JPH0533705B2 - - Google Patents
Info
- Publication number
- JPH0533705B2 JPH0533705B2 JP6910685A JP6910685A JPH0533705B2 JP H0533705 B2 JPH0533705 B2 JP H0533705B2 JP 6910685 A JP6910685 A JP 6910685A JP 6910685 A JP6910685 A JP 6910685A JP H0533705 B2 JPH0533705 B2 JP H0533705B2
- Authority
- JP
- Japan
- Prior art keywords
- cis
- methoxyphenyl
- compound
- water
- hydroxy
- 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 - Lifetime
Links
- 150000001875 compounds Chemical class 0.000 claims description 15
- 238000004519 manufacturing process Methods 0.000 claims description 4
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 3
- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 10
- 238000000034 method Methods 0.000 description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
- FEDJGPQLLNQAIY-UHFFFAOYSA-N 2-[(6-oxo-1h-pyridazin-3-yl)oxy]acetic acid Chemical compound OC(=O)COC=1C=CC(=O)NN=1 FEDJGPQLLNQAIY-UHFFFAOYSA-N 0.000 description 8
- 229960005316 diltiazem hydrochloride Drugs 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- 230000003287 optical effect Effects 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- -1 2-(methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one Chemical compound 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 206010002383 Angina Pectoris Diseases 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000006317 isomerization reaction Methods 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- NWOKCZSWYWTEGI-UHFFFAOYSA-N 2-(2-aminophenyl)sulfanylpropanoic acid Chemical compound OC(=O)C(C)SC1=CC=CC=C1N NWOKCZSWYWTEGI-UHFFFAOYSA-N 0.000 description 1
- OZQRVBYRWDEPAH-UHFFFAOYSA-N 2-(4-methoxyphenyl)-3-(2-nitrophenyl)sulfanylpropanoic acid Chemical compound COC1=CC=C(C=C1)C(C(=O)O)CSC1=C(C=CC=C1)[N+](=O)[O-] OZQRVBYRWDEPAH-UHFFFAOYSA-N 0.000 description 1
- DMEZIFVEDUYMCC-UHFFFAOYSA-N 2-hydroxy-3,5-dihydro-2H-1,5-benzothiazepin-4-one Chemical compound OC1SC2=C(NC(C1)=O)C=CC=C2 DMEZIFVEDUYMCC-UHFFFAOYSA-N 0.000 description 1
- GYDKDGGNLDFOIP-UHFFFAOYSA-N 3-(2-aminophenyl)sulfanyl-3-(4-methoxyphenyl)propanoic acid Chemical compound C1=CC(OC)=CC=C1C(CC(O)=O)SC1=CC=CC=C1N GYDKDGGNLDFOIP-UHFFFAOYSA-N 0.000 description 1
- UWSSBBSHFIAOPM-UHFFFAOYSA-N 4-[2-(dimethylamino)ethyl]-2-[(4-methoxyphenyl)methylidene]-1,4-benzothiazin-3-one Chemical compound C1=CC(OC)=CC=C1C=C1C(=O)N(CCN(C)C)C2=CC=CC=C2S1 UWSSBBSHFIAOPM-UHFFFAOYSA-N 0.000 description 1
- GTFMIJNXNMDHAB-UHFFFAOYSA-N 4h-1,4-benzothiazin-3-one Chemical compound C1=CC=C2NC(=O)CSC2=C1 GTFMIJNXNMDHAB-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- DASJFYAPNPUBGG-UHFFFAOYSA-N naphthalene-1-sulfonyl chloride Chemical compound C1=CC=C2C(S(=O)(=O)Cl)=CC=CC2=C1 DASJFYAPNPUBGG-UHFFFAOYSA-N 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 235000019260 propionic acid Nutrition 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
- 238000007363 ring formation reaction Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Description
【発明の詳細な説明】
本発明は、一般式〔〕
（式中、Ｒは水素、低級アルキル又は２−ジメ
チルアミノエチル基を示す）
で表される２−（４−メトキシフエニルメチリデ
ン）−2H−１，４−ベンゾチアジン−３（4H）−
オン及びそのＮ−置換体の製造方法に関するもの
である。[Detailed Description of the Invention] The present invention relates to the general formula [] (wherein, R represents hydrogen, lower alkyl or 2-dimethylaminoethyl group) 2-(4-methoxyphenylmethylidene)-2H-1,4-benzothiazine-3(4H)-
The present invention relates to a method for producing on and its N-substituted product.
