JPH02149550A - N-(2-carboxy-3',4'-dimethoxy-cynnamoyl)-anthranilic acid, and production thereof - Google Patents
N-(2-carboxy-3',4'-dimethoxy-cynnamoyl)-anthranilic acid, and production thereofInfo
- Publication number
- JPH02149550A JPH02149550A JP1214272A JP21427289A JPH02149550A JP H02149550 A JPH02149550 A JP H02149550A JP 1214272 A JP1214272 A JP 1214272A JP 21427289 A JP21427289 A JP 21427289A JP H02149550 A JPH02149550 A JP H02149550A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- dimethoxy
- anthranilic acid
- group
- cinnamoyl
- 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.)
- Pending
Links
- 238000004519 manufacturing process Methods 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 21
- -1 i.e. Chemical compound 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 12
- LGKDSFINXVEYKX-UHFFFAOYSA-N C(=O)(O)C1=C(C=CC(=O)NC=2C(C(=O)O)=CC=CC2)C=CC(=C1OC)OC Chemical compound C(=O)(O)C1=C(C=CC(=O)NC=2C(C(=O)O)=CC=CC2)C=CC(=C1OC)OC LGKDSFINXVEYKX-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 230000007062 hydrolysis Effects 0.000 claims description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 238000009835 boiling Methods 0.000 claims description 2
- 239000011541 reaction mixture Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 2
- 239000012442 inert solvent Substances 0.000 claims 1
- 229910000000 metal hydroxide Inorganic materials 0.000 claims 1
- 150000004692 metal hydroxides Chemical class 0.000 claims 1
- 239000011877 solvent mixture Substances 0.000 claims 1
- NZHGWWWHIYHZNX-CSKARUKUSA-N tranilast Chemical compound C1=C(OC)C(OC)=CC=C1\C=C\C(=O)NC1=CC=CC=C1C(O)=O NZHGWWWHIYHZNX-CSKARUKUSA-N 0.000 abstract description 4
- 229960005342 tranilast Drugs 0.000 abstract description 4
- NZHGWWWHIYHZNX-UHFFFAOYSA-N 2-((3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl)amino)benzoic acid Chemical compound C1=C(OC)C(OC)=CC=C1C=CC(=O)NC1=CC=CC=C1C(O)=O NZHGWWWHIYHZNX-UHFFFAOYSA-N 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 238000001640 fractional crystallisation Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 125000000962 organic group Chemical group 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- PCEMQCDPFYBPPF-UHFFFAOYSA-N 2-[(3,4-dimethoxyphenyl)methylidene]propanedioic acid Chemical compound COC1=CC=C(C=C(C(O)=O)C(O)=O)C=C1OC PCEMQCDPFYBPPF-UHFFFAOYSA-N 0.000 description 1
- 125000002672 4-bromobenzoyl group Chemical group BrC1=CC=C(C(=O)*)C=C1 0.000 description 1
- 101100167744 Caenorhabditis elegans let-711 gene Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000003232 p-nitrobenzoyl group Chemical group [N+](=O)([O-])C1=CC=C(C(=O)*)C=C1 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 125000005920 sec-butoxy group Chemical group 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
Abstract
Description
【発明の詳細な説明】
本発明は下記の式（１） の新規なＮ−（２−カルボ
キシ−３°、４−ジメトキシ−シンナモイル）−アンス
ラニル酸及びその製造方法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel N-(2-carboxy-3°,4-dimethoxy-cinnamoyl)-anthranilic acid represented by the following formula (1) and a method for producing the same.
この化合物はＮ−（３°、４−ジメトキシ−シンナモイ
ル）−アンスラニル酸（一般にトラニラストとして知ら
れている）を製造するための有用な中間化合物である。This compound is a useful intermediate compound for the preparation of N-(3°,4-dimethoxy-cinnamoyl)-anthranilic acid (commonly known as tranilast).
