JPH01319469A - Production of 4-(3,4-dimethoxy-6-methyl-2,5-benzoquinonyl)-4-phenyllactic acid amide derivative - Google Patents
Production of 4-(3,4-dimethoxy-6-methyl-2,5-benzoquinonyl)-4-phenyllactic acid amide derivativeInfo
- Publication number
- JPH01319469A JPH01319469A JP63150019A JP15001988A JPH01319469A JP H01319469 A JPH01319469 A JP H01319469A JP 63150019 A JP63150019 A JP 63150019A JP 15001988 A JP15001988 A JP 15001988A JP H01319469 A JPH01319469 A JP H01319469A
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- dimethoxy
- phenyl
- benzoquinonyl
- acid amide
- 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 claims description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 15
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims abstract description 14
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims abstract description 12
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 claims abstract description 6
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims abstract description 6
- DSBZYDDWLLIJJS-UHFFFAOYSA-N ubiquinol-0 Chemical compound COC1=C(O)C=C(C)C(O)=C1OC DSBZYDDWLLIJJS-UHFFFAOYSA-N 0.000 claims abstract description 5
- GDCVTHJYEIPTDX-UHFFFAOYSA-N 7-hydroxy-8,9-dimethoxy-6-methyl-5-phenyl-4,5-dihydro-3h-1-benzoxepin-2-one Chemical compound C1CC(=O)OC2=C(OC)C(OC)=C(O)C(C)=C2C1C1=CC=CC=C1 GDCVTHJYEIPTDX-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 3
- 239000000126 substance Substances 0.000 claims abstract 2
- -1 4-(3,4-dimethoxy-6-methyl-2,5-benzoquinonyl)-4-phenylbutyric acid amide derivative Chemical class 0.000 claims description 6
- 230000003647 oxidation Effects 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- AEUULUMEYIPECD-UHFFFAOYSA-N 5-phenyloxolan-2-one Chemical compound O1C(=O)CCC1C1=CC=CC=C1 AEUULUMEYIPECD-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 7
- 239000002253 acid Substances 0.000 abstract description 5
- 239000007800 oxidant agent Substances 0.000 abstract description 4
- 229910052760 oxygen Inorganic materials 0.000 abstract description 2
- 230000001590 oxidative effect Effects 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 10
- 238000000034 method Methods 0.000 description 7
- 239000013078 crystal Substances 0.000 description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 4
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- OQZGYMRYZAKXAF-UHFFFAOYSA-N 2-(4-methylcyclohexyl)acetic acid Chemical compound CC1CCC(CC(O)=O)CC1 OQZGYMRYZAKXAF-UHFFFAOYSA-N 0.000 description 3
- OCJLJTOTHQPPNX-UHFFFAOYSA-N 5-phenyl-3h-1-benzoxepin-2-one Chemical class C12=CC=CC=C2OC(=O)CC=C1C1=CC=CC=C1 OCJLJTOTHQPPNX-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229950009215 phenylbutanoic acid Drugs 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-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
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- KZKTYNGWYSNWKQ-UHFFFAOYSA-M azanium cesium sulfate Chemical compound [NH4+].[Cs+].[O-]S([O-])(=O)=O KZKTYNGWYSNWKQ-UHFFFAOYSA-M 0.000 description 2
- 230000003925 brain function Effects 0.000 description 2
- 229930188620 butyrolactone Natural products 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- PAWQVTBBRAZDMG-UHFFFAOYSA-N 2-(3-bromo-2-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC(Br)=C1F PAWQVTBBRAZDMG-UHFFFAOYSA-N 0.000 description 1