現在、血管拡張剤として労作性狭心症、陳旧性
心筋梗塞における狭心痛の改善に繁用されている
塩酸ジルチアゼムは、式〔〕
で示される光学活性体のうち、シス−ｄ体みが有
用である。従つて、塩酸ジルチアゼムの製造にあ
たつては、光学活性原料からの不斉合成を行う
か、合成過程のどこかで光学分割を行う必要があ
る。前者の方法として、例えば特開昭59−196863
号が知られているが、合成には高価な試薬と多段
階の反応操作を必要とし、到底実用的とは言いが
たい。又、後者の方法のうち、光学分割について
は幾つかの方法が知られているが、光学分割で副
生するシス−ｌ体を異性化して再利用する方法に
ついては全く知られていない。本発明者らは、一
般式〔〕
（式中、Ｒは前記と同じ）
で表される２−（メトキシフエニル）−３−ヒドロ
キシ−２，３−ジヒドロ−１，５−ベンゾチアゼ
ピン−４（5H）−オン及びそのＮ−置換体のシス
−ｌ体を化合物〔〕に誘導することを基本とす
る異性化反応を行わせて化合物〔〕のシス−dl
体に変換し、再び塩酸ジルチアゼムの合成中間体
に供する方法を見出し、本発明を完成したもので
ある。本発明により、塩酸ジルチアゼムを安価に
製造できるだけでなく、貴重な資源を大量に廃棄
することなく生産を行える点で、工業的に極めて
有用である。 Currently, diltiazem hydrochloride, which is frequently used as a vasodilator to improve exertional angina and anginal pain in old myocardial infarction, has the formula [] Among the optically active forms represented by, only the cis-d form is useful. Therefore, in producing diltiazem hydrochloride, it is necessary to carry out asymmetric synthesis from optically active raw materials or to carry out optical resolution somewhere in the synthesis process. As the former method, for example,
However, the synthesis requires expensive reagents and multi-step reaction operations, making it far from practical. Among the latter methods, although several methods are known for optical resolution, there is no known method for isomerizing and reusing the cis-l form produced as a by-product in optical resolution. The inventors have proposed the general formula [] (wherein R is the same as above) 2-(methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and its N- The cis-dl of the compound [] is obtained by conducting an isomerization reaction that basically derives the cis-l form of the substituent into the compound [].
The present invention was completed by discovering a method for converting the diltiazem hydrochloride into an intermediate for the synthesis of diltiazem hydrochloride. The present invention is extremely useful industrially because not only can diltiazem hydrochloride be produced at low cost, but also production can be done without disposing of large amounts of valuable resources.
７員環化合物〔〕（Ｒ＝Ｈ）をピリジン−
SOCi2中で処理すると、14％の収率で６員環化合
物〔〕を与えることは既知である〔H.
Kugita.、H.Inoue.、M.Ikezaki、S.Takeo.、
Chem.PHarm.Bull.、18、2028（1970）〕が実用性
に乏しい。本発明者らは、化合物〔〕を有機ス
ルホン酸クロリドと処理することにより化合物
〔〕を高収率で与えることを見出したものであ
る。有機スルホン酸クロリドとしては、ベンゼン
スルホニルクロリドやナフタレンスルホニルクロ
リド等が挙げられるが、工業的にも入手し易く安
価なトシルクロリド（ｐ−トルエンスルホニルク
ロリド）を用いることにより、最も好適に目的を
達することができる。この反応は、化合物〔〕
の２−ヒドロキシ基の有機スルホン酸エステルを
経由して進行するものであつて、実施例に示すよ
うに中間体を単離することもできる。 7-membered ring compound [] (R=H) with pyridine-
It is known that treatment in SOCi 2 gives a 6-membered ring compound in 14% yield [H.
Kugita., H. Inoue., M. Ikezaki, S. Takeo.