この新規な、下記式 （１） ％式％ モイル）−アンスラニル酸は今日まで知られていない。This new formula (1) below %formula% Moyl)-anthranilic acid is unknown to date.
このものは下記式（ＩＩ）のＮ−（２−アルコキシカル
ボニル−３°、４−ジメトキシ−シンナモイル）−アン
スラニル酸誘導体
（但しこの式においてＲはカルボキシエステル化基を、
そてしＲ’は水素又はカルボキシエステル化基を表わす
）からそのカルボキシエステル化基を解裂分離すること
によってほぼ定量的な収量で（Ｊることができる。This product is an N-(2-alkoxycarbonyl-3°,4-dimethoxy-cinnamoyl)-anthranilic acid derivative of the following formula (II) (however, in this formula, R represents a carboxyesterification group,
(R' represents hydrogen or a carboxyesterified group) by cleaving and separating the carboxyesterified group (R' represents hydrogen or a carboxyesterified group) in an almost quantitative yield.
Ｒ又はＲ１によって表わされる適当なカルボキシエステ
ル化基は容易に解裂除去することのできる如何なる有機
基であってもよい。A suitable carboxyesterifying group represented by R or R1 can be any organic group that can be easily cleaved off.
適当なカルボキシエステル化基は例えば脂肪族アルコー
ル、芳香脂肪族アルコール又はフェノールから誘導され
た有機基であることができる。Suitable carboxyesterifying groups can be, for example, organic groups derived from aliphatic alcohols, araliphatic alcohols or phenols.
面記式（１） のＲ及びＲ１は直鎖状又は分岐鎖状の
置換又は非置換の、好ましくは１ないし４個の炭素原子
を有するアルキル基、例えばメチル、エチル、プロピル
、１ｓｏ−プロピル、ブチル、 ５ｅｃ−ブチル又はｔ
ｅｒｔ−ブチルを表わすが、これらは場合により１ない
し４個の炭素原子のアルコキシ基（例えばメトキシ、エ
トキシ、プロポキシ、１ｓｏ−プロポキシ、ブトキシ、
ｔｅｒｔ−ブトキシ及びｓｅｃ−ブトキシ等）、ハロ
ゲン（例えば弗素、塩素、臭素又はよう素）、シアノ基
、脂肪族又は芳香族アシル基（例えば ｐ−ブロモベン
ゾイル又はｐ−ニトロベンゾイル等）又はＣｌ−４のア
ルコキシカルボニル（例えばメトキシカルボニル、エト
キシカルボニル、プロポキシカルボニル、１ｓｏ−プロ
ポキシカルボニル、ブトキシ力ルボニネル、ｔｅｒｔ−
ブトキシカルボニル、５ｅｃ−ブトキシカルボニル等に
よって置換されていてもよく、あるいはまたＲ及びＲ１
は３ないし６個の炭素原子を有するシクロアルキル基（
例えばシクロプロピル、シクロブチル、シクロペンチル
またはシクロヘキシル等）を表わすこともできる。R and R1 in surface formula (1) are linear or branched substituted or unsubstituted alkyl groups preferably having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 1so-propyl, Butyl, 5ec-butyl or t
ert-butyl, which optionally represents an alkoxy group of 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, 1so-propoxy, butoxy,
tert-butoxy and sec-butoxy), halogens (e.g. fluorine, chlorine, bromine or iodine), cyano groups, aliphatic or aromatic acyl groups (e.g. p-bromobenzoyl or p-nitrobenzoyl etc.) or Cl-4 alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1so-propoxycarbonyl, butoxycarbonyl, tert-
may be substituted with butoxycarbonyl, 5ec-butoxycarbonyl, etc., or alternatively R and R1
is a cycloalkyl group having 3 to 6 carbon atoms (
For example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl).
