド誘導体を
製造原料として用いることによりきわめて容易にしかも
効率よく目的とする３−フェニルー２−キノロン誘導体
を製造できることを見出し、本発明をなすに至った。As a result of intensive studies to solve these problems, the present inventors have found that the desired 3-phenyl-2-quinolone derivative can be produced very easily and efficiently by using a certain type of phenylmalonic acid monoanilide derivative as a production raw material. We have discovered that this can be done, and have come up with the present invention.
本発明の一般式
（式中のＸＳＹおよびＺは前記と同じ意味をもつ）で表
されるフェニルマロン酸モノアニリドｍ導体は、縮合剤
の存在下で閉環させることにより、きわめて容易に骨粗
髭症治療剤として有用な、一般式
（式中のＸ，ＹおよびＺは前記と同じ意味をもつ）で表
される３−フェニル−２−ヰノロン誘導体を製造するこ
とができる。The phenylmalonic acid monoanilide m-conductor represented by the general formula (in the formula, XSY and Z have the same meanings as above) of the present invention can be used to easily cure osteoporosis by ring-closing it in the presence of a condensing agent. 3-Phenyl-2-winolone derivatives of the general formula (wherein X, Y and Z have the same meanings as above) can be prepared that are useful as therapeutic agents.
本発明の前記一般式（１）の化合物を用いる前記一般式
（ｎ）の化合物の製造方法を好適に実施するには、一般
式（Ｉ）で表される化合物を無溶媒またはベンゼン、ク
ロロホルムなどの不活性有機溶媒中、縮合剤を適当量加
え、室温ないし６０℃で約１〜ｌ５時間反応させ、反応
終了後、常法に従い処理することにより目的物を得るこ
とができる。In order to suitably carry out the method for producing the compound of the general formula (n) using the compound of the general formula (1) of the present invention, the compound represented by the general formula (I) may be prepared without a solvent or in benzene, chloroform, etc. The desired product can be obtained by adding an appropriate amount of a condensing agent in an inert organic solvent, reacting at room temperature to 60°C for about 1 to 15 hours, and after the reaction is completed, processing according to a conventional method.
本発明の製造方法において製造原料として用いられる前
記一般式（Ｉ）で表される化合物は新規化合物であり、
以下のようにして製造することができる。すなわち、一
般式
（式中のＸは前記と同じ意味をもつ）で表されるアニリ
ン誘導体と、一般式
（式中のＹおよびＺは前記と同じ意味をもち、Ｒは低級
アルヰル基である）で表されるフェニルマロン酸モノエ
ステノレ誘導体とを脱水縮合剤存在下、室温で反応させ
、ついで適当な方法によりエステル基を除去することに
より容易に製造することができる。The compound represented by the general formula (I) used as a production raw material in the production method of the present invention is a new compound,
It can be manufactured as follows. That is, an aniline derivative represented by the general formula (X in the formula has the same meaning as above) and a general formula (in the formula, Y and Z have the same meaning as above, and R is a lower alwyl group) It can be easily produced by reacting the phenylmalonic acid monoester derivative represented by the formula at room temperature in the presence of a dehydration condensing agent, and then removing the ester group by an appropriate method.
本製造方法において出発原科として用いられる一般式（
Ｖ）および（ＶＩ）で表される化合物はいずれも公知化
合物であり、市販品として人手するかあるいは文献記載
の方法に従い容易に製造することができる。The general formula (
The compounds represented by V) and (VI) are both known compounds and can be easily produced manually as commercial products or according to methods described in literature.
本発明の製造方法において用いられる縮合剤としては、
一般に脱水縮合反応に用いられるものであればよいが製
造原料の分解および副反応を抑えるようにできるだけ温
和な条件で反応を進行できるものがよい。The condensing agent used in the production method of the present invention includes:
Generally, any material used in dehydration condensation reactions may be used, but it is preferable to use one that allows the reaction to proceed under conditions as mild as possible so as to suppress decomposition of raw materials and side reactions.
このようなものとして、トリメチルシリルホスファイト
、ポリリン酸エステル、トリフルオ口酢酸無水物、五塩
化リン、オキシ塩化リンまたは塩化チオニルなどをあげ
ることができる。これらの中でもトリメチルシリルホス
ファイトが最モ好マしい。Examples of these include trimethylsilyl phosphite, polyphosphoric acid ester, trifluoroacetic anhydride, phosphorus pentachloride, phosphorus oxychloride, and thionyl chloride. Among these, trimethylsilyl phosphite is most preferred.