Chem.PHarm.Bull., 18, 2028 (1970)] is of little practical use. The present inventors have discovered that compound [] can be obtained in high yield by treating compound [] with an organic sulfonic acid chloride. Examples of the organic sulfonic acid chloride include benzenesulfonyl chloride and naphthalenesulfonyl chloride, but the purpose can be achieved most preferably by using tosyl chloride (p-toluenesulfonyl chloride), which is industrially easily available and inexpensive. I can do it. This reaction is carried out with the compound []
The intermediate can also be isolated as shown in the examples.
この様にして得られる６員環化合物〔〕は、
過酸化水素で処理した後、水素化ホウ素ナトリウ
ムで還元すると、選択的に化合物〔〕のシス−
dl体を与えることは既知である（特公昭59−
20273号）。殊に化合物〔〕のＮ−未置換体（Ｒ
＝Ｈ）については従来の知見がないが、Ｎ−置換
体の場合より一層容易に同様の反応が進行するこ
とが分かつた。 The 6-membered ring compound [] obtained in this way is
After treatment with hydrogen peroxide, reduction with sodium borohydride selectively reduces the cis-
It is known that it gives the dl form (Special Publication No. 1983-
No. 20273). In particular, the N-unsubstituted product (R
Although there is no prior knowledge regarding =H), it has been found that a similar reaction proceeds more easily than in the case of N-substituted products.
本発明の原料であるｌ−シス−２−（４−メト
キシフエニル）−３−ヒドロキシ−２，３−ジヒ
ドロ−１，５−ベンゾチアゼピン−４（5H）−オ
ン〔〕は、光学分割をシス−２−ヒドロキシ−
３−（４−メトキシフエニル）−３−（２−アミノ
フエニルチオ）プロピオン酸の段階で行つた場合
（特願昭59−97606号及び特開昭59−231065号）、
特公昭53−18038号（キシレン中、水を除去しな
がら加熱する方法）他に従つて得ることができ
る。又、光学分割をシス−２−ヒドロキシ−３−
（４−メトキシフエニル）−３−（２−ニトロフエ
ニルチオ）プロピオン酸で行つた場合（特公昭49
−27576号及び特公昭53−18038号）も、ニトロ基
を還元して上記シス−２−ヒドロキシ−３−（４
−メトキシフエニル）−３−（２−アミノフエニル
チオ）プロピオン酸に誘導した後、同様に閉環反
応に付して式〔〕の化合物を得ることができ
る。更にこのものは、他の塩酸ジルチアゼム合成
中間体であるシス−２−（４−メトキシフエニル）
−３−アセチルオキシ−２，３−ジヒドロ−１，
５−ベンゾチアゼピン−４（5H）−オンを稀アル
カリ水溶液と処理することにより得ることができ
る。 l-cis-2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one [], which is a raw material of the present invention, can be optically resolved. cis-2-hydroxy-
When carried out at the stage of 3-(4-methoxyphenyl)-3-(2-aminophenylthio)propionic acid (Japanese Patent Application No. 59-97606 and JP-A No. 59-231065),
It can be obtained according to Japanese Patent Publication No. 53-18038 (method of heating in xylene while removing water) and others. In addition, optical resolution was performed using cis-2-hydroxy-3-
When carried out with (4-methoxyphenyl)-3-(2-nitrophenylthio)propionic acid (Japanese Patent Publication No. 49
-27576 and Japanese Patent Publication No. 53-18038), the above cis-2-hydroxy-3-(4
-methoxyphenyl)-3-(2-aminophenylthio)propionic acid, and then subjected to a ring-closing reaction in the same manner to obtain a compound of formula []. Furthermore, this compound is a synthetic intermediate for diltiazem hydrochloride, cis-2-(4-methoxyphenyl).
-3-acetyloxy-2,3-dihydro-1,
It can be obtained by treating 5-benzothiazepin-4(5H)-one with a dilute aqueous alkaline solution.
