JPH07103115B2 - Method for crystallizing 2- (10,11-dihydro-10-oxodibenzo [b, f] thiepin-2-yl) propionic acid - Google Patents
Method for crystallizing 2- (10,11-dihydro-10-oxodibenzo [b, f] thiepin-2-yl) propionic acidInfo
- Publication number
- JPH07103115B2 JPH07103115B2 JP28726086A JP28726086A JPH07103115B2 JP H07103115 B2 JPH07103115 B2 JP H07103115B2 JP 28726086 A JP28726086 A JP 28726086A JP 28726086 A JP28726086 A JP 28726086A JP H07103115 B2 JPH07103115 B2 JP H07103115B2
- Authority
- JP
- Japan
- Prior art keywords
- oxodibenzo
- thiepin
- dihydro
- propionic acid
- crystallizing
- 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 - Fee Related
Links
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（Ｉ） で表わされる２−（10,11−ジヒドロ−10−オキソジベ
ンゾ［b,f］チエピン−２−イル）プロピオン酸の結晶
化方法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention has the general formula (I) And a crystallization method of 2- (10,11-dihydro-10-oxodibenzo [b, f] thiepin-2-yl) propionic acid represented by
上記、一般式（Ｉ）で表わされる化合物は、優れた抗炎
症作用並びに鎮痛作用を有し医薬品として有用であるこ
とが知られている。It is known that the compound represented by the general formula (I) has excellent anti-inflammatory action and analgesic action and is useful as a pharmaceutical.
従来、この化合物（Ｉ）を製造する方法としては、５−
（１−カルボキシエチル）−２−フェニルチオフェニル
酢酸をポリリン酸で閉環し化合物（Ｉ）を得る方法（特
開昭57-171991,57-106678）,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
オンアミドを加水分解する方法（特公昭61-7199）等が
知られている。Conventionally, as a method for producing this compound (I), 5-
Method for obtaining compound (I) by ring-closing (1-carboxyethyl) -2-phenylthiophenylacetic acid with polyphosphoric acid (JP-A-57-171991, 57-106678), 2- (10,11-dihydro-10)
A method of hydrolyzing -oxodibenzo [b, f] thiepin-2-yl) propionamide (Japanese Patent Publication No. 61-7199) and the like are known.
この化合物（Ｉ）は、溶媒が残りやすく単離の際、塩化
メチレン、ベンゼン、アルコール、エーテル、ヘキサン
等の有機溶媒から晶出させると溶媒が残留し、そのため
医薬品として使用するためには長時間、高温での乾燥工
程が必要であった。The solvent of this compound (I) is likely to remain, and during isolation, the solvent remains when crystallized from an organic solvent such as methylene chloride, benzene, alcohol, ether, hexane, etc. A high temperature drying process was required.
本発明者らは、かかる状況において残留溶媒が微量に存
在す２−（10,11−ジヒドロ−10−オキソジベンゾ［b,
f］チエピン−２−イル）プロピオン酸につき、その残
留有機溶媒を除去する工業的、経済的に有利な方法を見
出し本発明を完成した。The present inventors have found that 2- (10,11-dihydro-10-oxodibenzo [b,
f] Thiepin-2-yl) propionic acid was found to be an industrially and economically advantageous method for removing the residual organic solvent, and the present invention was completed.
即ち、本発明は、 一般式（Ｉ） で表される２−（10,11−ジヒドロ−10−オキソジベン
ゾ［b,f］チエピン−２−イル）プロピオン酸をアセト
ン−水系から再結晶することを特徴とする高純度の結晶
性２−（10,11−ジヒドロ−10−オキソジベンゾ［b,f］
チエピン−２−イル）プロピオン酸を得る方法に関す
る。That is, the present invention has the general formula (I) 2- (10,11-dihydro-10-oxodibenzo [b, f] thiepin-2-yl) propionic acid represented by the formula: highly pure crystalline 2- characterized by recrystallization from an acetone-water system (10,11-dihydro-10-oxodibenzo [b, f]
Thiepin-2-yl) propionic acid.