これらの縮合剤はすべて公知化合物であり、ほとんどの
ものは市販品として入手することができる。また、トリ
メチルシリルホスファイト、ポリリン酸エステルは文献
記載の方法により容易に製造することができる〔テトラ
ヘドロン レターズ（Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔ
ｔｅｒｓ） 、２２巻、１９号、１９８１年、１８０３
〜１８０４ページ、同２３巻、１４号、１９８２年、１
４６７〜１４７０ページ、リエージェンッ フォー オ
ーガニ７ク シンセシス（Ｒｅａｇｅｎｔｓ ｆｏｒ
ＯｒｇａｎｉｃＳｙｎｔｈｅｓｉｓ）、１巻、８９２〜
８９４ページ、シンセティック リエージェンッ（Ｓｙ
ｎｔｈｅｔｉｃ Ｒｅａｇｅｎｔｓ）、６巻、３７４〜
３７５ページ〕。All of these condensing agents are known compounds, and most of them are commercially available. Furthermore, trimethylsilyl phosphite and polyphosphoric acid ester can be easily produced by the method described in the literature [Tetrahedron Let
ters), Volume 22, No. 19, 1981, 1803
~1804 pages, Volume 23, No. 14, 1982, 1
Pages 467-1470, Reagents for Organi 7 Synthesis
Organic Synthesis), Volume 1, 892~
Page 894, Synthetic Regeneration (Sy
nthetic Reagents), Volume 6, 374~
375 pages].
本発明の製造方法における反応温度および反応時間は、
製造原料または縮合剤の種類または量により多少異なる
が、通常、室温ないし６０℃で、約１−１５時間反応さ
せれば十分である。The reaction temperature and reaction time in the production method of the present invention are:
It is usually sufficient to carry out the reaction at room temperature to 60° C. for about 1 to 15 hours, although this may vary depending on the type or amount of the raw materials or condensing agent.
本発明の前記一般式（Ｉ）の化合物を用いる前記一般式
（ＩＩ）の化合物の製造方法は、従来の方法に比べ緩和
な条件で反応が進行し、操作も簡単で、安全にしかも容
易に目的物を得ることができるので、工業的に有用な方
法である。The method for producing the compound of general formula (II) using the compound of general formula (I) of the present invention allows the reaction to proceed under milder conditions than conventional methods, is simple to operate, and is safe and easy. This is an industrially useful method because the desired product can be obtained.
本発明を詳述するために以下に参考例および実施例をあ
げる。なお、各参考例および実施例の中の化合物の融点
はすべて未補正である。また、化合物のＮＭＲスペクト
ルは日本電子ＪＮＭ−ＧＸ２７０型高分解能核磁気共鳴
装置を用いて測定した。Reference examples and examples are given below to explain the present invention in detail. Note that the melting points of the compounds in each Reference Example and Examples are all uncorrected. Moreover, the NMR spectrum of the compound was measured using a JEOL JNM-GX270 high-resolution nuclear magnetic resonance apparatus.
参考例 １
２−メトキシ力ルボニル−２−（２，４−ジメトキシフ
エニル〉酢酸
水素化ナトリウム（６０％、油性）３．５ｇおよび乾燥
ジメチルスルホキシド２０＋ｎｊ！をアルゴン気流中で
７０℃、２時間撹拌した。この溶液を乾燥トルエン３５
ｍｉ２で希釈した。この溶液に５．０ｇ の２．４−ジ
メトキシフェニル酢酸メチルを乾燥トルエン３５−に溶
解した溶液を室温で滴下し、３０分間撹拌した。反応液
に乾燥トルエン３５−を加え、−３０℃に冷却し、ドラ
イアイス２１ ｇを少量ずつ添加し、４℃で２時間撹拌
した。反応液に２０％リン酸を水冷下に加え、ｐＨ４に
した後、酢酸エチルで抽出した。酢酸エチル層を飽和食
塩水で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒
を減圧下６０℃で留去し、残留物をエーテルより再結晶
を行って、白色結晶の目的物５．２ｇを得た。Reference Example 1 2-Methoxycarbonyl-2-(2,4-dimethoxyphenyl) 3.5 g of sodium acetate hydride (60%, oily) and 20+nj! of dry dimethyl sulfoxide were stirred at 70°C for 2 hours in an argon stream. This solution was diluted with dry toluene for 35 minutes.
Diluted with mi2. A solution of 5.0 g of methyl 2.4-dimethoxyphenylacetate dissolved in dry toluene was added dropwise to this solution at room temperature, and the mixture was stirred for 30 minutes. 35 cm of dry toluene was added to the reaction solution, cooled to -30°C, 21 g of dry ice was added little by little, and the mixture was stirred at 4°C for 2 hours. 20% phosphoric acid was added to the reaction solution under water cooling to adjust the pH to 4, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off at 60° C. under reduced pressure, and the residue was recrystallized from ether to obtain 5.2 g of the desired product as white crystals.