- AGIJRRREJXSQJR-UHFFFAOYSA-N 2h-thiazine Chemical compound N1SC=CC=C1 AGIJRRREJXSQJR-UHFFFAOYSA-N 0.000 description 1
- LTZWZLMNYYAVLP-UHFFFAOYSA-N 4-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dien-1-yl)-4-phenylbutanoic acid Chemical compound O=C1C(OC)=C(OC)C(=O)C(C(CCC(O)=O)C=2C=CC=CC=2)=C1C LTZWZLMNYYAVLP-UHFFFAOYSA-N 0.000 description 1
- VEPXJUZVHXLWFP-UHFFFAOYSA-N C=1C=CC=CC=1C(CCC(=O)N)C1=CC(=O)C=CC1=O Chemical class C=1C=CC=CC=1C(CCC(=O)N)C1=CC(=O)C=CC1=O VEPXJUZVHXLWFP-UHFFFAOYSA-N 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- RUTXIHLAWFEWGM-UHFFFAOYSA-H iron(3+) sulfate Chemical compound [Fe+3].[Fe+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O RUTXIHLAWFEWGM-UHFFFAOYSA-H 0.000 description 1
- 229910000360 iron(III) sulfate Inorganic materials 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000005502 peroxidation Methods 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 229920003255 poly(phenylsilsesquioxane) Polymers 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910001923 silver oxide Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は、４−（３，４−ジメトキシ−６−メチル−２
，５−ベンゾキノニル）−４−フェニル酪酸アミド誘導
体の製造法に関する。Detailed Description of the Invention [Industrial Field of Application] The present invention provides 4-(3,4-dimethoxy-6-methyl-2
, 5-benzoquinonyl)-4-phenylbutyric acid amide derivative.
本発明の方法により製造される４−（３，４−ジメトキ
シ−６−メチル−２，５−ベンゾキノニル）−４−フェ
ニル酪酸アミド誘導体は、抗脳虚血作用、抗ハイボキシ
ア作用、抗過酸化脂質作用等の薬理作用を示し、脳機能
改善薬として有用な化合物である。The 4-(3,4-dimethoxy-6-methyl-2,5-benzoquinonyl)-4-phenylbutyric acid amide derivative produced by the method of the present invention has anti-cerebral ischemic action, anti-hyboxia action, and anti-lipid peroxidation action. It is a compound that exhibits pharmacological effects such as brain function improvement and is useful as a brain function improving drug.
Ｔ−フェニル−γ−ブチロラクトンとフェノール誘導体
とを酸、例えばポリリン酸や硫酸等の存在下に反応して
５−フェニル−１−ベンズオキセピン−２−オン誘導体
を得る方法に関しては、特開昭６１−１４８１７４号公
報、特開昭６１−１５５３５８号公報、特開昭６２−２
６９５３号公報等に、又その５−フェニル−１−ベンズ
オキセピン−２−オン誘導体にアミン類を反応せしめた
後、酸化剤、例えば硝酸第二セシウムアンモニウムやニ
トロソジスルホン酸カリウム等により酸化して４−（２
，５−ベンゾキノニル）−４−フェニル酪酸アミド誘導
体を得る方法に関しては特開昭６２−２２６９５３号公
報に、それぞれ本発明者らによって開示されている。A method for obtaining 5-phenyl-1-benzoxepin-2-one derivatives by reacting T-phenyl-γ-butyrolactone and a phenol derivative in the presence of an acid such as polyphosphoric acid or sulfuric acid is disclosed in JP-A-61-1999. 148174, JP 61-155358, JP 62-2
6953, etc., and after reacting the 5-phenyl-1-benzoxepin-2-one derivative with amines, it is oxidized with an oxidizing agent such as caesium ammonium nitrate or potassium nitrosodisulfonate to obtain 4- (2
, 5-benzoquinonyl)-4-phenylbutyric acid amide derivatives are disclosed by the present inventors in JP-A-62-226953.
〔発明が解決しようとする課題］
しかしながら、前記公報に記載の５−フェニル−１−ベ
ンズオキセピン−２−オン誘導体の製造法に於いては、
酸として取り扱いや後処理が困難なボＩＪ ＩＪン酸、
硫酸、五酸化燐、塩化アルミニウム、オキシ塩化燐等や
、高価なナフタレン−β−スルホン酸、パラトルエンス
ルホン酸等が用いられており、更に収率も高々３０％と
非常に低いものである。[Problems to be Solved by the Invention] However, in the method for producing 5-phenyl-1-benzoxepin-2-one derivatives described in the above publication,
IJ acid, which is difficult to handle and post-process as an acid;
Sulfuric acid, phosphorus pentoxide, aluminum chloride, phosphorus oxychloride, etc., expensive naphthalene-β-sulfonic acid, para-toluenesulfonic acid, etc. are used, and the yield is very low, at most 30%.
