JPH0129793B2 - - Google Patents
Info
- Publication number
- JPH0129793B2 JPH0129793B2 JP55181248A JP18124880A JPH0129793B2 JP H0129793 B2 JPH0129793 B2 JP H0129793B2 JP 55181248 A JP55181248 A JP 55181248A JP 18124880 A JP18124880 A JP 18124880A JP H0129793 B2 JPH0129793 B2 JP H0129793B2
- Authority
- JP
- Japan
- Prior art keywords
- general formula
- acid
- reaction
- derivative represented
- propionic acid
- 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
- 238000004519 manufacturing process Methods 0.000 claims description 14
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical group S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 13
- -1 dibenzothiepine propionic acid derivative Chemical class 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 8
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 150000001990 dicarboxylic acid derivatives Chemical class 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- MUXFZBHBYYYLTH-UHFFFAOYSA-N Zaltoprofen Chemical compound O=C1CC2=CC(C(C(O)=O)C)=CC=C2SC2=CC=CC=C21 MUXFZBHBYYYLTH-UHFFFAOYSA-N 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-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
- 125000003118 aryl group Chemical group 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- JMIYLNQBNSEKAO-UHFFFAOYSA-N 2-(2-phenylsulfanylphenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC=C1SC1=CC=CC=C1 JMIYLNQBNSEKAO-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- UTFSPWRTXCDUIJ-UHFFFAOYSA-N 3-fluoro-4-(trifluoromethoxy)phenol Chemical compound OC1=CC=C(OC(F)(F)F)C(F)=C1 UTFSPWRTXCDUIJ-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-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
- 239000003513 alkali Substances 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 229940111131 antiinflammatory and antirheumatic product propionic acid derivative Drugs 0.000 description 2
- SLUNEGLMXGHOLY-UHFFFAOYSA-N benzene;hexane Chemical compound CCCCCC.C1=CC=CC=C1 SLUNEGLMXGHOLY-UHFFFAOYSA-N 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 125000002560 nitrile group Chemical group 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000004325 thiepin-2-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C(*)S1 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- IDNUTZUTSRAEMZ-UHFFFAOYSA-N 2-[5-(1-cyanoethyl)-2-phenylsulfanylphenyl]acetic acid Chemical compound OC(=O)CC1=CC(C(C#N)C)=CC=C1SC1=CC=CC=C1 IDNUTZUTSRAEMZ-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- MNZMECMQTYGSOI-UHFFFAOYSA-N acetic acid;hydron;bromide Chemical compound Br.CC(O)=O MNZMECMQTYGSOI-UHFFFAOYSA-N 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000001760 anti-analgesic effect Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 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
- 229940113118 carrageenan Drugs 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- IPBVNPXQWQGGJP-UHFFFAOYSA-N phenyl acetate Chemical class CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Landscapes
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】
本発明は一般式（）
で表わされるジベンゾチエピンプロピオン酸誘導