融 点 ： １２３ 〜 １２６℃ＩＲ （ＫＢｒ
）： ｖｃｏ １７５０． １７００ ｃｍ−
’ＮＭＲ （ＣＤＣＩ，）
δ： ３．７６（ｓ． ３Ｈ）， ３．８０（ｓ． ６
１）． ４．９２（ｓ．ＩＨ）． ６．４７（ｄ． Ｉ
Ｈ， Ｊ＝２．２８２）． ６、５０（ｄｄ， ｌ｝Ｉ
， Ｊ＝２．２． ８．２Ｈｚ）． ７．２４（ｄ．１
Ｎ， Ｊ・８． ２Ｈｚ）
参考例 ２
２−メトキシカルボニル−２−（２．４−ジメトキシフ
ェニル〉酢酸５．１ｇおよびｍ−アニシジン２．６ｇ
ヲ乾燥クロロホルム４０−に溶解した。この溶液に室温
でＮ，Ｎ”−ジシクロへキシルカルボジイミド４．３ｇ
および４−ジメチルアミノビリジン１００ｍｇを加え、
室温で一夜撹拌した。反応液に酢酸エチルを加え、氷冷
し、析出結晶をろ去した後、飽和食塩水、１０％炭酸水
素ナトリウム、飽和食塩水で順次洗浄した。有機層を無
水硫酸マグネシウムで乾燥した後、減圧下６０℃で溶媒
を留去し、シリカゲルカラムクロマトグラフィー（溶出
溶媒：クロロホルム）で精製した後、エーテルより結晶
化し、無色結晶の目的物５．７ｇを得た。Melting point: 123-126℃IR (KBr
): vco 1750. 1700 cm-
'NMR (CDCI,) δ: 3.76 (s. 3H), 3.80 (s. 6
1). 4.92 (s.IH). 6.47 (d. I
H, J=2.282). 6, 50(dd, l}I
, J=2.2. 8.2Hz). 7.24 (d.1
N, J・8. 2Hz) Reference Example 2 2-Methoxycarbonyl-2-(2.4-dimethoxyphenyl>acetic acid 5.1g and m-anisidine 2.6g
It was dissolved in 40% dry chloroform. Add 4.3 g of N,N"-dicyclohexylcarbodiimide to this solution at room temperature.
and 100 mg of 4-dimethylaminopyridine,
Stir overnight at room temperature. Ethyl acetate was added to the reaction solution, the mixture was cooled with ice, and the precipitated crystals were filtered off, and then washed successively with saturated brine, 10% sodium bicarbonate, and saturated brine. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off at 60°C under reduced pressure, purified by silica gel column chromatography (elution solvent: chloroform), and then crystallized from ether to give 5.7 g of the desired product as colorless crystals. I got it.
融 点 ＝ ９６ 〜 ９７ ℃［Ｒ （ＫＢｒ
）： ”ＣＧ １７３０． １６６０ ｃｍ−
’ＮＭＲ （ＣＤＣＩ，）
δ： ３．７７（ｓ， ３ｔｌ）， ３．７８（ｓ．
３Ｈ）． ３．８Ｈｓ，３８）． ３．８４（ｓ． ３
｝１）， ４．８８（ｓ， １｝１），６．４５ 〜６
．５５（＋ｎ． ２｝１）． ６．６４（ｄｄ， ｌｔ
ｌ，Ｊ＝２．８． ８．２Ｈｚ）． ６．９０ｄ， Ｉ
ｌｌ， Ｊ＝８．２Ｈｚ）． ７．１７（ｔ， １｝１
， Ｊ＝８．２Ｈｚ＞． ７．３０ 〜７．４０（ｍ，
２Ｈ）， ８．５０（ｂｒ−ｓ，− １ｔｌ）参考例
３
２−（３−メトキシーフエニルカルバモイル）−２−
（２．４−ジメトキシフェニル）酢酸メチル５．０ｇを
メタノール１６０ ｒｎｌに溶解し、２規定水酸化ナト
リウム水溶液２４ｍｌを加え、６０℃で１時間加熱した
。メタノールを減圧下６０℃で留去し、残留液に水を加
え、酢酸エチルで洗浄した。水層を水冷下２０％リン酸
１０ｍｊ！を加えてｐＨ４とし、酢酸エチルで抽出した
。Melting point = 96 ~ 97 °C [R (KBr
): “CG 1730. 1660 cm-
'NMR (CDCI,) δ: 3.77 (s, 3tl), 3.78 (s.