又、特開昭６２−２２６９５３号公報記載の４−（２，
５−ベンゾキノニル）−４−フェニル酪酸アミド誘導体
を得る方法は、酸化剤として塩化第二鉄、硫酸第二鉄、
酸化銀、硫酸第二セシウムアンモニウム、過酸類、空気
酸化等の緩和な酸化剤を用いたり、ニトロソジスルホン
酸カリウム（フレミー塩）、サルコミンなどの存在下の
酸素気流を用いる方法が記載されており、これらには高
価な硫硝第二セシウムアンモニウムやニトロソジスルホ
ン酸カリウムヲ用いなければならないという問題がある
。Also, 4-(2,
The method for obtaining the 5-benzoquinonyl)-4-phenylbutyric acid amide derivative uses ferric chloride, ferric sulfate,
Methods using mild oxidizing agents such as silver oxide, cesium ammonium sulfate, peracids, and air oxidation, and using an oxygen stream in the presence of potassium nitrosodisulfonate (Flemy salt), sarcomine, etc. are described. These methods have the problem of having to use expensive cesium ammonium sulfate and potassium nitrosodisulfonate.
この様な状況の下、大量合成に適した安価で、効率良く
、且つ簡便な、４−（３，４−ジメトキシ−６−メチル
−２，５−ベンゾキノニル）−４−フェニル酪酸アミド
誘導体の製造法の開発が求められている。Under these circumstances, we sought to produce a 4-(3,4-dimethoxy-6-methyl-2,5-benzoquinonyl)-4-phenylbutyric acid amide derivative that is inexpensive, efficient, and simple and suitable for large-scale synthesis. Development of laws is required.
〔課題を解決するための手段］
本発明者らは、上記問題点を解決すべく鋭意研究を重ね
た結果、２，３−ジメトキシ−５−メチル−１，４−ヒ
ドロキノンとγ−フェニルーＴ−ブチロラクトンとの反
応に於いて酸としてトリフルオロメタンスルホン酸が、
又 ４−（３，４−ジメトキシ−６−メチル−２，５−
ベンゾキノニル）−４−フェニル酪酸アミド誘導体の合
成に於いて酸化剤として二酸化マンガンが、極めて効率
良く用いられることを見出し、本発明を完成した。[Means for Solving the Problems] As a result of extensive research to solve the above problems, the present inventors found that 2,3-dimethoxy-5-methyl-1,4-hydroquinone and γ-phenyl-T- Trifluoromethanesulfonic acid is used as the acid in the reaction with butyrolactone.
Also 4-(3,4-dimethoxy-6-methyl-2,5-
The present invention was completed based on the discovery that manganese dioxide can be used extremely efficiently as an oxidizing agent in the synthesis of benzoquinonyl)-4-phenylbutyric acid amide derivatives.
本発明に従えば、２，３−ジメトキシ−５−メチル−１
゜４−ヒドロキノンとＴ−フェニル−Ｔ−ブチロラクト
ンとをトリフルオロメタンスルホン酸の存在下に縮合せ
しめた後、トリエチルアミン及び無水酢酸で処理して８
．９−ジメトキシ−７−ヒドロキシ−６−メチル−５−
フェニル−２，３，４，５−テトラヒドロ−１−ベンズ
オキセピン−２−オンとし、続いてモルホリン又はチオ
モルホリンと縮合せしめた後、二酸化マンガンで酸化す
ることから成る式（１）（式中Ｘは、酸素原子又は硫黄
原子を示す）で表される ４−（３，４−ジメトキシ−
６−メチル−２，５−ベンゾキノニル）−４−フェニル
酪酸アミド誘導体の製造法が提供される。According to the invention, 2,3-dimethoxy-5-methyl-1
゜4-Hydroquinone and T-phenyl-T-butyrolactone are condensed in the presence of trifluoromethanesulfonic acid, and then treated with triethylamine and acetic anhydride to form 8
．． 9-dimethoxy-7-hydroxy-6-methyl-5-
Formula (1) consisting of phenyl-2,3,4,5-tetrahydro-1-benzoxepin-2-one, followed by condensation with morpholine or thiomorpholine and oxidation with manganese dioxide (wherein X is , represents an oxygen atom or a sulfur atom) 4-(3,4-dimethoxy-
A method for producing a 6-methyl-2,5-benzoquinonyl)-4-phenylbutyric acid amide derivative is provided.
