JPH0333713B2 - - Google Patents
Info
- Publication number
- JPH0333713B2 JPH0333713B2 JP9639382A JP9639382A JPH0333713B2 JP H0333713 B2 JPH0333713 B2 JP H0333713B2 JP 9639382 A JP9639382 A JP 9639382A JP 9639382 A JP9639382 A JP 9639382A JP H0333713 B2 JPH0333713 B2 JP H0333713B2
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- spectrum
- benzothiazepine
- benzothiazin
- methoxyphenyl
- 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
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 150000001875 compounds Chemical class 0.000 description 17
- 238000002329 infrared spectrum Methods 0.000 description 16
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- -1 ketoamide benzothiazepine derivative Chemical class 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- 238000000921 elemental analysis Methods 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 11
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 125000001309 chloro group Chemical group Cl* 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000005051 trimethylchlorosilane Substances 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 150000007657 benzothiazepines Chemical class 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 description 3
- AGIJRRREJXSQJR-UHFFFAOYSA-N 2h-thiazine Chemical group N1SC=CC=C1 AGIJRRREJXSQJR-UHFFFAOYSA-N 0.000 description 3
- XQIRIYJOVQEBDL-UHFFFAOYSA-N 4h-1,2-benzothiazin-3-one Chemical compound C1=CC=C2SNC(=O)CC2=C1 XQIRIYJOVQEBDL-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 3
- 229910001958 silver carbonate Inorganic materials 0.000 description 3
- 230000000304 vasodilatating effect Effects 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
- GTFMIJNXNMDHAB-UHFFFAOYSA-N 4h-1,4-benzothiazin-3-one Chemical compound C1=CC=C2NC(=O)CSC2=C1 GTFMIJNXNMDHAB-UHFFFAOYSA-N 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- ACKFDYCQCBEDNU-UHFFFAOYSA-J lead(2+);tetraacetate Chemical compound [Pb+2].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O ACKFDYCQCBEDNU-UHFFFAOYSA-J 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- SOLZKLRPOOXCFC-UHFFFAOYSA-N 2-(2-hydroxyethyl)-4h-1,4-benzothiazin-3-one Chemical compound C1=CC=C2NC(=O)C(CCO)SC2=C1 SOLZKLRPOOXCFC-UHFFFAOYSA-N 0.000 description 1
- BUPJWEJVHXHTFA-UHFFFAOYSA-N 2-benzylidene-4-methyl-1,4-benzothiazin-3-one Chemical compound S1C2=CC=CC=C2N(C)C(=O)C1=CC1=CC=CC=C1 BUPJWEJVHXHTFA-UHFFFAOYSA-N 0.000 description 1
- QAAPUFQFGYHNNV-UHFFFAOYSA-N 5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-1,5-benzothiazepine-3,4-dione Chemical compound C1=CC(OC)=CC=C1C1C(=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 QAAPUFQFGYHNNV-UHFFFAOYSA-N 0.000 description 1
- TWRLBZYUAXDKSW-UHFFFAOYSA-N 5H-1,2-benzothiazepine-3,4-dione Chemical compound S1NC(C(CC2=C1C=CC=C2)=O)=O TWRLBZYUAXDKSW-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 241000551547 Dione <red algae> Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- FAPDDOBMIUGHIN-UHFFFAOYSA-K antimony trichloride Chemical compound Cl[Sb](Cl)Cl FAPDDOBMIUGHIN-UHFFFAOYSA-K 0.000 description 1
- 229940085242 benzothiazepine derivative selective calcium channel blockers with direct cardiac effects Drugs 0.000 description 1
- DAMJCWMGELCIMI-UHFFFAOYSA-N benzyl n-(2-oxopyrrolidin-3-yl)carbamate Chemical compound C=1C=CC=CC=1COC(=O)NC1CCNC1=O DAMJCWMGELCIMI-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- JHXKRIRFYBPWGE-UHFFFAOYSA-K bismuth chloride Chemical compound Cl[Bi](Cl)Cl JHXKRIRFYBPWGE-UHFFFAOYSA-K 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000003218 coronary vasodilator agent Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Description
【発明の詳細な説明】
本発明は新規なベンゾチアゼピン誘導体であ
る。DETAILED DESCRIPTION OF THE INVENTION The present invention is a novel benzothiazepine derivative.