更に、Ｒ及びＲ１はまた例えば、場合によりｌないし４
個の炭素原子を有するアルキル（例えばメチル、エチル
、プロピル、１ｓｏ−プロピル、ブチル、５ｅｃ−ブチ
ル又はｔｅｒｔ−ブチル）、工ないし４個の炭素原子を
有するアルコキシ（例えばメトキシ、エトキシ、プロポ
キシ、１ｓｏ−プロポキシ、ブトキシ又はｔｅｒｔ−ブ
トキシ）、ハロゲン（例えば弗素、塩素、臭素又は沃素
）、ニトロ、シアノ、アルキル基中に１ないし４個の炭
素原子を有するジアルキルアミノ（例えばジメチルアミ
ノ、ジエチルアミノ又はメチルエチルアミノ）、アルキ
ル基中に１ないし４個の炭素原子を有するアルキルチオ
（例えばメチルチオ、エチルチオ、プロピルチオ、１ｓ
ｏ−プロピルチオ、ブチルチオ、 ｔｅｒＬ−ブチルチ
オ又は ８０Ｃ−ブチルチオ等）或はメルカプト基によ
って置換されていてもよい、置換又は非置換のベンジル
基を表わすことができる。Furthermore, R and R1 can also be, for example, optionally 1 to 4
Alkyl having 4 carbon atoms (e.g. methyl, ethyl, propyl, 1so-propyl, butyl, 5ec-butyl or tert-butyl), alkoxy having 4 carbon atoms (e.g. methoxy, ethoxy, propoxy, 1so- propoxy, butoxy or tert-butoxy), halogen (e.g. fluorine, chlorine, bromine or iodine), nitro, cyano, dialkylamino having 1 to 4 carbon atoms in the alkyl group (e.g. dimethylamino, diethylamino or methylethylamino) ), alkylthio having 1 to 4 carbon atoms in the alkyl group (e.g. methylthio, ethylthio, propylthio, Is
o-propylthio, butylthio, terL-butylthio or 80C-butylthio) or a substituted or unsubstituted benzyl group which may be substituted with a mercapto group.
Ｒ及びＲ１は同一であっても異なっていてもよい。R and R1 may be the same or different.
前記式 （ＩＩ）の好ましい化合物は式 （Ｉ Ｉ）に
おいて
Ｒがベンジル、又は場合によりハロゲンによって置換さ
れているｌないし４個の炭素原子のアルキル基を表わし
、そして
Ｒ１が水素、ベンジル、又は場合によりハロゲンによっ
て置換されているｌないし４個の炭素原子のアルキルを
表わす
ものである。Preferred compounds of formula (II) above are those in which R represents benzyl or an alkyl group of 1 to 4 carbon atoms optionally substituted by halogen, and R1 is hydrogen, benzyl or represents alkyl of 1 to 4 carbon atoms substituted by halogen.
式 （ＩＩ）の化合物の更に好ましいものはこの式にお
いて
Ｒがベンジル、メチル、エチル、１ｓｏ−プロピル、プ
ロピル、ブチル、 ｔｅｒｔ−ブチル又はトリフルオロ
メチルを表わし、そして
Ｒ１が水素、ベンジル、メチル、エチル、１ｓｏ−プロ
ピル、プロピル、ブチル、ｔｅｒＬ−ブチル又はトリフ
ルオロメチルを表わす
ものである。Further preference is given to compounds of formula (II) in which R represents benzyl, methyl, ethyl, 1so-propyl, propyl, butyl, tert-butyl or trifluoromethyl, and R1 is hydrogen, benzyl, methyl, ethyl , 1so-propyl, propyl, butyl, terL-butyl or trifluoromethyl.
式 （Ｉりの化合物の最も好ましいものはこの式におい
て
Ｒがメチル又はエチルであり、そして
Ｒ１がメチル又はエチルである
ものである。The most preferred compounds of formula I are those in which R is methyl or ethyl and R1 is methyl or ethyl.
そのカルボキシエステル化基は式（ＩＩ）の化合物から
公知の如何なる方法によっても解裂分離させることがで
きる。最も好ましい方法は加水分解である。The carboxyesterified group can be cleaved off from the compound of formula (II) by any known method. The most preferred method is hydrolysis.