本発明は、以下の方法により実施することができる。The present invention can be carried out by the following method.
２．３−ジメトキシ−５−メチル−１，４−ヒドロキノ
ンとＴ−フェニル−Ｔ−ブチロラクトンの好ましくは当
モル量を、１，２−ジクロロエタンにン容解し、温度を
０〜５０°Ｃ１好ましくは２５°Ｃ以下に保ちながらト
リフルオロメタンスルホン酸の０．１〜１．０モル当量
、好ましくは０．２モル当量を滴加する。次に、同じ温
度で２４時間以内、好ましくは約１２時間撹拌後、トリ
エチルアミン１．０〜２．０モル当量、好ましくは１．
２モル当量を加え、続いて無水酢酸を０．８〜１．２モ
ル当量、好ましくは１．０モル当量を加え、更に１〜５
時間同温度で撹拌する。2. Preferably equimolar amounts of 3-dimethoxy-5-methyl-1,4-hydroquinone and T-phenyl-T-butyrolactone are dissolved in 1,2-dichloroethane, and the temperature is preferably 0 to 50°C. 0.1 to 1.0 molar equivalent, preferably 0.2 molar equivalent, of trifluoromethanesulfonic acid is added dropwise while maintaining the temperature below 25°C. Then, after stirring at the same temperature within 24 hours, preferably about 12 hours, 1.0 to 2.0 molar equivalents of triethylamine, preferably 1.
2 molar equivalents of acetic anhydride are added, followed by 0.8 to 1.2 molar equivalents, preferably 1.0 molar equivalents of acetic anhydride, and an additional 1 to 5 molar equivalents of acetic anhydride are added.
Stir at the same temperature for the same time.
反応液を常法により水洗、乾燥後濃縮し、結晶化するこ
とにより、約８５％の収率で８，９−ジメトキシ−７−
ヒドロキシ−６−メチル−５−フェニル−２，３゜４．
５−テトラヒドロ−１−ベンズオキセピン−２−オンを
得ることができる。The reaction solution was washed with water, dried, concentrated, and crystallized using a conventional method to obtain 8,9-dimethoxy-7-
Hydroxy-6-methyl-5-phenyl-2,3°4.
5-tetrahydro-1-benzoxepin-2-one can be obtained.
この様にして得られる８、９−ジメトキシ−７−ヒドロ
キシ−６−メチル−５−フェニル−２，３，４，５−テ
トラヒドロ−１−ベンズオキセピン−２−オンヲ１．２
−ジクロロエタンに溶解し、モルホリン又はチオモルホ
リンの１．０〜２．０モル当量を加えて１時間加熱還流
する。反応液を冷却し、５０°Ｃ以下、好ましくは２５
°Ｃ以下に保ちながら二酸化マンガンの２〜１０モル当
量を加え、更に１時間撹拌する。反応液を常法により濾
過、濃縮後結晶化し、粗結晶を再結晶することにより、
目的とする４−（３，４−ジメトキシ−６−メチル−２
，５−ベンゾキノニル）−４−フェニル酪酸のモルホリ
ンアミド又はチオモルホリンアミドを、約８５％の収率
で得ることができる。1.2 of 8,9-dimethoxy-7-hydroxy-6-methyl-5-phenyl-2,3,4,5-tetrahydro-1-benzoxepin-2-one thus obtained
-Dissolve in dichloroethane, add 1.0 to 2.0 molar equivalents of morpholine or thiomorpholine, and heat under reflux for 1 hour. Cool the reaction solution to below 50°C, preferably 25°C.