体の製造法に関する。
一般式（）で表わされるジベンゾチエピンプ
ロピオン酸誘導体は、優れた抗炎症作用、鎮痛作
用を有することが知られている。例えばカラゲニ
ン浮腫法による抗炎症作用では、２−（10，11−
ジヒドロ−10−オキソジベンゾ〔ｂ，ｆ〕チエピ
ン−２−イル）−プロピオン酸は、インドメサシ
ンの２倍の効力を有し酢酸ライジング法による鎮
痛作用では、アスピリンの20倍もの効力を有す
る。また、ラツトにおける急性毒性値、LD50値
は、232mgであり安全性の高い有用な抗炎症剤と
して期待される。
従来、一般式（）のジベンゾチエピンプロピ
オン酸誘導体は、次に示される方法により製造さ
れてきた（特開昭55−53282）。
（式中、Ｒは低級アルキル基を示す。）
しかしながら、前記公知製造法は、収率および
工程数、さらには操作上、工業的に製造する場
合、かならずしも満足のゆくものではなかつた。
本発明者らは、一般式（）で表わされるジベ
ンゾチエピンプロピオン酸誘導体の新規な製造法
について鋭意検討した結果、工業的かつ経済的に
有利な製造法を見出し本発明を完成した。
従つて、本発明の目的は、一般式（）で表わ
されるジベンゾチエピンプロピオン酸誘導体の新
規な製造法を提供せんとするものである。
本発明の製造法は次の反応工程により示され
る。
すなわち、一般式（）のフエニル酢酸エステ
ル誘導体のニトリル基およびエステル基を加水分
解し、ジカルボン酸誘導体（）とした後、縮合
剤の存在下閉環せしめ一般式（）のジベンゾチ
エピンプロピオン酸誘導体が得られる。
本発明は、前記公知製法に比べ製造工程数を実
質的に一工程以上短縮したのみならず中間原料で
ある一般式（）の化合物を容易に単離精製する
ことが可能であり、一般式（）の化合物の純度
について従来ほど注意を払う必要がなく、また、
公知方法による化合物（）から化合物（）へ
の閉環反応にみられる低収率、さらには化合物
（）を加水分解反応に付した後得られる粗生成
物から化合物（）を単離精製するために必要で
あつたカラムクロマトグラフイー処理等工業的製
造において重大な問題点を、一般式（）のジカ
ルボン酸誘導体を閉環反応に付すことにより改善
した工業的かつ経済的に有利な製造法である。例
えば、本発明の実施例において、特に好ましい２
−（10，11−ジヒドロ−10−オキソジベンゾ〔ｂ，
ｆ〕チエピン−２−イル）プロピオン酸は、５−
（α−シアノ）エチル−２−フエニルチオフエニ
ル酢酸エステルを臭化水素酸−酢酸中加水分解し
て５−（α−カルボキシエチル）−２−フエニルチ
オフエニル酢酸とし、次に硫酸又はポリリン酸中
閉環反応に付した後得られる粗生成物を従来必要
であつたカラムクロマトグラフイーによる処理を
おこなうことなく再結晶により通算収率50％以上
で得られる。
即ち、本発明の製法により前記公知方法による
通算収率（約28％）を大巾に向上させることに成
功した。
ニトリル基およびエステル基の加水分解反応
は、水あるいは、アルコール類、たとえばメタノ
ール、エタノール等さらには、テトラヒドロフラ
ン、ジオキサン、ジメチルホルムアミド、酢酸な
ど一般に使用される有機溶媒を水との共存下に用
い塩酸、硫酸、臭化水素酸などの鉱酸あるいは水
酸化ナトリウム、水酸化カリウム等のアルカリ存
在下で反応させる。反応温度は特に限定されるも
のではないが、好ましくは室温から加熱還流の範
囲であり、反応時間は用いる溶媒、反応温度、さ
らには、酸あるいはアルカリの量によつて異なる
が、多くは、数時間で行うことが出来る。反応
後、溶媒抽出、次に溶媒留去等の通常の処理をお
こなえばよい。
尚、一般式（）の低級アルキル基としては、
メチル基、エチル基、プロピル基又はブチル基等
が挙げられる。
必要により再結晶して得られるジカルボン酸誘
導体（）の閉環反応に際し、使用される硫酸、
ポリリン酸あるいはポリリン酸エステル等の縮合
剤の量は、原料である一般式（）の化合物に対
して１〜30倍（重量）用いれば良い。反応温度は
室温から150℃で反応時間は0.5〜５時間が好まし
い。硫酸を用いる場合は、室温以下の反応温度で
も長時間反応させることにより、反応を完結させ
ることができる。反応後、反応物を水あるいは氷
水に加えるか、場合により水あるいは氷水を反応
物に加えてから有機溶媒により抽出した後、溶媒
を留去して目的物（）を得ることができる。必
要なら再結晶を行い容易に精製することが可能で
ある。
以下、実施例によつて本発明を説明する。
実施例 １
５−（α−カルボキシエチル）−２−フエニルチ
オフエニル酢酸
エチル５−（α−シアノエチル）−２−フエニル
チオフエニルアセート（）11.0ｇに酢酸55ml、
47％臭化水素酸55mlを順次加え、撹拌下に５時間
加熱還流する。反応物を減圧濃縮し、冷水を加え
酢酸エチルで抽出する。酢酸エチル層を飽和食塩
水で洗浄後、飽和炭酸水素ナトリウム溶液ととも
に振とうし、水層を分取する。水層は塩酸酸性と
したのち酢酸エチルで抽出する。酢酸エチル層は
飽和食塩水で洗浄後、無水硫酸マグネシウムで乾
燥した。酢酸エチルを減圧下で留去し、ほぼ無色
の結晶9.6ｇを得た。ベンゼン−ｎ−ヘキサンよ
り再結晶して融点143〜144.5℃の無色結晶として
５−（α−カルボキシエチル）−２−フエニルチオ
フエニル酢酸8.4ｇを得た（収率78.5％）。
IRνKBr naxcm-1：3400〜2400、1690（COOH）
NMR（DMSO−d6）δ：1.36（3H、ｄ、Ｊ＝７
Hz、＝CHCH3 ）3.70（3H、ｑ、Ｊ＝７Hz、＝Ｃ
ＨCH3＋−ＣH2 CO2H）
7.10〜7.50（8H、ｍ、芳香族プロトン）12.20
（2H、ｂ、−COOＨ×２）
実施例 ２
２−（10，11−ジヒドロ−10−オキソジベンゾ
〔ｂ，ｆ〕チエピン−２−イル）−プロピオン酸
５−（α−カルボキシエチル）−２−フエニルチ
オフエニル酢酸（）1.0ｇに濃硫酸10ｇを加え、
時々振とうして室温で１時間放置する。氷水を加
えクロロホルムで抽出した。クロロホルム層を飽
和食塩水で洗浄したのち、無水硫酸マグネシウム
で乾燥した。クロロホルムを減圧下に留去して得
られた残渣にエーテルを加えて結晶化させたのち
ベンゼン−ｎ−ヘキサンより再結晶して融点
130.5〜131.5℃の微黄色結晶として２−（10，11
−ジヒドロ−10−オキソジベンゾ〔ｂ，ｆ〕チエ
ピン−２−イル）プロピオン酸0.6ｇを得た（収
率63.6％）。
IRνKBr naxcm-1：1710、1675（CO）
NMR（CDC13）δ：1.46（3H、ｄ、Ｊ＝７Hz、＝
CHCH3 ）3.68（1H、ｑ、Ｊ＝７Hz、＝ＣＨ
CH3）4.29（2H、ｓ、−ＣH2 CO−）6.92〜7.64
（6H、ｍ、芳香族プロトン）8.07（1H、dd、Ｊ
＝８、２Hz、C9−Ｈ）10.02（1H、b.s、−COO
Ｈ）
MSm／ｅ：298（M+）
実施例 ３
２−（10，11−ジヒドロ−10−オキソジベンゾ
〔ｂ，ｆ〕チエピン−２−イル）−プロピオン酸
５−（α−カルボキシエチル）−２−フエニルチ
オフエニル酢酸（）1.0ｇにポリリン酸20.6ｇ