本発明方法では２−（10,11−ジヒドロ−10−オキソジ
ベンゾ［b,f］チエピン−２−イル）プロピオン酸とし
ては公知の方法で得られたものまたはそれを更にカラム
クロマトグラフィ、再結晶、アミン塩等により精製した
ものを用いてよい。In the method of the present invention, 2- (10,11-dihydro-10-oxodibenzo [b, f] thiepin-2-yl) propionic acid obtained by a known method or it is further subjected to column chromatography, recrystallization, Those purified with an amine salt or the like may be used.
次に、本発明方法を詳細に説明する。Next, the method of the present invention will be described in detail.
まず、化合物（Ｉ）をアセトンに溶解させる場合、使用
する量は特に制限はない。少ない場合は溶解に時間がか
かりまた加熱する必要がある。また多い場合は晶出させ
る時、多量の水が必要となるので効率が悪い。従って化
合物（Ｉ）１重量部に対してアセトン３〜10倍量（w/
v）好ましくは４〜８倍量使用することで室温で溶解で
きる。First, when the compound (I) is dissolved in acetone, the amount used is not particularly limited. When the amount is small, it takes time to dissolve and it is necessary to heat. In addition, when the amount is large, a large amount of water is required for crystallization, resulting in poor efficiency. Therefore, the amount of acetone is 3 to 10 times (w / w) relative to 1 part by weight of the compound (I).
v) It can be dissolved at room temperature by preferably using 4 to 8 times the amount.
溶けにくい場合、使用したアセトンの10％の水を加えて
溶解させるか、濾過等により不溶物を除去する。If it is difficult to dissolve, add 10% water of the used acetone to dissolve it, or remove insoluble matter by filtration.
得られた溶液に、使用したアセトンに対し50〜60％の水
を加え、望ましくは化合物（Ｉ）の核を接種した後、激
しく撹拌しながらこの溶液に使用したアセトンに対し1.
4〜2.0倍量の水を滴下する。加える水の量はこれより多
くてもよいが通常1.4〜2.0倍量使用すれば、定量的に結
晶が得られる。To the resulting solution was added 50-60% water based on the acetone used, preferably inoculated with a core of compound (I), and then 1. with respect to the acetone used in this solution with vigorous stirring.
Add 4 to 2.0 times the amount of water dropwise. The amount of water to be added may be larger than this, but usually 1.4 to 2.0 times the amount of water is used to quantitatively obtain crystals.
滴下する際、初期は少量づつ滴下することが望ましい。
滴下終了後、撹拌を続け析出した結晶を濾取し、アセト
ン−水系で洗浄した後減圧下、乾燥、望ましくは60℃以
下で乾燥することにより、残留溶媒（アセトン）が従来
方法（塩化メチレン/n−ヘキサン系）に比べ有意に減少
したである結晶性２−（10,11−ジヒドロ−10−オキソ
ジベンゾ［b,f］チエピン−２−イル）プロピオン酸を
得ることができる。When dropping, it is desirable to add little by little at the beginning.
After completion of the dropwise addition, the precipitated crystals were collected by filtration, washed with an acetone-water system, and then dried under reduced pressure, preferably at 60 ° C. or lower, whereby the residual solvent (acetone) was removed by a conventional method (methylene chloride / methylene chloride / methylene chloride). It is possible to obtain crystalline 2- (10,11-dihydro-10-oxodibenzo [b, f] thiepin-2-yl) propionic acid, which is significantly reduced compared to (n-hexane type).
次に、実施例を挙げて本発明を更に詳しく説明する。Next, the present invention will be described in more detail with reference to examples.
実施例 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100gを400mlのアセト
ンと40mlの水の混合溶媒に溶かした後、水188mlを加
え、次いで２−（10,11−ジヒドロ−10−オキソジベン
ゾ［b,f］チエピン−２−イル）プロピオン酸を接種す
る。次に激しく撹拌しながら水576mlを40分間かけて滴
下する。滴下終了後20分間撹拌を続け析出した結晶を濾
取したのち、減圧下60℃で乾燥して２−（10,11−ジヒ
ドロ−10−オキソジベンゾ［b,f］チエピン−２−イ
ル）プロピオン酸を白色結晶として得た。（定量的） ガスクロマトグラフィ（カラム;POLAPAK・QS,2mm×1m,
キャリヤー；N2 1kg/cm2，カラム温度;170℃，検出;FI
D）により残留溶媒（アセトン）が210ppmであることを
確認した。Example 2- (10,11-dihydro-10-oxodibenzo [b, f] thiepin-2-yl) propionic acid 100 g was dissolved in a mixed solvent of 400 ml of acetone and 40 ml of water, and then 188 ml of water was added, It is then inoculated with 2- (10,11-dihydro-10-oxodibenzo [b, f] thiepin-2-yl) propionic acid. Then 576 ml of water are added dropwise over 40 minutes with vigorous stirring. After completion of the dropwise addition, stirring was continued for 20 minutes, and the precipitated crystals were collected by filtration, dried under reduced pressure at 60 ° C., and 2- (10,11-dihydro-10-oxodibenzo [b, f] thiepin-2-yl) propion. The acid was obtained as white crystals. (Quantitative) Gas chromatography (column; POLAPAK ・ QS, 2mm × 1m,
Carrier; N 2 1kg / cm 2 , Column temperature; 170 ℃, Detection; FI
It was confirmed from D) that the residual solvent (acetone) was 210 ppm.