一方、異性化後の化合物〔〕はアルコール性
アルカリと処理することにより、容易に上記２−
ヒドロキシ−３−（４−メトキシフエニル）−３−
（２−アミノフエニルチオ）プロピオン酸に戻し
て光学分割に付することができ（参考例参照）、
又、２−（４−メトキシフエニル）−３−アセトキ
シ−５−（２−ジメチルアミノエチル）−２，３−
ジヒドロ−１，５−ベンゾチアゼピン−４（5H）
−オンに誘導してから光学分割（例えば特開昭58
−32872号又は特開昭59−20273号）して、所望す
る塩酸ジルチアゼムを得ることができる。 On the other hand, the compound [] after isomerization can be easily treated with an alcoholic alkali to facilitate the above 2-
Hydroxy-3-(4-methoxyphenyl)-3-
It can be converted back to (2-aminophenylthio)propionic acid and subjected to optical resolution (see reference example).
Also, 2-(4-methoxyphenyl)-3-acetoxy-5-(2-dimethylaminoethyl)-2,3-
Dihydro-1,5-benzothiazepine-4 (5H)
− Optical splitting after inducing the ON state (for example,
-32872 or JP-A-59-20273) to obtain the desired diltiazem hydrochloride.
以上のように、不斉炭素２個を持つ化合物
〔〕のシス−ｌ体を、短い工程と簡単な操作に
より、シス構造を保持したままdl体に変換できる
本発明の方法は、工業的な塩酸ジルチアゼム製造
に益すること大であり、本工程を繰り返すことに
より、実質的にシス−dl体のすべてをシス−ｄ体
に変換を可能とするものである。又、所望によ
り、シス−dl体をシス−ｌ体に変換することも、
化学的に何等の変更を加える必要がなく、本発明
の範囲において実施可能である。 As described above, the method of the present invention is capable of converting the cis-l form of a compound with two asymmetric carbon atoms into the dl form while retaining the cis structure through short steps and simple operations. This is greatly beneficial to the production of diltiazem hydrochloride, and by repeating this step, substantially all of the cis-dl form can be converted to the cis-d form. Also, if desired, the cis-dl form can be converted to the cis-l form,
It is possible to implement the method within the scope of the present invention without making any chemical changes.
以下に実例を挙げて、本反応を更に詳しく説明
する。 This reaction will be explained in more detail by giving examples below.
実施例 １
ｌ−シス−２−（４−メトキシフエニル）−３−
ヒドロキシ−２，３−ジヒドロ−１，５−ベンゾ
チアゼピン−４（5H）−オン6.04ｇ、ピリジン20
mlの混合液に５℃でｐ−トルエンスルホニルクロ
リド5.7ｇを含むピリジン15ml溶液を30分を要し
て滴下した。一夜放置後75℃で1.5時間加熱撹拌
し、水0.71に注ぎ室温下２時間撹拌後、析出結晶
をろ取、乾燥し、２−（４−メトキシフエニルメ
チリデン）−2H−１，４−ベンゾチアジン−３
（4H）−オンの淡黄色針状晶3.75ｇを得た。Example 1 l-cis-2-(4-methoxyphenyl)-3-
Hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one 6.04 g, pyridine 20
15 ml of a pyridine solution containing 5.7 g of p-toluenesulfonyl chloride was added dropwise to the 15 ml mixture at 5° C. over 30 minutes. After standing overnight, the mixture was heated and stirred at 75°C for 1.5 hours, poured into 0.71% water, and stirred at room temperature for 2 hours. The precipitated crystals were collected by filtration and dried. Benzothiazine-3
3.75 g of pale yellow needle crystals of (4H)-one were obtained.