を加え、70℃で３時間、加熱、撹拌する。冷水を
加え、クロロホルムで抽出した。クロロホルム層
を飽和食塩水で洗浄したのち無水硫酸マグネシウ
ムで乾燥した。クロロホルムを減圧下に留去して
得られた残渣を放置し、結晶化させ、ベンゼン−
ｎ−ヘキサンより再結晶し、融点130.5〜131.5℃
の微黄色結晶として２−（10，11−ジヒドロ−10
−オキソジベンゾ〔ｂ，ｆ〕チエピン−２−イ
ル）−プロピオン酸0.8ｇを得た（収率84.8％）。
IRνKBr naxcm-1：1710、1675（CO）
NMR（CDC13）δ：1.46（3H、ｄ、Ｊ＝７Hz、＝
CHCH3 ）3.68（1H、ｑ、Ｊ＝７Hz、＝ＣＨ
CH3）4.29（2H、ｓ、−ＣH2 CO−）6.92〜7.64
（6H、ｍ、芳香族プロトン）8.07（1H、dd、Ｊ
＝８、２Hz、C9−Ｈ）10.02（1H、b.s、−COO
Ｈ）
MSm／ｅ：298（M+） [Detailed Description of the Invention] The present invention relates to the general formula () This invention relates to a method for producing a dibenzothiepine propionic acid derivative represented by: Dibenzothiepine propionic acid derivatives represented by the general formula () are known to have excellent anti-inflammatory and analgesic effects. For example, the anti-inflammatory effect of carrageenan edema method is 2-(10,11-
Dihydro-10-oxodibenzo[b,f]thiepin-2-yl)-propionic acid has twice the potency of indomethacin and is 20 times as potent as aspirin in analgesic action by the acetic acid writhing method. In addition, the acute toxicity value, LD 50 value in rats was 232 mg, and it is expected to be a highly safe and useful anti-inflammatory agent. Conventionally, dibenzothiepine propionic acid derivatives of the general formula () have been produced by the method shown below (Japanese Patent Application Laid-open No. 53282-1982). (In the formula, R represents a lower alkyl group.) However, the above-mentioned known production methods are not always satisfactory in terms of yield, number of steps, and operation when industrially produced. The present inventors have conducted extensive studies on a new method for producing a dibenzothiepine propionic acid derivative represented by the general formula (), and as a result, have found an industrially and economically advantageous production method and have completed the present invention. Therefore, an object of the present invention is to provide a novel method for producing a dibenzothiepine propionic acid derivative represented by the general formula (). The production method of the present invention is illustrated by the following reaction steps. That is, the nitrile group and ester group of the phenyl acetate derivative of the general formula () are hydrolyzed to form a dicarboxylic acid derivative (), and then the ring is closed in the presence of a condensing agent to obtain the dibenzothiepine propionic acid derivative of the general formula (). can get. The present invention not only substantially shortens the number of manufacturing steps by one step or more compared to the above-mentioned known manufacturing method, but also makes it possible to easily isolate and purify the compound of the general formula (), which is an intermediate raw material. ) does not require as much attention as before regarding the purity of the compound, and