前記式 （ＩＩ）の化合物の加水分解は好ましくは塩基
の存在のもとに行なわれる。適当な塩基の例としては例
えば水酸化ナトリウム及び水酸化カリウムのようなアル
カリ水酸化物をあげることができる。この塩基は一般に
前記式 （ＩＩ）の化合物１モルについて２ないし５、
好ましくは２．５ ないし３．５ モルの量で用い
られる。The hydrolysis of the compound of formula (II) is preferably carried out in the presence of a base. Examples of suitable bases include alkali hydroxides such as sodium hydroxide and potassium hydroxide. The base is generally 2 to 5 per mole of the compound of formula (II),
Preferably it is used in an amount of 2.5 to 3.5 mol.
この加水分解は溶媒の存在のもとに行なうことができる
。好ましい溶媒は水及びアルコール、中でもｌないし４
個の炭素原子を有する脂肪族アルコール、例えばメタノ
ール、エタノール、プロパツール、 １ｓｏ−プロパツ
ール、ブタノール等、更にはまた水とアルコールとの混
合物である。This hydrolysis can be carried out in the presence of a solvent. Preferred solvents are water and alcohols, especially 1 to 4
aliphatic alcohols having 5 carbon atoms, such as methanol, ethanol, propatool, 1so-propatol, butanol, etc., and also mixtures of water and alcohol.
式 （１１の化合物を良好な収率で作り出し、そして反
応を短時間で行なわせるためには水とアルコールとの混
合物を用いるのが好ましい、この水とアルコールとの比
率は広い範囲で変化させることができる。In order to produce the compound of formula (11) in good yields and to carry out the reaction in a short time, it is preferred to use a mixture of water and alcohol; the ratio of water and alcohol can be varied within a wide range. Can be done.
反応は室温において実施することもできるが、しかしな
がらその加水分解は好ましくはその反応混合物の沸点に
おいて行なうのが良い。後者の場合には反応は１ないし
４時間以内に完了させることができる。The reaction can also be carried out at room temperature, however the hydrolysis is preferably carried out at the boiling point of the reaction mixture. In the latter case the reaction can be completed within 1 to 4 hours.
本発明に従う方法によって式 （１１の化合物は２つの
異性体の混合物として得ることができる。By the process according to the invention the compound of formula (11) can be obtained as a mixture of two isomers.
この２つの異性体の比率は２：１であり、そしてそれら
は公知の方法、例えば分別結晶によって分離することが
できる。上世の異性体の融点は １８０℃であり、そし
て制量の異性体のそれは２１０℃である。The ratio of the two isomers is 2:1 and they can be separated by known methods, such as fractional crystallization. The melting point of the upper isomer is 180°C and that of the lower isomer is 210°C.
しかしながら式 （１） の化合物をトラニラストの
製造のために用いる場合には上記のような分離は不必要
であり、と言うのはトラニラストは両方の異性体から同
じ収率で得られるからである。However, when the compound of formula (1) is used for the preparation of tranilast, such a separation is unnecessary, since tranilast can be obtained in the same yield from both isomers.
前記式 （１１）の新規化合物は下記式 （ＩＩＩ）（
但しこの式においてＲは前述の意味を有する）の （３
，４−ジメトキシフェニル）メチレンマロン酸のモノエ
ステルの反応性誘導体を下記式 （ＩＶＩｃｏｏｎ’
／
（但しＲ１は前記の意味を有する）の化合物と縮合反応
させることによって簡単に且つ良好な収率で得ることが
できる。The new compound of formula (11) has the following formula (III) (
However, in this formula, R has the above-mentioned meaning) of (3
, 4-dimethoxyphenyl) methylenemalonic acid by condensation reaction with a compound of the following formula (IVIcoon' / (where R1 has the above meaning)) easily and in a good yield. be able to.