3H). 3.8Hs, 38). 3.84 (s. 3
}1), 4.88(s, 1}1), 6.45 ~6
．． 55 (+n. 2}1). 6.64(dd, lt
l, J=2.8. 8.2Hz). 6.90d, I
ll, J=8.2Hz). 7.17(t, 1}1
, J=8.2Hz>. 7.30 ~7.40 (m,
2H), 8.50 (br-s, - 1tl) Reference example 3 2-(3-methoxyphenylcarbamoyl)-2-
5.0 g of methyl (2.4-dimethoxyphenyl)acetate was dissolved in 160 rnl of methanol, 24 ml of 2N aqueous sodium hydroxide solution was added, and the mixture was heated at 60° C. for 1 hour. Methanol was distilled off at 60°C under reduced pressure, water was added to the residual liquid, and the mixture was washed with ethyl acetate. Water layer is cooled with 20% phosphoric acid 10mj! was added to adjust the pH to 4, and the mixture was extracted with ethyl acetate.
有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで
乾燥した。減圧下６０℃で溶媒を留去し、残留物をエー
テルより再結晶して４．４ｇの白色結晶の目的物を得た
。The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off at 60° C. under reduced pressure, and the residue was recrystallized from ether to obtain 4.4 g of the desired product as white crystals.
融 点＝１２３〜１２６℃
ＩＲ （κＢｒ）： Ｌ’ＣＯ １７００， １
６７０ （；，ｎ−１ＮＭＲ （Ｃ口Ｃｔ，）
δ： ３．７９（ｓ， ３８）． ３．８３（ｓ， ３
Ｈ）， ３．８６（ｓ，３Ｈ）． ４．６３（ｓ． １
｝１）． ６．５０ 〜６．６０（ｍ，２Ｈ）． ６．
７０（ｄ． ＩＨ， Ｊ＝８．２Ｈｚ）． ６．８１（
ｄ，ＬＨ， Ｊ＝８． ２Ｈｚ）． ７． １０（
ｓ． ＩＨ）． ７． ２０（ｔ．ＩＨ， Ｊ＝
８．２１１ｚ）． ７．２５（ｄ， １８， Ｊ
＝８。２１｛ｚ）． ７． ７０（ｂｒ−ｓ， Ｉ
Ｈ）実施例 １
２− （３一メ｝＋シーフエニル力ルバモイル）−２−
（２．４−ジメトキシフェニル）酢酸１．０ｇをトリメ
チルシリルホスファイト１０−に溶解し、６０℃で一夜
攪拌した。反応液に水一酢酸エチル（１／１）８０ｍｊ
！を加え、３０分間攪拌した。析出結晶をろ取し、酢酸
エチルで洗浄し、減圧下で乾燥し、６６３ ｍｇの目的
物を得た。Melting point = 123-126°C IR (κBr): L'CO 1700, 1
670 (;, n-1NMR (C mouth Ct,) δ: 3.79 (s, 38). 3.83 (s, 3
H), 3.86 (s, 3H). 4.63 (s. 1
}1). 6.50 - 6.60 (m, 2H). 6.
70 (d. IH, J=8.2Hz). 6.81 (
d, LH, J=8. 2Hz). 7. 10(
s. IH). 7. 20(t.IH, J=
8.211z). 7.25 (d, 18, J
=8.21{z). 7. 70(br-s, I
H) Example 1 2- (31me}+Seaphenylic Rubamoyl)-2-
1.0 g of (2.4-dimethoxyphenyl)acetic acid was dissolved in 10-trimethylsilyl phosphite and stirred at 60°C overnight. Add water monoethyl acetate (1/1) 80mj to the reaction solution
! was added and stirred for 30 minutes. The precipitated crystals were collected by filtration, washed with ethyl acetate, and dried under reduced pressure to obtain 663 mg of the desired product.