In order to address the low yield observed in the ring-closing reaction of compound () to compound () by known methods, and to isolate and purify compound () from the crude product obtained after subjecting compound () to hydrolysis reaction. This is an industrially and economically advantageous production method that overcomes serious problems in industrial production, such as the necessary column chromatography treatment, by subjecting the dicarboxylic acid derivative of general formula () to a ring-closing reaction. For example, in the embodiments of the present invention, particularly preferred 2
-(10,11-dihydro-10-oxodibenzo[b,
f] Thiepin-2-yl)propionic acid is 5-
(α-cyano)ethyl-2-phenylthiophenylacetate was hydrolyzed in hydrobromic acid-acetic acid to give 5-(α-carboxyethyl)-2-phenylthiophenylacetic acid, and then sulfuric acid Alternatively, the crude product obtained after ring-closing reaction in polyphosphoric acid can be recrystallized in a total yield of 50% or more without the conventionally necessary column chromatography treatment. That is, the production method of the present invention succeeded in significantly improving the total yield (about 28%) obtained by the above-mentioned known method. The hydrolysis reaction of nitrile groups and ester groups can be carried out using water, alcohols such as methanol, ethanol, etc., and commonly used organic solvents such as tetrahydrofuran, dioxane, dimethylformamide, acetic acid, etc. in the coexistence of water, hydrochloric acid, The reaction is carried out in the presence of a mineral acid such as sulfuric acid or hydrobromic acid or an alkali such as sodium hydroxide or potassium hydroxide. The reaction temperature is not particularly limited, but is preferably in the range of room temperature to reflux, and the reaction time varies depending on the solvent used, the reaction temperature, and the amount of acid or alkali. It can be done in time. After the reaction, usual treatments such as solvent extraction and then solvent distillation may be performed. In addition, as the lower alkyl group in general formula (),
Examples include methyl group, ethyl group, propyl group, and butyl group. Sulfuric acid used in the ring-closing reaction of the dicarboxylic acid derivative () obtained by recrystallization if necessary,
The amount of the condensing agent such as polyphosphoric acid or polyphosphoric acid ester may be 1 to 30 times (by weight) the compound of the general formula () as a raw material. The reaction temperature is preferably from room temperature to 150°C and the reaction time is preferably 0.5 to 5 hours. When using sulfuric acid, the reaction can be completed by allowing the reaction to proceed for a long time even at a reaction temperature of room temperature or lower. After the reaction, the reaction product is added to water or ice water, or water or ice water is added to the reaction product as the case may be, and then extracted with an organic solvent, and the solvent is distilled off to obtain the desired product (). If necessary, it can be easily purified by recrystallization. The present invention will be explained below with reference to Examples. Example 1 5-(α-carboxyethyl)-2-phenylthiophenyl acetate To 11.0 g of ethyl 5-(α-cyanoethyl)-2-phenylthiophenyl acetate (), 55 ml of acetic acid,