式 （ＩＩ）の化合物の製造は本出願人の共出願中の特
許出願の明細書に詳細に記述されている。The preparation of compounds of formula (II) is described in detail in the specification of the applicant's co-pending patent application.
〔実施例Ｊ
以Ｆに本発明を幾つかの例により更に詳細に説明するが
、これらの例は本発明に何等の制限を与えるものではな
い。[Example J to F] The present invention will be explained in more detail with reference to some examples, but these examples are not intended to limit the present invention in any way.
別−−１
Ｎ−（３’、４−ジメトキシ−２−カルボキシ−シンナ
モイル）−アンスラニル酸〔式（りの化合物〕の製造
１３０ ｍｌ のメタノールと ３０ ｍｌ の水
との混合物中に６ ｇ （０，１５モル）の水酸化ナト
リウムを溶解した溶液にＮ−（３°、４°−ジメＬキシ
ー２−メトキシカルボニル−シンナモイル）−アンスラ
ニル酸メチルエステル２０ｇ（口、０５モル）を加え、
ついでこの混合物を３時間還流させる。メタノールを減
圧のもとに蒸留除去した後、残留した溶液を３０ｍ１の
水で稀釈し、そしてそれぞれ３０ ｍｌ のクロロホ
ルムで２回抽出する。Separate--1 Preparation of N-(3',4-dimethoxy-2-carboxy-cinnamoyl)-anthranilic acid [compound of formula (RI)] 6 g (0 , 15 mol) of sodium hydroxide was added with 20 g (0.05 mol) of N-(3°, 4°-dimethyl-2-methoxycarbonyl-cinnamoyl)-anthranilic acid methyl ester,
This mixture is then refluxed for 3 hours. After distilling off the methanol under reduced pressure, the remaining solution is diluted with 30 ml of water and extracted twice with 30 ml of chloroform each time.
その水相部をＩｇ の活性炭と共に３０分間撹拌し、
次いでその活性炭は濾過分離する。濾液に冷却しながら
！：Ｉ塩酸水溶液をｐＨ１になるまで加える。沈殿を濾
過し、水洗した後、減圧のもとに５０℃において乾燥す
る。 １８．２０ ｇ （９８％）の表題の化合物が
得られる。このものは２つの幾何異性体の２＝１の混合
物であり、薄層クロマトグラフ（溶離剤：クロロホルム
／メタノール／水＝ ５０／４０１５）によってそれぞ
れ０．３９及び０゜５の１（、ｆ直のスポットを示す。The aqueous phase was stirred with Ig activated carbon for 30 minutes,
The activated carbon is then filtered off. While cooling the filtrate! :I Add aqueous hydrochloric acid solution until the pH becomes 1. The precipitate is filtered, washed with water and then dried at 50° C. under reduced pressure. 18.20 g (98%) of the title compound are obtained. This is a 2=1 mixture of two geometric isomers, with 1 (, f direct) of 0.39 and 0. Indicates the spot.
各異性体は ９０％ 濃度の水性メタノール溶液から分
別結晶によって互いに分離することができる。The isomers can be separated from each other by fractional crystallization from 90% strength aqueous methanol solutions.
各異性体の分析値は下記の通りである：１） Ｒｅ
＝ ０．３９
融点＝ １７８−１８０℃ （分解）
Ｉｎ （にＯｒ）＋ １７３０．１６９５．１６４５
ｃｆｆｉ−’ （Ｃｏ）’Ｉｔ−ＮＭＲ（ＤＭＳＯＩ：
３．５０ （ｓ、 ３８．０Ｃｔｌａ）。The analytical values for each isomer are as follows: 1) Re
= 0.39 Melting point = 178-180℃ (decomposition) In (Or) + 1730.1695.1645
cffi-'(Co)'It-NMR (DMSOI:
3.50 (s, 38.0Ctla).