Add 2-10 molar equivalents of manganese dioxide while keeping the temperature below °C and stir for an additional hour. By filtering and concentrating the reaction solution in a conventional manner, crystallizing it, and recrystallizing the crude crystals,
Target 4-(3,4-dimethoxy-6-methyl-2
, 5-benzoquinonyl)-4-phenylbutyric acid can be obtained in a yield of about 85%.
上記両反応に於いて用いられる溶媒としては、反応に関
与しないものであれば特に限定されないが、前記１，２
−ジクロロエタンが最適である。The solvent used in both of the above reactions is not particularly limited as long as it does not participate in the reaction, but
-Dichloroethane is most suitable.
〔実施例］
以下、本発明を実施例を以てより詳細に説明するが、本
発明をこれらの実施例に限定するものでないことは勿論
である。[Examples] Hereinafter, the present invention will be explained in more detail with reference to Examples, but it goes without saying that the present invention is not limited to these Examples.
ｋＬ例」−
４−（４−（３，４−ジメトキシ−６−メチル−２，５
−ベンゾキノニル）−４−フェニルブチリル） −２，
３，４，５−テトラヒドロ−４１１−チアジンの合成二
重ヒ二し＝８．９−ジメトキシ−７−ヒドロキシ−６−
メチル−５−フェニル−２，３，４，５−テトラヒドロ
−１−ベンズオキセピン−２−オン
２．３−ジメトキシ−５−メチル−１，４−ヒドロキノ
ン７．６８ｇ（０，０４１６モル）とＴ−フェニル−Ｔ
−ブチロラクトン６．７６ｇ（０，０４１６モル）を１
，２−ジクロロエタン３８ｍ１に溶解後、反応温度を２
５°Ｃ以下に保ちながらトリフルオロメタンスルホン酸
０．７３８ｍ１ を滴加し、滴加柊了後同温度で１２時
間撹拌した。続いて反応液温度を同じ＜２５°Ｃ以下に
保ちながら、トリエチルアミン６．９６ｍ１ 、次に無
水酢酸３．９３ｍ１を滴加し、更に１時間室温で撹拌し
た。Example: 4-(4-(3,4-dimethoxy-6-methyl-2,5
-benzoquinonyl)-4-phenylbutyryl) -2,
Synthesis of 3,4,5-tetrahydro-411-thiazine
Methyl-5-phenyl-2,3,4,5-tetrahydro-1-benzoxepin-2-one 7.68 g (0,0416 mol) of 2,3-dimethoxy-5-methyl-1,4-hydroquinone and T- Phenyl-T
-6.76 g (0,0416 mol) of butyrolactone in 1
, 2-dichloroethane (38ml), the reaction temperature was reduced to 2.
0.738 ml of trifluoromethanesulfonic acid was added dropwise while keeping the temperature below 5°C, and after the addition was complete, the mixture was stirred at the same temperature for 12 hours. Subsequently, 6.96 ml of triethylamine and then 3.93 ml of acetic anhydride were added dropwise while maintaining the reaction solution temperature at the same <25° C., and the mixture was further stirred at room temperature for 1 hour.
反応混合物を各１５ｍ！の水で３回洗浄した後、硫酸マ
グネシウムで乾燥し、濾過後液量が約１５ｍ１になるま
で濃縮した。残液にイソプロピルエーテル２０＋ｎ ｌ
を加えて結晶を析出させ、結晶を濾取後イソプロピルエ
ーテル１０ｍ１で３回洗浄し、減圧下に乾燥して標記化
合’ｊＩＪ１０．２７ｇ （収率７５．０χ）を得た。15 m each of reaction mixture! The solution was washed three times with water, dried over magnesium sulfate, filtered, and concentrated to a volume of about 15 ml. Add isopropyl ether 20+n l to the remaining liquid
was added to precipitate crystals, and the crystals were collected by filtration, washed three times with 10 ml of isopropyl ether, and dried under reduced pressure to obtain 10.27 g (yield: 75.0x) of the title compound 'jIJ.