Add 55 ml of 47% hydrobromic acid one after another, and heat under reflux for 5 hours while stirring. The reaction mixture was concentrated under reduced pressure, added with cold water, and extracted with ethyl acetate. After washing the ethyl acetate layer with saturated brine, it is shaken with saturated sodium bicarbonate solution and the aqueous layer is separated. The aqueous layer is acidified with hydrochloric acid and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure to obtain 9.6 g of almost colorless crystals. Recrystallization from benzene-n-hexane gave 8.4 g of 5-(α-carboxyethyl)-2-phenylthiophenyl acetic acid as colorless crystals with a melting point of 143 to 144.5°C (yield 78.5%). IRν KBr nax cm -1 : 3400-2400, 1690 (COOH) NMR (DMSO-d 6 ) δ: 1.36 (3H, d, J=7
Hz, =CHC H3 )3.70(3H,q,J=7Hz,=C
HCH3 + -CH2CO2H ) 7.10-7.50 ( 8H, m, aromatic proton) 12.20
(2H, b, -COO H x 2) Example 2 2-(10,11-dihydro-10-oxodibenzo[b,f]thiepin-2-yl)-propionic acid 5-(α-carboxyethyl)- Add 10 g of concentrated sulfuric acid to 1.0 g of 2-phenylthiophenyl acetic acid (),
Leave at room temperature for 1 hour, shaking occasionally. Ice water was added and extracted with chloroform. The chloroform layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The residue obtained by distilling off chloroform under reduced pressure was crystallized by adding ether, and then recrystallized from benzene-n-hexane to obtain the melting point.
2-(10,11
0.6 g of -dihydro-10-oxodibenzo[b,f]thiepin-2-yl)propionic acid was obtained (yield 63.6%). IRν KBr nax cm -1 : 1710, 1675 (CO) NMR (CDC1 3 ) δ: 1.46 (3H, d, J = 7Hz, =
CHC H 3 ) 3.68 (1H, q, J=7Hz, =C H
CH3 )4.29 (2H, s, -CH2CO- )6.92~7.64
(6H, m, aromatic proton) 8.07 (1H, dd, J
=8,2Hz,C9 - H)10.02(1H,bs,-COO
H) MSm/e: 298 (M + ) Example 3 2-(10,11-dihydro-10-oxodibenzo[b,f]thiepin-2-yl)-propionic acid 5-(α-carboxyethyl)- 20.6 g of polyphosphoric acid in 1.0 g of 2-phenylthiophenyl acetic acid ()
Add and heat and stir at 70°C for 3 hours. Cold water was added and extracted with chloroform. The chloroform layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The residue obtained by distilling off chloroform under reduced pressure was left to crystallize, and benzene-
Recrystallized from n-hexane, melting point 130.5-131.5℃
2-(10,11-dihydro-10
0.8 g of -oxodibenzo[b,f]thiepin-2-yl)-propionic acid was obtained (yield 84.8%). IRν KBr nax cm -1 : 1710, 1675 (CO) NMR (CDC1 3 ) δ: 1.46 (3H, d, J = 7Hz, =
CHC H 3 ) 3.68 (1H, q, J=7Hz, =C H
CH3 )4.29 (2H, s, -CH2CO- )6.92~7.64
(6H, m, aromatic proton) 8.07 (1H, dd, J
=8,2Hz,C9 - H)10.02(1H,bs,-COO
H) MSm/e: 298 (M + )
Claims (1)
下、閉環せしめることを特徴とする一般式（） で表わされるジベンゾチエピンプロピオン酸誘導
体の製造法。 ２ 縮合剤が硫酸、ポリリン酸またはポリリン酸
エステルであることを特徴とする特許請求の範囲
第１項記載の製造法。 ３ 一般式（） （式中、Ｒは低級アルキル基を示す。） で表わされる化合物を加水分解し、一般式（） で表わされるジカルボン酸誘導体とした後縮合剤
の存在下閉環せしめることを特徴とする一般式
（） で表わされるジベンゾチエピンプロピオン酸誘導
体の製造法。 ４ 縮合剤が硫酸、ポリリン酸またはポリリン酸
エステルであることを特徴とする特許請求の範囲