（式中、R1は水素、ハロゲンまたは低級アルコ
キシ基、R2は低級アルキル基、低級アルコキシ
アルキル基、水酸基もしくはハロゲンで置換され
た低級アルキル基、または低級ジアルキルアミノ
アルキル基を表わす）で示される２−フエニル
〔または２−（４−置換フエニル）〕−５−置換−
１，５−ベンゾチアゼピン−３，４（2H，5H）．
ジオンまたはその酸付加塩に関する。 (In the formula, R 1 represents hydrogen, halogen or a lower alkoxy group, R 2 represents a lower alkyl group, a lower alkoxyalkyl group, a hydroxyl group, a lower alkyl group substituted with a halogen, or a lower dialkylaminoalkyl group) 2-phenyl [or 2-(4-substituted phenyl)]-5-substituted-
1,5-benzothiazepine-3,4(2H,5H).
It relates to diones or acid addition salts thereof.
ベンゾチアゼピン誘導体の中には冠血管拡張作
用あるいは、中枢神経系等に対して作用するもの
が多く知られており医薬品として非常に興味ある
化合物である。 Many benzothiazepine derivatives are known to have coronary vasodilatory effects or actions on the central nervous system, and are therefore very interesting compounds as pharmaceuticals.
本願発明の新規化合物（）は従来のベンゾチ
アゼピン誘導体としては全く知られていなかつた
ケトアミド系のベンゾチアゼピン誘導体で、すぐ
れた薬理作用たとえば冠血管拡張作用、抗不整脈
作用、鎮痛作用および血小板凝集抑制作用等を有
し、医薬品として有用なものである。 The novel compound () of the present invention is a ketoamide benzothiazepine derivative that has not been known at all as a conventional benzothiazepine derivative, and has excellent pharmacological effects such as coronary vasodilatory effect, antiarrhythmic effect, analgesic effect, and platelet aggregation effect. It has inhibitory effects and is useful as a medicine.
また本発明の新規化合物（）は冠血管拡張剤
として労作性狭心症、陳旧性心筋梗塞における狭
心症の改善等の治療剤として知られているα−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）−シス−２，３−
ジヒドロ−１，５−ベンゾチアゼピン−４（5H）
オンの合成中間体としても有用な化合物である。 In addition, the novel compound () of the present invention is known as a coronary vasodilator and a therapeutic agent for exertion angina pectoris, angina pectoris caused by old myocardial infarction, etc.
-(4-methoxyphenyl)-3-acetoxy-5
-(2-dimethylaminoethyl)-cis-2,3-
Dihydro-1,5-benzothiazepine-4 (5H)
It is also a useful compound as an intermediate for the synthesis of ion.
本発明の新規目的化合物（）は、たとえば次
の合成経路により得られる。 The novel target compound () of the present invention can be obtained, for example, by the following synthetic route.
（式中、R1およびR2は前記と同義、Ｘはハロゲ
ンを表わす）
すなわち、２−フエニルメチレン〔または２−
〔（４−置換フエニル）メチレン〕〕−４−置換−
2H−１，４−ベンゾチアジン−３（4H）−オン
（）にトリメチルハロゲノシラン、過酸化水素
と水を作用させるとチアジン環がベンゾチアゼピ
ン環へ拡大して式（）の化合物が得られる。反
応は塩化メチレンのような非反応性溶媒中で、一
発に室温または冷却下に行われる。 (In the formula, R 1 and R 2 have the same meanings as above, and X represents a halogen.) That is, 2-phenylmethylene [or 2-
[(4-substituted phenyl)methylene]]-4-substituted-
When 2H-1,4-benzothiazin-3(4H)-one () is reacted with trimethylhalogenosilane, hydrogen peroxide, and water, the thiazine ring expands into a benzothiazepine ring, yielding a compound of formula (). The reaction is carried out in one shot at room temperature or under cooling in a non-reactive solvent such as methylene chloride.