ユｊＬ二２ ： ４− Ｃ４−（３，４−ジメトキシ−
６−メチル−２，５−ベンゾキノニル）−４−フェニル
ブチリル） −２゜３．４．５−テトラヒドロ−４Ｈ−
チアジン工程−１で得た８、９−ジメトキシ−７−ヒド
ロキシ−６−メチル−５−フェニル−２，３，４，５−
テトラヒドロ−１−へ、ンズオキセピンー２−オン９．
５８ｇ（０，０２９２モル）を１，２−ジクロロエタン
５０ｍ ｌに溶解し、チオモルホリン２．９３ｍ１を加
えた後、１時間加熱還流した。反応液を室温までに冷却
し、２５°Ｃ以下に保ちながら二酸化マンガン１４．３
７ｇを加え、更に１時間撹拌した。反応液にセライト２
ｇを加えて混合後濾過、１．２−ジクロロエタンで洗浄
した。濾液及び洗液を合わせ、濃縮して約１７ｍ１とし
た後エタノール６０ｍ１を加えて結晶を析出させた。結
晶を濾取し、約１０ｍ１のエタノールで２回洗浄した後
乾燥して標記化合物１０．６５ｇ （収率８５，０％）
を得た。UjL22: 4-C4-(3,4-dimethoxy-
6-Methyl-2,5-benzoquinonyl)-4-phenylbutyryl) -2゜3.4.5-tetrahydro-4H-
8,9-dimethoxy-7-hydroxy-6-methyl-5-phenyl-2,3,4,5- obtained in thiazine step-1
Tetrahydro-1-to, nzoxepin-2-one9.
58 g (0,0292 mol) was dissolved in 50 ml of 1,2-dichloroethane, 2.93 ml of thiomorpholine was added, and the mixture was heated under reflux for 1 hour. Cool the reaction solution to room temperature, and add 14.3% manganese dioxide while keeping the temperature below 25°C.
7 g was added and further stirred for 1 hour. Celite 2 in the reaction solution
After mixing, the mixture was filtered and washed with 1,2-dichloroethane. The filtrate and washing liquid were combined and concentrated to about 17 ml, and 60 ml of ethanol was added to precipitate crystals. The crystals were collected by filtration, washed twice with about 10 ml of ethanol, and then dried to yield 10.65 g of the title compound (yield: 85.0%).
I got it.
得られた化合物の融点は、１３１〜１３３ ’Ｃであっ
た。The melting point of the obtained compound was 131-133'C.
災恭」じ工： Ｎ−（４−（３，４−ジメトキシ−６
−メチル−２，５−ベンゾキノニル）−４−フェニルブ
チリル１モルホリンの合成
実施例Ｉに準じ、工程−２におけるチオモルホリンに代
えモルホリンを用いることにより標記化合物を約６３％
の収率で得た。Disaster: N-(4-(3,4-dimethoxy-6)
-Methyl-2,5-benzoquinonyl)-4-phenylbutyryl 1 Synthesis of morpholine According to Example I, by using morpholine in place of thiomorpholine in step-2, the title compound was reduced to about 63%.
It was obtained in a yield of .
得られた化合物の融点は７４〜７６°Ｃであった。The melting point of the obtained compound was 74-76°C.