第３項記載の製造法。[Claims] 1 General formula () General formula () characterized by ring-closing a dicarboxylic acid derivative represented by in the presence of a condensing agent A method for producing a dibenzothiepine propionic acid derivative represented by 2. The manufacturing method according to claim 1, wherein the condensing agent is sulfuric acid, polyphosphoric acid, or polyphosphoric acid ester. 3 General formula () (In the formula, R represents a lower alkyl group.) By hydrolyzing the compound represented by the general formula () A general formula () characterized in that the dicarboxylic acid derivative represented by the formula () is prepared and then ring-closed in the presence of a condensing agent. A method for producing a dibenzothiepine propionic acid derivative represented by 4. The production method according to claim 3, wherein the condensing agent is sulfuric acid, polyphosphoric acid, or polyphosphoric acid ester.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP18124880A JPS57106678A (en) | 1980-12-23 | 1980-12-23 | Preparation of dibenzothiepinpropionic acid derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP18124880A JPS57106678A (en) | 1980-12-23 | 1980-12-23 | Preparation of dibenzothiepinpropionic acid derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS57106678A JPS57106678A (en) | 1982-07-02 |
| JPH0129793B2 true JPH0129793B2 (en) | 1989-06-14 |
Family
ID=16097378
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP18124880A Granted JPS57106678A (en) | 1980-12-23 | 1980-12-23 | Preparation of dibenzothiepinpropionic acid derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS57106678A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005247778A (en) * | 2004-03-05 | 2005-09-15 | Shigeji Maekawa | Method for producing dibenzothiepinpropionic acid derivative |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0309626B1 (en) * | 1987-09-30 | 1992-05-06 | Nippon Chemiphar Co., Ltd. | Process for the preparation of dibenzothiepin derivative |
| JP5937679B2 (en) | 2012-04-24 | 2016-06-22 | 日本ケミファ株式会社 | Method for producing zaltoprofen and derivatives thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5553282A (en) * | 1978-10-17 | 1980-04-18 | Nippon Chemiphar Co Ltd | Dibenzothiepin derivative and its preparation |
| JPS55153782A (en) * | 1979-05-17 | 1980-11-29 | Dainippon Pharmaceut Co Ltd | Dibenzo (b,f) thiepin derivative |
| JPS55164681A (en) * | 1979-06-01 | 1980-12-22 | Merck & Co Inc | Prostaglandin antagonist |
-
1980
- 1980-12-23 JP JP18124880A patent/JPS57106678A/en active Granted
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5553282A (en) * | 1978-10-17 | 1980-04-18 | Nippon Chemiphar Co Ltd | Dibenzothiepin derivative and its preparation |
| JPS55153782A (en) * | 1979-05-17 | 1980-11-29 | Dainippon Pharmaceut Co Ltd | Dibenzo (b,f) thiepin derivative |
| JPS55164681A (en) * | 1979-06-01 | 1980-12-22 | Merck & Co Inc | Prostaglandin antagonist |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005247778A (en) * | 2004-03-05 | 2005-09-15 | Shigeji Maekawa | Method for producing dibenzothiepinpropionic acid derivative |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS57106678A (en) | 1982-07-02 |
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