また、化合物（）に、たとえば30％過酸化水
素水のような形で過酸化水素およびトリメチルハ
ロゲノシランを作用させて、先ず新規化合物であ
る２−（ハロゲノフエニルメチル）〔または２−
〔ハロゲノ（４−置換フエニル）メチル〕〕−２−
ヒドロキシ−４−置換−2H−１，４ベンゾチア
ジン−３（4H）−オン（）に導き、次いで、ア
セトン、テトラヒドロフラン、アセトニトリルま
たはこれ等の混合物のような溶媒中で塩化アンチ
モン、炭酸銀、塩化ビスマス等のような無機塩を
作用させるか、あるいは単に水を作用させるとチ
アジン環が拡大して式（）の新規な目的化合物
が得られる。反応は冷却または室温下に行われ
る。 In addition, by reacting hydrogen peroxide and trimethylhalogenosilane, for example, in a 30% hydrogen peroxide solution, with the compound (2), the new compound 2-(halogenophenylmethyl) [or 2-
[halogeno(4-substituted phenyl)methyl]]-2-
hydroxy-4-substituted-2H-1,4benzothiazin-3(4H)-one () and then treated with antimony chloride, silver carbonate, bismuth chloride in a solvent such as acetone, tetrahydrofuran, acetonitrile or mixtures thereof. When treated with an inorganic salt such as or simply with water, the thiazine ring expands and a novel target compound of formula () is obtained. The reaction is carried out with cooling or at room temperature.
化合物（）はまた、次の合成経路によつても
得ることができる。 Compound () can also be obtained by the following synthetic route.
（式中、R1およびR2は前記と同義）
すなわち、化合物（）に氷酢酸やベンゼンの
ような溶媒中で四酢酸鉛を作用せると新規化合物
２−（アセトキシフエニルメチル）〔または２−
〔アセトキシ（４−置換フエニル）メチル〕〕−２
−アセトキシ−４−置換−2H−１，４ベンゾチ
アジン−３（4H）−オン（）が得られる。次い
でこの化合物をたとえば水酸化アルカリを用いて
加水分解すると新規化合物２−（ヒドロキシフエ
ニルメチル〔または、２−〔ヒドロキシ（４−置
換フエニル）メチル〕〕−２−ヒドロキシ−４−置
換−2H−１，４−ベンゾチアジン−３（4H）−オ
ン（）が得られる。この化合物（）にチオニ
ルハライド、たとえば塩化チオニルを反応させる
とチアジン環が拡大して新規化合物（）が生成
する。反応は冷却または室温化に行われる。反応
後の処理および精製は通常の方法、たとえば、抽
出、再結晶、カラムクロマトグラフイ、活性炭処
理等によつて行なわれ。 (In the formula, R 1 and R 2 have the same meanings as above.) That is, when compound () is treated with lead tetraacetate in a solvent such as glacial acetic acid or benzene, a new compound 2-(acetoxyphenylmethyl) [or 2 −
[acetoxy(4-substituted phenyl)methyl]]-2
-acetoxy-4-substituted-2H-1,4benzothiazin-3(4H)-one () is obtained. This compound is then hydrolyzed using, for example, alkali hydroxide to form a new compound 2-(hydroxyphenylmethyl [or 2-[hydroxy(4-substituted phenyl)methyl]]-2-hydroxy-4-substituted-2H- 1,4-benzothiazin-3(4H)-one () is obtained. When this compound () is reacted with a thionyl halide, such as thionyl chloride, the thiazine ring expands to form a new compound (). The reaction is cooled. Alternatively, the reaction is carried out at room temperature. Post-reaction treatments and purification are carried out by conventional methods, such as extraction, recrystallization, column chromatography, activated carbon treatment, etc.
かくして得られた式（）の化合物は、所望に
より公知の方法で塩酸塩、硫酸塩、硝酸塩等の無
機酸塩に、あるいはメタンスルホン酸塩、コハク
酸塩、マレイン酸塩、酒石酸塩等の有機酸塩に変
換することができる。 The compound of formula () thus obtained can be converted into inorganic acid salts such as hydrochloride, sulfate, nitrate, etc., or organic acid salts such as methanesulfonate, succinate, maleate, tartrate, etc. by known methods, if desired. Can be converted to acid salts.
次に実施例を挙げて本発明を詳細に説明する。 Next, the present invention will be explained in detail with reference to Examples.
実施例 １
(1) ２−フエニルメチレン−４−メチル−2H−
１，４−ベンゾチアジン−３（4H）−オン１ｇ
と30％過酸化水素水0.58mlとを10mlのテトラヒ
ドロフランにとかし、−20〜−10℃に冷却し、
この溶液にトリメチルクロロシラン1.43mlを
徐々に15分間にて滴下した後に４時間攪拌す
る。さらに室温で２時間攪拌して反応は終了す
る。反応液を氷水20mlに注ぎ、酢酸エチル10ml
で２回抽出を行なう。抽出液を水洗し無水芒硝
で乾燥後、溶媒を減圧下で留去すると２−（ク
ロロフエニルメチル）−２−ヒドロキシ−４−
メチル−2H−１，４−ベンゾチアジン−３
（4H）−オンの油状物0.96ｇを得る。Example 1 (1) 2-phenylmethylene-4-methyl-2H-
1,4-benzothiazin-3(4H)-one 1g
and 0.58 ml of 30% hydrogen peroxide solution in 10 ml of tetrahydrofuran, cooled to -20 to -10°C,
To this solution, 1.43 ml of trimethylchlorosilane was gradually added dropwise over 15 minutes, followed by stirring for 4 hours. After further stirring at room temperature for 2 hours, the reaction is completed. Pour the reaction solution into 20ml of ice water and add 10ml of ethyl acetate.