３、７６ （ｓ、 ３１１．０ＣＩＩｓ）、６．９６−
８．７１ （ｍ、７１１． ａｒｏｍ、 ）、７．６５
（ｓ、 ０１．−Ｃ１ｌ：）、＋１．５０ （ｓ、
ＩＨ，ＮＨ）
Ｒ，＝ ０．５０
融点・２０８−２１０℃ （分解）
ＩＲ（にＢｒｌ： １６９５、１６７０ ｃｍ−’
’ＩＩ−ＮＭＲ［ＤＭＳＯ）： ３．７８ （ｓ、
３１１゜３、８３ （ｓ、 ３Ｈ。3,76 (s, 311.0CIIs), 6.96-
8.71 (m, 711. arom, ), 7.65
(s, 01.-C1l:), +1.50 (s,
IH, NH) R, = 0.50 Melting point・208-210℃ (decomposition) IR(Brl: 1695, 1670 cm-'
'II-NMR [DMSO): 3.78 (s,
311°3, 83 (s, 3H.
７．０３−８．６３ （ａ＋。7.03-8.63 (a+.
７．５８ （ｓ、Ｉｌｌ。7.58 (s, Ill.
（ＣＯ） ＯＣＨ３）。(CO) OCH3).
ＯＣＲ，）。OCR,).
７Ｈ，ａｒｏｍ、ｌ。7H, aroma, l.
−ＣＩ量＝）、
Ｉｔ、 ７０ （ｓ、 １８． Ｎｔｌ１例−−
Ｚ
Ｎ−（２−カルボキシ−３゛、４−ジメトキシ−シンナ
モイルツーアンスラニル酸の製造
例１に記載した方法で式 （目）の他の種々の出発化合
物から標題の化合物を製造する０式 （，１１１の各置
換基とそれぞれの？８媒及び収率な下記衣１にまとめて
示す。-CI amount=), It, 70 (s, 18. Ntl1 example--
Preparation of ZN-(2-carboxy-3',4-dimethoxy-cinnamoyltuanthranilic acid) Formula 0 to prepare the title compound from various other starting compounds of formula (2) by the method described in Example 1. (, 111, each substituent, their respective ?8 solvents and yields are summarized in Table 1 below.
このようにして得られた式（［） の化合物の物理的
特性は例１にあげたものと一致する。The physical properties of the compound of formula ([) thus obtained correspond to those given in Example 1.
表１Table 1
Claims (7)
ンナモイル）−アンスラニル酸。(1) N-(2-carboxy-3',4'-dimethoxy-cinnamoyl)-anthranilic acid of the following formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I).
４′−ジメトキシ−シンナモイル）−アンスラニル酸を
製造するに当り、下記式（II） ▲数式、化学式、表等があります▼（II） （この式においてＲはカルボキシエステル化基を表わし
、そてしＲ＾１は水素原子またはカルボキシエステル化
基を意味する）のＮ−（２−アルコキシカルボニル−３
′，４′−ジメトキシ−シンナモイル）−アンスラニル
酸からそのカルボキシエステル化基を解裂除去すること
を特徴とする、製造方法。(2) N-(2-carboxy-3' of the above formula (I),
In producing 4'-dimethoxy-cinnamoyl)-anthranilic acid, the following formula (II) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) (In this formula, R represents a carboxyesterification group, and R^1 means a hydrogen atom or a carboxyesterified group) N-(2-alkoxycarbonyl-3
1. A process for producing ',4'-dimethoxy-cinnamoyl)-anthranilic acid, which comprises cleaving and removing its carboxyesterification group.
意味を有する化合物を塩基及び不活性の溶媒又は溶媒混
合物の存在のもとに加水分解する、請求項２記載の方法
。(3) The method according to claim 2, wherein the compound in the formula (II) in which R and R^1 have the same meanings as above is hydrolyzed in the presence of a base and an inert solvent or solvent mixture.
に実施する、請求項２記載の方法。(4) The method according to claim 2, wherein the hydrolysis is carried out in the presence of an alkaline metal hydroxide.