参考例 従来方法（塩化メチレン/n−ヘキサン）で再結晶 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7gを塩化メチレン30ml
に溶解し、これを21mlまでエバポレートした後、ｎ−ヘ
キサン14ccを加え、室温で２時間攪拌した後、結晶6.32
g（収率90％）を得、これを60℃で24時間減圧乾燥する
ことで、２−（10,11−ジヒドロ−10−オキソジベンゾ
［b,f］チエピン−２−イル）プロピオン酸の結晶を得
た。Reference example Recrystallization by conventional method (methylene chloride / n-hexane) 2- (10,11-dihydro-10-oxodibenzo [b, f] thiepin-2-yl) propionic acid 7g methylene chloride 30ml
It was then dissolved in and evaporated to 21 ml, 14 cc of n-hexane was added, and the mixture was stirred at room temperature for 2 hours, then crystal 6.32
g (yield 90%) was obtained and dried under reduced pressure at 60 ° C. for 24 hours to give 2- (10,11-dihydro-10-oxodibenzo [b, f] thiepin-2-yl) propionic acid. Crystals were obtained.
上記の実施例と同様にガスクロマトグラフィにより、残
留溶媒量を測定すると塩化メチレン1980ppm、ｎ−ヘキ
サン2020ppmであった。When the amount of residual solvent was measured by gas chromatography in the same manner as in the above-mentioned examples, it was 1980 ppm of methylene chloride and 2020 ppm of n-hexane.
Claims (1)
ンゾ［b,f］チエピン−２−イル）プロピオン酸をアセ
トン−水系から再結晶することを特徴とする、高純度の
結晶性２−（10,11−ジヒドロ−10−オキソジベンゾ
［b,f］チエピン−２−イル）プロピオン酸を得る方
法。1. A general formula (I) 2- (10,11-dihydro-10-oxodibenzo [b, f] thiepin-2-yl) propionic acid represented by the following formula: highly pure crystalline 2- A method of obtaining (10,11-dihydro-10-oxodibenzo [b, f] thiepin-2-yl) propionic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP28726086A JPH07103115B2 (en) | 1986-12-02 | 1986-12-02 | Method for crystallizing 2- (10,11-dihydro-10-oxodibenzo [b, f] thiepin-2-yl) propionic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP28726086A JPH07103115B2 (en) | 1986-12-02 | 1986-12-02 | Method for crystallizing 2- (10,11-dihydro-10-oxodibenzo [b, f] thiepin-2-yl) propionic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS63139181A JPS63139181A (en) | 1988-06-10 |
| JPH07103115B2 true JPH07103115B2 (en) | 1995-11-08 |
Family
ID=17715097
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP28726086A Expired - Fee Related JPH07103115B2 (en) | 1986-12-02 | 1986-12-02 | Method for crystallizing 2- (10,11-dihydro-10-oxodibenzo [b, f] thiepin-2-yl) propionic acid |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH07103115B2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6107502A (en) * | 1997-10-13 | 2000-08-22 | Sumitomo Chemical Company, Limited | Method for purifying transition metal compound and method for producing the same |
-
1986
- 1986-12-02 JP JP28726086A patent/JPH07103115B2/en not_active Expired - Fee Related
Non-Patent Citations (1)
| Title |
|---|
| 丸善株式会社フィーザー有機化学実験第３版（１９７４）Ｐ．２９−３２ |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS63139181A (en) | 1988-06-10 |
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