Perform extraction twice. After washing the extract with water and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 2-(chlorophenylmethyl)-2-hydroxy-4-
Methyl-2H-1,4-benzothiazine-3
0.96 g of (4H)-one oil is obtained.
IRスペクル：（Neatcm-1）3300（broad，weak）
1670，1585。IR spectrum: (Neatcm -1 ) 3300 (broad, weak)
1670, 1585.
NMRスペクトル：（CDCl3，ppm），3.40（ｓ，
1H），3.53（s3H），5.85（ｓ），6.05（ｓ），6.95−
7.80（ｍ，9H）
元素分析値（％） C16H14ClNO2Sとして
理論値 Ｃ，60.09：Ｈ，4.41；Ｎ，4.38
実測値 Ｃ，59.87；Ｈ，4.38；Ｎ，4.26
(2) ２−（クロロフエニルメチル）−２−ヒドロキ
シ−４−メチル−2H−１，４−ベンゾチアジ
ン−３（4H）−オン１ｇをアセトン30mlにとか
し、この液を氷冷し炭酸銀1.04ｇを加えて30分
度攪拌する。不溶物を除去して減圧下で溶媒を
留去すると油状の２−フエニル−５−メチル−
１，５−ベンゾチアゼピン−３，４−（2H，
5H）−ジオン0.73ｇを得る。NMR spectrum: (CDCl 3 , ppm), 3.40 (s,
1H), 3.53 (s3H), 5.85 (s), 6.05 (s), 6.95−
7.80 (m, 9H) Elemental analysis value (%) C 16 H 14 ClNO 2 As S Theoretical value C, 60.09: H, 4.41; N, 4.38 Actual value C, 59.87; H, 4.38; N, 4.26 (2) 2 Dissolve 1 g of -(chlorophenylmethyl)-2-hydroxy-4-methyl-2H-1,4-benzothiazin-3(4H)-one in 30 ml of acetone, cool the solution on ice, add 1.04 g of silver carbonate, and add 30 Stir a few minutes. After removing insoluble matter and distilling off the solvent under reduced pressure, an oily 2-phenyl-5-methyl-
1,5-benzothiazepine-3,4-(2H,
0.73 g of 5H)-dione is obtained.
I.R.スペクトル：（Neat，cm-1）3300（broad，
weak），1720，1660，1580。IR spectrum: (Neat, cm -1 ) 3300 (broad,
weak), 1720, 1660, 1580.
N.M.R.スペクトル：（CDCl3.ppm）3.45（ｓ，
3H），5.50（ｓ，1H），7.05−7.60（ｍ，9H）
元素分析値（％） C16H13NO2Sとして
理論値 Ｃ，67.84；Ｈ，4.63；Ｎ，4.95
実測値 Ｃ，67.68；Ｈ，4.69；Ｎ，5.07
実施例 ２
(1) ２−（４−クロロフエニルメチレン）−４−メ
チル−2H−１，４−ベンゾチアジン−３（4H）
−１ｇと30％過酸化水素水0.51mlとをテトラヒ
ドロフラン10mlにとかし−20〜−10℃に保ちつ
つ、トリメチルクロロシラン1.26mlを徐々に15
分間で滴下し４時間攪拌する。さらに室温で２
時間攪拌した後、これを氷水20mlに注ぎ、酢酸
エチル10mlで２回抽出を行なう。抽出液を水洗
し、無水芒硝で乾燥後、溶媒を減圧下で留去す
ると油状の２−〔クロロ（４−クロロフエニル）
メチル〕−２−ヒドロキシ−４−メチル−2H−
１，４−ベンゾチアジン−３（4H）−オン0.67
ｇを得る。NMR spectrum: (CDCl 3 .ppm) 3.45 (s,
3H), 5.50 (s, 1H), 7.05-7.60 (m, 9H) Elemental analysis value (%) As C 16 H 13 NO 2 S Theoretical value C, 67.84; H, 4.63; N, 4.95 Actual value C, 67.68 ;H, 4.69;N, 5.07 Example 2 (1) 2-(4-chlorophenylmethylene)-4-methyl-2H-1,4-benzothiazine-3(4H)
-1 g and 0.51 ml of 30% hydrogen peroxide solution are dissolved in 10 ml of tetrahydrofuran, and while keeping the temperature between -20 and -10°C, gradually add 1.26 ml of trimethylchlorosilane to 15 ml of 30% hydrogen peroxide solution.