融 点＝３００℃以上
ＩＲ （ＫＢｒ）： ｖｃＱ １６４０ ｃｍ
−’ＮＭＲ （ＤＭＳＯ−ｄ．）
δ： ３．７９（ｓ， ：Ｅ）， ３．９２（ｓ． ６
Ｈ）， ６．６０〜６．７５（ｍ， ２Ｈ）， ６．８
５〜６．９０（ｍ， ２Ｈ）． ７．１２（ｄ，ＩＨ，
Ｊ＝８．２Ｈｚ）． ７．８７（ｄ． １Ｍ， Ｊ＝
９．９Ｈｚ）．９．５５（ｓ， ＩＨ）， １１．
２５（Ｓ， ＩＨ）実施例 ２
トリメチルシリルホスファイトの代わりに以下にあげる
縮合剤を用いて、以下の条件で反応を行い、実施例ｌに
記載の方法と同様に処理して３− （２．４−ジメトキ
シフェニル）−４−ヒドロキシ−７−メトキシ−ＩＨ−
キノリン−２−オンを製造した。Melting point = 300℃ or higher IR (KBr): vcQ 1640 cm
-'NMR (DMSO-d.) δ: 3.79 (s, :E), 3.92 (s. 6
H), 6.60-6.75 (m, 2H), 6.8
5-6.90 (m, 2H). 7.12 (d, IH,
J=8.2Hz). 7.87 (d. 1M, J=
9.9Hz). 9.55 (s, IH), 11.
25(S, IH) Example 2 Using the condensing agent listed below instead of trimethylsilyl phosphite, the reaction was carried out under the following conditions and treated in the same manner as in Example 1 to obtain 3-(2. 4-dimethoxyphenyl)-4-hydroxy-7-methoxy-IH-
Quinolin-2-one was produced.
Claims (5)
素原子または炭素数１〜３のアルコキシ基であり、Ｚは
炭素数１〜３のアルコキシ基である）で表されるフェニ
ルマロン酸モノアニリド誘導体(1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (X and Y in the formula may be the same or different and are a hydrogen atom or an alkoxy group having 1 to 3 carbon atoms, and Z is a phenylmalonic acid monoanilide derivative represented by ~3 alkoxy group)
ド誘導体(2) The phenylmalonic acid monoanilide derivative according to claim 1, which is represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼
素原子または炭素数１〜３のアルコキシ基であり、Ｚは
炭素数１〜３のアルコキシ基である）で表されるフェニ
ルマロン酸モノアニリド誘導体を、縮合剤の存在下で、
閉環させることを特徴とする、一般式 ▲数式、化学式、表等があります▼ （式中のＸ、ＹおよびＺは前記と同じ意味をもつ）で表
される３−フェニル−２−キノロン誘導体の製造方法(3) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (X and Y in the formula may be the same or different and are a hydrogen atom or an alkoxy group having 1 to 3 carbon atoms, and Z is a ~3 alkoxy group) in the presence of a condensing agent,
A 3-phenyl-2-quinolone derivative represented by the general formula ▲ mathematical formula, chemical formula, table, etc. ▼ (X, Y and Z in the formula have the same meanings as above), which is characterized by ring closure. Production method
る請求項３記載の製造方法(4) The manufacturing method according to claim 3, using a phenylmalonic acid monoanilide derivative represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼
求項３記載の製造方法(5) The manufacturing method according to claim 3, wherein the condensing agent is trimethylsilyl phosphite.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1160233A JPH0753704B2 (en) | 1989-06-22 | 1989-06-22 | Process for producing phenylmalonic acid monoanilide derivative and 3-phenyl-2-quinolone derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1160233A JPH0753704B2 (en) | 1989-06-22 | 1989-06-22 | Process for producing phenylmalonic acid monoanilide derivative and 3-phenyl-2-quinolone derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0324047A true JPH0324047A (en) | 1991-02-01 |
| JPH0753704B2 JPH0753704B2 (en) | 1995-06-07 |
Family
ID=15710586
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1160233A Expired - Lifetime JPH0753704B2 (en) | 1989-06-22 | 1989-06-22 | Process for producing phenylmalonic acid monoanilide derivative and 3-phenyl-2-quinolone derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0753704B2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1981341A2 (en) * | 2006-01-30 | 2008-10-22 | Merck and Co., Inc. | Inhibitors of fatty acid synthase (fas) |
| WO2017097870A1 (en) * | 2015-12-11 | 2017-06-15 | Bayer Cropscience Aktiengesellschaft | Substituted malonic acid amides as insecticides |
-
1989
- 1989-06-22 JP JP1160233A patent/JPH0753704B2/en not_active Expired - Lifetime
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1981341A2 (en) * | 2006-01-30 | 2008-10-22 | Merck and Co., Inc. | Inhibitors of fatty acid synthase (fas) |
| EP1981341A4 (en) * | 2006-01-30 | 2011-01-05 | Merck Sharp & Dohme | Inhibitors of fatty acid synthase (fas) |
| WO2017097870A1 (en) * | 2015-12-11 | 2017-06-15 | Bayer Cropscience Aktiengesellschaft | Substituted malonic acid amides as insecticides |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0753704B2 (en) | 1995-06-07 |
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