m.p.205〜208℃
IR（KBr）3200、1655cm-1
NMR（d6−DMSO，ppm）3.85（ｓ，3H）、
7.00〜7.08（8H）、7.80（ｓ，1H）
実施例 ２
ｌ−シス−２−（４−メトキシフエニル）−３−
ヒドロキシ−５−（２−ジメチルアミノエチル）−
２，３−ジヒドロ−１，５−ベンゾチアゼピン−
４（5H）−オン1.1ｇをピリジン1.5mlに溶解し、氷
冷下ピリジン1.5ml及びｐ−トルエンスルホニル
クロリド0.64ｇの溶液を加え、氷冷下３時間、室
温下２時間撹拌した。次いで、水10mlを加え30分
間撹拌し、酢酸エチルを加え、水洗、乾燥し、濃
縮した。次に、ピリジン６mlを加え、100℃で20
時間加熱し、酢酸エチルを加え、水洗、乾燥、濃
縮後、ベンゼンを加え、残つたピリジンを留去し
た。この操作を、ピリジン臭が消失するまで繰り
返した。これをカラムクロマトにて精製し、２−
（４−メトキシフエニルメチリデン）−４（２−ジ
メチルアミノエチル）−2H−１，４−ベンゾチア
ジン−３（4H）−オンの淡黄色針状晶660mgを得
た。 mp205~208℃ IR (KBr) 3200, 1655cm -1 NMR (d 6 -DMSO, ppm) 3.85 (s, 3H),
7.00-7.08 (8H), 7.80 (s, 1H) Example 2 l-cis-2-(4-methoxyphenyl)-3-
Hydroxy-5-(2-dimethylaminoethyl)-
2,3-dihydro-1,5-benzothiazepine-
1.1 g of 4(5H)-one was dissolved in 1.5 ml of pyridine, and a solution of 1.5 ml of pyridine and 0.64 g of p-toluenesulfonyl chloride was added under ice cooling, followed by stirring for 3 hours under ice cooling and 2 hours at room temperature. Next, 10 ml of water was added, stirred for 30 minutes, ethyl acetate was added, washed with water, dried, and concentrated. Next, add 6 ml of pyridine and heat at 100℃ for 20 minutes.
After heating for an hour, ethyl acetate was added, washed with water, dried, and concentrated, benzene was added and the remaining pyridine was distilled off. This operation was repeated until the pyridine odor disappeared. This was purified by column chromatography, and 2-
660 mg of light yellow needles of (4-methoxyphenylmethylidene)-4(2-dimethylaminoethyl)-2H-1,4-benzothiazin-3(4H)-one were obtained.
m.p.102〜104℃
IR（KBr）1635cm-1
NMR（CDCl3，ppm）2.38（ｓ，6H）、2.70
（ｔ，2H）、3.85（ｓ，3H）、4.22（ｔ，2H）、
6.95〜7.70（8H）、7.82（ｓ，1H）
実施例 ３
ｌ−シス−２−（４−メトキシフエニル）−３−
ヒドロキシ−５−メチル−２，３−ジヒドロ−
１，５−ベンゾチアゼピン−４（5H）−オン2.29
ｇをピリジン20mlに溶解し、ｐ−トルエンスルホ
ニルクロリド2.9ｇを加え、一夜撹拌した。次い
で、水を加え、クロロホルム抽出し、希塩酸、炭
酸水素ナトリウム水溶液、水で順次洗浄後、硫酸
マグネシウムで乾燥、濃縮乾固し、ｌ−シス−２
−（４−メトキシフエニル）−３−ｐ−トルエンス
ルホニルオキシ−５−メチル−２，３−ジヒドロ
−１，５−ベンゾチアゼピン−４（5H）−オン3.0
ｇを得た。 mp102~104℃ IR (KBr) 1635cm -1 NMR (CDCl 3 , ppm) 2.38 (s, 6H), 2.70
(t, 2H), 3.85 (s, 3H), 4.22 (t, 2H),
6.95-7.70 (8H), 7.82 (s, 1H) Example 3 l-cis-2-(4-methoxyphenyl)-3-
Hydroxy-5-methyl-2,3-dihydro-
1,5-benzothiazepine-4(5H)-one 2.29
g was dissolved in 20 ml of pyridine, 2.9 g of p-toluenesulfonyl chloride was added, and the mixture was stirred overnight. Next, water was added, extracted with chloroform, washed sequentially with dilute hydrochloric acid, aqueous sodium bicarbonate solution, and water, dried over magnesium sulfate, concentrated to dryness, and l-cis-2
-(4-methoxyphenyl)-3-p-toluenesulfonyloxy-5-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one 3.0
I got g.