ル又はそれらの混合物の存在のもとに実施する、請求項
２記載の方法。(5) The process according to claim 2, wherein the hydrolysis is carried out in the presence of water, C_1_-_4 aliphatic alcohols or mixtures thereof.
温度において実施する、請求項２記載の方法。(6) A process according to claim 2, wherein the hydrolysis is carried out at a temperature between room temperature and the boiling point of the reaction mixture.
キルであり、そしてＲ＾１がＣ＿１＿−＿５のアルキル
又はフェニル−（Ｃ＿１＿−＿４アルキル）である化合
物を使用する、請求項２記載の方法。(7) The compound according to claim 2, wherein in the formula (II), R is C_1_-_4 alkyl, and R^1 is C_1_-_5 alkyl or phenyl-(C_1_-_4 alkyl). Method.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU2251-2635/88 | 1988-05-23 | ||
| HU882635A HU200996B (en) | 1988-05-23 | 1988-05-23 | Process for producing n-(3', 4'-dimethoxycinnamoyl)-anthranilic acid (tranilast) |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63153677A Division JPH01313457A (en) | 1988-05-23 | 1988-06-23 | Production of n-(3', 4'-dimethoxy-cinnamoyl)- anthranylic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH02149550A true JPH02149550A (en) | 1990-06-08 |
Family
ID=10960384
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63153677A Pending JPH01313457A (en) | 1988-05-23 | 1988-06-23 | Production of n-(3', 4'-dimethoxy-cinnamoyl)- anthranylic acid |
| JP1214271A Pending JPH02138243A (en) | 1988-05-23 | 1989-08-22 | Tranilast intermediate product and preparation thereof |
| JP1214272A Pending JPH02149550A (en) | 1988-05-23 | 1989-08-22 | N-(2-carboxy-3',4'-dimethoxy-cynnamoyl)-anthranilic acid, and production thereof |
Family Applications Before (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63153677A Pending JPH01313457A (en) | 1988-05-23 | 1988-06-23 | Production of n-(3', 4'-dimethoxy-cinnamoyl)- anthranylic acid |
| JP1214271A Pending JPH02138243A (en) | 1988-05-23 | 1989-08-22 | Tranilast intermediate product and preparation thereof |
Country Status (2)
| Country | Link |
|---|---|
| JP (3) | JPH01313457A (en) |
| HU (1) | HU200996B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115243670A (en) | 2020-03-06 | 2022-10-25 | 西姆莱斯股份公司 | Cosmetic or pharmaceutical use of avenanthramide L |
| EP4114348A1 (en) | 2020-03-06 | 2023-01-11 | Symrise AG | Composition comprising an aventhramide or an analogue thereof with improved stability |
| CA3172769A1 (en) | 2020-03-06 | 2021-09-10 | Symrise Ag | Composition or oat extract comprising avenanthramide and .beta.-glucan |
| US20230129036A1 (en) | 2020-03-06 | 2023-04-27 | Symrise Ag | Avenanthramide compositions with improved solubility comprising 4-hydroxyphenone |
| WO2021175452A1 (en) | 2020-03-06 | 2021-09-10 | Symrise Ag | Composition comprising an avenanthramide or an analogue thereof with improved skin penetration |
| CN115626879B (en) * | 2022-10-08 | 2024-01-30 | 广州同隽医药科技有限公司 | Preparation method of 2-phenylpropionamido-benzoic acid derivative |
-
1988
- 1988-05-23 HU HU882635A patent/HU200996B/en unknown
- 1988-06-23 JP JP63153677A patent/JPH01313457A/en active Pending
-
1989
- 1989-08-22 JP JP1214271A patent/JPH02138243A/en active Pending
- 1989-08-22 JP JP1214272A patent/JPH02149550A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| HUT49846A (en) | 1989-11-28 |
| JPH02138243A (en) | 1990-05-28 |
| HU200996B (en) | 1990-09-28 |
| JPH01313457A (en) | 1989-12-18 |
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