Add dropwise over minutes and stir for 4 hours. 2 more at room temperature
After stirring for an hour, it was poured into 20 ml of ice water and extracted twice with 10 ml of ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain oily 2-[chloro(4-chlorophenyl).
methyl]-2-hydroxy-4-methyl-2H-
1,4-Benzothiazin-3(4H)-one 0.67
get g.
I.R.スペクトル：（Neat，cm-1），3350，1675，
1585。IR spectrum: (Neat, cm -1 ), 3350, 1675,
1585.
N.M.R.スペクトル（CDCl3，ppm）3.40（ｓ，
1H），3.50（ｓ，3H），6.05（ｓ，1H），6.96−7.80
（ｍ，8H）。NMR spectrum (CDCl 3 , ppm) 3.40 (s,
1H), 3.50 (s, 3H), 6.05 (s, 1H), 6.96-7.80
(m, 8H).
元素分析値（％） C16H13Cl2NO2Sとして
理論値 Ｃ，54.23；Ｈ，3.70；Ｎ，3.95
実測値 Ｃ，54.34；Ｈ，4.00；Ｎ，3.88
(2) ２−〔クロロ（４−クロロフエニル）メチル〕
−２−ヒドロキシ−４−メチル−2H−１，４
−ベンゾチアジン−３（4H）−オン１ｇをアセ
トン20mlにとかし、氷冷して炭酸銀0.93ｇを加
えて30分間攪拌する。不溶物を除去して減圧下
で溶媒を留去して、２−（４−クロロフエニル）
−５−メチル−１，５−ベンゾチアゼピン−
３，４（2H，5H）−ジオンの油状物質0.72ｇを
得る。Elemental analysis value (%) As C 16 H 13 Cl 2 NO 2 S Theoretical value C, 54.23; H, 3.70; N, 3.95 Actual value C, 54.34; H, 4.00; N, 3.88 (2) 2-[chloro( 4-chlorophenyl)methyl]
-2-hydroxy-4-methyl-2H-1,4
-Dissolve 1 g of benzothiazin-3(4H)-one in 20 ml of acetone, cool on ice, add 0.93 g of silver carbonate, and stir for 30 minutes. Insoluble matter was removed and the solvent was distilled off under reduced pressure to obtain 2-(4-chlorophenyl).
-5-methyl-1,5-benzothiazepine-
0.72 g of 3,4(2H,5H)-dione oil is obtained.
I.R.スペクトル：（Neat cm-1）1665，1580。IR spectrum: (Neat cm -1 ) 1665, 1580.
N.M.R.スペクトル：（CDCl3，ppm）3.53（ｓ，
3H），5.12（ｓ，1H），6.95−7.80（ｍ，8H）
元素分析値（％） C16H12ClNO2Sとして
理論値 Ｃ，60.47；Ｈ，3.77；4.40
実測値 Ｃ，60.78；Ｈ，3.51；4.26
実施例 ３
(1) ２−（４−メトキシフエニルメチレン）−４−
メトキシメチル−2H−１，４−ベンゾチアジ
ン−３（4H）−オン10ｇをテトラヒドロフラン
60mlにとかし、この溶液に60％過酸化水素2.5
mlを加え、−10〜−20℃に冷却してトリメチル
クロロシラン13mlを徐々に10〜20分間で滴下
後、同温度にて一晩放置、これを氷水200mlに
注ぎ、クロロホルム100mlで２回抽出する。抽
出液を無水芒硝で乾燥後、減圧下で溶媒を留去
すると２−〔クロロ（４−メトキシフエニル）
メチル〕−２−ヒドロキシ−４−メトキシメチ
ル−2H−１，４−ベンゾチアジン−３（4H）−
オンの油状物質11ｇを得る。NMR spectrum: (CDCl 3 , ppm) 3.53 (s,
3H), 5.12 (s, 1H), 6.95-7.80 (m, 8H) Elemental analysis value (%) As C 16 H 12 ClNO 2 S Theoretical value C, 60.47; H, 3.77; 4.40 Actual value C, 60.78; H , 3.51; 4.26 Example 3 (1) 2-(4-methoxyphenylmethylene)-4-
10 g of methoxymethyl-2H-1,4-benzothiazin-3(4H)-one was added to tetrahydrofuran.