m.p.148〜150℃
IR（KBr）1170、1685cm-1
NMR（CDCl3，ppm）2.48（ｓ，3H）、3.40
（ｓ，3H）、3.88（ｓ，3H）、5.12（ｄ，Ｊ＝７
Hz，1H）、5.24（ｄ，Ｊ＝７Hz、1H）、6.80〜
7.80（8H）
上記で得た化合物1.8ｇをピリジン10mlに溶解
し、100℃で15時間加熱撹拌した。この反応液に
酢酸エチルを加え、水、希塩酸、水で順次洗浄
後、硫酸マグネシウムで乾燥し、濃縮、カラムク
ロマトにて精製し、２−（４−メトキシフエニル
メチリデン）−４−メチル−2H−１，４−ベンゾ
チアジン−３（4H）−オン0.97ｇを得た。 mp148~150℃ IR (KBr) 1170, 1685cm -1 NMR (CDCl 3 , ppm) 2.48 (s, 3H), 3.40
(s, 3H), 3.88 (s, 3H), 5.12 (d, J=7
Hz, 1H), 5.24 (d, J=7Hz, 1H), 6.80~
7.80 (8H) 1.8 g of the compound obtained above was dissolved in 10 ml of pyridine, and the mixture was heated and stirred at 100° C. for 15 hours. Ethyl acetate was added to this reaction solution, washed sequentially with water, diluted hydrochloric acid, and water, dried over magnesium sulfate, concentrated, and purified by column chromatography. 0.97 g of 2H-1,4-benzothiazin-3(4H)-one was obtained.
m.p.85〜90℃
IR（KBr）1650cm-1
NMR（CDCl3，ppm）3.55（ｓ，3H）、3.85
（ｓ，3H）、7.00〜7.70（8H）、7.85（ｓ，1H）
参考例 １
２−（４−メトキシフエニルメチリデン）−2H
−１，４−ベンゾチアジン−３（（4H）−オン0.14
ｇをTHF10mlに溶解し、30％過酸化水素0.1ml、
濃塩酸３滴を氷冷下加え、24時間室温放置した。
次いで水５mlを加え、２時間後アンモニア水でPH
7.0とし、水素化ホウ素ナトリウム過剰量加え、
20分後酢酸エチル抽出し、水洗乾燥後、濃縮し、
dl−シス−２−（４−メトキシフエニル）−３−ヒ
ドロキシ−２，３−ジヒドロ−１，５−ベンゾチ
アゼピン−４（5H）−オン0.1ｇを得た。 mp85~90℃ IR (KBr) 1650cm -1 NMR (CDCl 3 , ppm) 3.55 (s, 3H), 3.85
(s, 3H), 7.00-7.70 (8H), 7.85 (s, 1H) Reference example 1 2-(4-methoxyphenylmethylidene)-2H
-1,4-Benzothiazin-3((4H)-one 0.14
Dissolve g in 10ml of THF, add 0.1ml of 30% hydrogen peroxide,
Three drops of concentrated hydrochloric acid were added under ice cooling, and the mixture was left at room temperature for 24 hours.
Next, add 5 ml of water, and after 2 hours, adjust the pH with ammonia water.
7.0, add excess amount of sodium borohydride,
After 20 minutes, extract with ethyl acetate, wash with water, dry, and concentrate.
0.1 g of dl-cis-2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one was obtained.
m.p.166〜167℃（dl体） 本品は再結晶すればm.p.171〜172℃を示す。 m.p.166-167℃ (DL body) This product exhibits m.p. 171-172℃ when recrystallized.
IR（KBr）1670cm-1
NMR（CDCl3，ppm）2.00（ｄ，Ｊ＝９Hz，
1H）、3.80（ｓ，3H）、4.50（ABq，Ｊ＝７Hz，
９Hz，1H）、5.10（ｄ，Ｊ＝７Hz，1H）、6.90
〜7.70（8H）、8.54（ｓ，1H）
参考例 ２
２−（４−メトキシフエニルメチリデン）−2H
−１，４−ベンゾチアジン−３（（4H）−オン283
ｇをTHF20mlに溶解し、−10℃で30％過酸化水素
0.15ml及びトリメチルシリルクロリド0.38mlを加
え、室温で一夜放置した。次いで、水５mlを加え
２時間撹拌後、適量の水素化ホウ素ナトリウムを
加えた。30分後、酢酸エチル抽出し、水洗、乾燥
後、濃縮し、dl−シス−２−（４−メトキシフエ
ニル）−３−ヒドロキシ−２，３−ジヒドロ−１，
５−ベンゾチアゼピン−４（5H）−オン0.21ｇを
得た。 IR (KBr) 1670cm -1 NMR (CDCl 3 , ppm) 2.00 (d, J = 9Hz,
1H), 3.80 (s, 3H), 4.50 (ABq, J=7Hz,
9Hz, 1H), 5.10 (d, J=7Hz, 1H), 6.90
~7.70 (8H), 8.54 (s, 1H) Reference example 2 2-(4-methoxyphenylmethylidene)-2H
-1,4-Benzothiazin-3((4H)-one283
Dissolve g in 20ml of THF and add 30% hydrogen peroxide at -10℃.