Claims (1)
キノンとγ−フェニル−γ−ブチロラクトンとをトリフ
ルオロメタンスルホン酸の存在下に縮合せしめた後、ト
リエチルアミン及び無水酢酸で処理して８，９−ジメト
キシ−７−ヒドロキシ−６−メチル−５−フェニル−２
，３，４，５−テトラヒドロ−１−ベンズオキセピン−
２−オンとし、続いてモルホリン又はチオモルホリンと
縮合せしめた後、二酸化マンガンで酸化することを特徴
とする式（ I ） ▲数式、化学式、表等があります▼（ I ） （式中Ｘは、酸素原子又は硫黄原子を示す）で表わされ
る４−（３，４−ジメトキシ−６−メチル−２，５−ベ
ンゾキノニル）−４−フェニル酪酸アミド誘導体の製造
法。[Claims] After condensing 1,2,3-dimethoxy-5-methyl-1,4-hydroquinone and γ-phenyl-γ-butyrolactone in the presence of trifluoromethanesulfonic acid, triethylamine and acetic anhydride are added. 8,9-dimethoxy-7-hydroxy-6-methyl-5-phenyl-2
,3,4,5-tetrahydro-1-benzoxepine-
2-one, followed by condensation with morpholine or thiomorpholine, and oxidation with manganese dioxide (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, X is A method for producing a 4-(3,4-dimethoxy-6-methyl-2,5-benzoquinonyl)-4-phenylbutyric acid amide derivative represented by (representing an oxygen atom or a sulfur atom).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63150019A JPH01319469A (en) | 1988-06-20 | 1988-06-20 | Production of 4-(3,4-dimethoxy-6-methyl-2,5-benzoquinonyl)-4-phenyllactic acid amide derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63150019A JPH01319469A (en) | 1988-06-20 | 1988-06-20 | Production of 4-(3,4-dimethoxy-6-methyl-2,5-benzoquinonyl)-4-phenyllactic acid amide derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01319469A true JPH01319469A (en) | 1989-12-25 |
Family
ID=15487711
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63150019A Pending JPH01319469A (en) | 1988-06-20 | 1988-06-20 | Production of 4-(3,4-dimethoxy-6-methyl-2,5-benzoquinonyl)-4-phenyllactic acid amide derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01319469A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2014516051A (en) * | 2011-05-26 | 2014-07-07 | インディアナ ユニバーシティー リサーチ アンド テクノロジー コーポレーション | Quinone compounds for treating APE1-mediated diseases |
-
1988
- 1988-06-20 JP JP63150019A patent/JPH01319469A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2014516051A (en) * | 2011-05-26 | 2014-07-07 | インディアナ ユニバーシティー リサーチ アンド テクノロジー コーポレーション | Quinone compounds for treating APE1-mediated diseases |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JPH0579055B2 (en) | ||
| US4748278A (en) | Process for the isolation of p-hydroxybenzaldehyde | |
| JPH01319469A (en) | Production of 4-(3,4-dimethoxy-6-methyl-2,5-benzoquinonyl)-4-phenyllactic acid amide derivative | |
| JPS63196573A (en) | Quinazolineacetic acid derivative | |
| JPH0826236B2 (en) | Method for producing azomethine or indoaniline dye | |
| US4080505A (en) | α-Chlorocarboxylic acids | |
| JPH0610158B2 (en) | Method for producing 3-fluorobenzoic acids | |
| US5130434A (en) | Preparation of 3-methylquinoline-8-carboxylic acid | |
| CN112898221A (en) | Preparation method and intermediate of benzoxazine diketone compound C | |
| JPS61152674A (en) | Production of dibenzo(b,e)oxepine derivative | |
| JPH03279343A (en) | Method for producing cyclic ketones | |
| JPS59163370A (en) | Preparation of 0-(aminomethyl)phenylacetic lactam | |
| SU592826A1 (en) | Method of preparing /3,4 | |
| JPS6139946B2 (en) | ||
| JPS6372676A (en) | Novel manufacture of quinoline-2,3-dicarboxylic acid | |
| JPS62481A (en) | Production method of nitrophthalides | |
| SU1703655A1 (en) | Method of 3-trifluoroacetylcamphorate dioxomolybdenum preparation | |
| JPH08119913A (en) | Production of p-dialkylaminocinnamaldehyde | |
| JPH01261355A (en) | Production of benzoic acid derivative | |
| JPH01175977A (en) | Method for optically resolving optically active gamma-lactone using clathrate compound of cholic acid | |
| JPS61100546A (en) | Production of alpha-aromatic group-substituted alkanoic acid | |
| JPH0812658A (en) | Production of sydnones | |
| JPH01254658A (en) | Novel pyrrolidinone and production thereof | |
| JPS6037112B2 (en) | Method for producing 2,3-dicyan-1,4-dithia-anthrahydroquinone or -anthraquinone | |
| JPS62267271A (en) | Manufacture of 4(5)-methyl-5(4)-thiomethylimidazole and acidaddition salt of same |