0.15 ml and 0.38 ml of trimethylsilyl chloride were added and left at room temperature overnight. Next, 5 ml of water was added and after stirring for 2 hours, an appropriate amount of sodium borohydride was added. After 30 minutes, it was extracted with ethyl acetate, washed with water, dried, and concentrated to give dl-cis-2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,
0.21 g of 5-benzothiazepine-4(5H)-one was obtained.
参考例 ３
dl−シス−２−（４−メトキシフエニル）−３−
ヒドロキシ−２，３−ジヒドロ−１，５−ベンゾ
チアゼピン−４（5H）−オン0.9ｇ、水５ml、エタ
ノール５ml及び水酸化ナトリウム0.3ｇを混合し、
70℃で４時間加熱撹拌した。冷後、水50mlに注加
後、6N塩酸にてPH2.8とし、析出結晶をろ取、乾
燥し、dl−２−ヒドロキシ−３−（４−メトキシ
フエニル）−３−（２−アミノフエニルチオ）プロ
ピオン酸0.9ｇを得た。Reference example 3 dl-cis-2-(4-methoxyphenyl)-3-
Mix 0.9 g of hydroxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one, 5 ml of water, 5 ml of ethanol, and 0.3 g of sodium hydroxide,
The mixture was heated and stirred at 70°C for 4 hours. After cooling, the pH was adjusted to 2.8 with 6N hydrochloric acid, and the precipitated crystals were collected by filtration and dried to give dl-2-hydroxy-3-(4-methoxyphenyl)-3-(2-amino). 0.9 g of phenylthio)propionic acid was obtained.
Claims (1)
チルアミノエチル基を示す） で表される化合物〔〕のシス−ｌ体を、有機ス
ルホン酸クロリドと反応させることを特徴とす
る、一般式 （式中、Ｒは前記と同じ） で表される化合物〔〕の製造方法。[Claims] 1. General formula (In the formula, R represents hydrogen, lower alkyl or 2-dimethylaminoethyl group) A general formula characterized by reacting the cis-l form of the compound [] with an organic sulfonic acid chloride. (In the formula, R is the same as above.) A method for producing a compound [] represented by:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6910685A JPS61229874A (en) | 1985-04-03 | 1985-04-03 | Production of benzothiazine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6910685A JPS61229874A (en) | 1985-04-03 | 1985-04-03 | Production of benzothiazine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS61229874A JPS61229874A (en) | 1986-10-14 |
| JPH0533705B2 true JPH0533705B2 (en) | 1993-05-20 |
Family
ID=13393042
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP6910685A Granted JPS61229874A (en) | 1985-04-03 | 1985-04-03 | Production of benzothiazine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS61229874A (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2703564B2 (en) * | 1987-07-31 | 1998-01-26 | 田辺製薬株式会社 | 1,5-benzothiazepine derivatives |
| JPH0730058B2 (en) * | 1988-05-14 | 1995-04-05 | 参天製薬株式会社 | 3-oxo-1,4-benzothiazine derivative |
| US7049312B1 (en) * | 1999-06-03 | 2006-05-23 | Abbott Gmbh & Co. Kg | Benzothiazinone and benzoxazinone compounds |
| JP2014522396A (en) | 2011-05-27 | 2014-09-04 | テンプル・ユニバーシティ−オブ・ザ・コモンウェルス・システム・オブ・ハイアー・エデュケイション | Substituted 2-benzylidene-2H-benzo [b] [1,4] thiazin-3 (4H) -one, derivatives thereof and therapeutic use thereof |
-
1985
- 1985-04-03 JP JP6910685A patent/JPS61229874A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS61229874A (en) | 1986-10-14 |
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