Dissolve 2.5% hydrogen peroxide into this solution to 60ml
ml, cooled to -10 to -20°C, gradually added 13 ml of trimethylchlorosilane dropwise over 10 to 20 minutes, left overnight at the same temperature, poured into 200 ml of ice water, and extracted twice with 100 ml of chloroform. . After drying the extract over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 2-[chloro(4-methoxyphenyl)].
Methyl]-2-hydroxy-4-methoxymethyl-2H-1,4-benzothiazine-3(4H)-
Obtain 11 g of oily substance.
I.R.スペクトル：（Neat，cm-1）3300，1690，
1605，1580
N.M.R.スペクトル：（CDCl3，ppm）3.44（ｓ，
1H），3.49（ｓ，3H），3.82（ｓ，3H），5.45
（quartet，2H），6.03（ｓ，1H），6.80（−7.70（ｍ
，
8H）
元素分析値（％） C18H18ClNO4Sとして
理論値 Ｃ，56.91；Ｈ，4.77；Ｎ，3.68
実測値 Ｃ，57.03；Ｈ，4.79；Ｎ，3.71
(2) ２−〔クロロ（４−メトキシフエニル）メチ
ル〕２−ヒドロキシ−４−メトキシメチル−
2H−１，４−ベンゾチアジン−３（4H）−オン
10ｇをテトラヒドロフラン20mlにとかし内温０
〜10℃に保ち、三塩化アンチモン13ｇをアセト
ニトリル100mlにとかした液を滴下する。同温
度で１時間攪拌後クロロホルム150mlを加えて
激しく攪拌を行ないつつ、氷水100mlを加える。
析出した固形物を除去した後溶媒層を分取し、
無水芒硝で乾燥して溶媒を留去する。エチルア
ルコールで再結晶を行ない２−（４−メトキシ
フエニル）−５−メトキシメチル−１，５−ベ
ンゾチアゼピン３，４−（2H，5H）−ジオン
5.73ｇを得る。融点124.5−125.5℃
IRスペクトル：（Nujol，cm-1）1720，1670，
1610，1585
N.M.R.スペクトル：（CDCl3，ppm）3.54（ｓ，
3H），3.79（ｓ，3H），5.06（ｓ，1H），5.42（ｑ，
2H），6.76−7.80（ｍ，8H）
元素分析値（％） C18H17NO4Sとして
理論値 Ｃ，62.97；Ｈ，4.99；Ｎ，4.08
実測値 Ｃ，62.75；Ｈ，4.93；Ｎ，4.06
実施例 ４
２−（４−メトキシフエニルメチレン）−４−
（２−ヒドロキシエチル）−2H−１，４−ベンゾ
チアジン−３（4H）−オンを用いて、実施例３と
同様の反応工程を経て、２−（４−メトキシフエ
ニル）−５−（２−ヒドロキシエチル）−１，５−
ベンゾチアゼピン−３，４（2H，5H）−ジオンの
油状物を得る。IR spectrum: (Neat, cm -1 ) 3300, 1690,
1605, 1580 NMR spectrum: (CDCl 3 , ppm) 3.44 (s,
1H), 3.49 (s, 3H), 3.82 (s, 3H), 5.45
(quartet, 2H), 6.03 (s, 1H), 6.80 (-7.70 (m)
，
8H) Elemental analysis value (%) C 18 H 18 ClNO 4 As S Theoretical value C, 56.91; H, 4.77; N, 3.68 Actual value C, 57.03; H, 4.79; N, 3.71 (2) 2-[chloro( 4-methoxyphenyl)methyl]2-hydroxy-4-methoxymethyl-
2H-1,4-benzothiazin-3(4H)-one
Dissolve 10g in 20ml of tetrahydrofuran and bring the internal temperature to 0.
While keeping the temperature at ~10°C, a solution prepared by dissolving 13 g of antimony trichloride in 100 ml of acetonitrile is added dropwise. After stirring at the same temperature for 1 hour, 150 ml of chloroform was added, and while stirring vigorously, 100 ml of ice water was added.
After removing the precipitated solid matter, separate the solvent layer,
Dry with anhydrous sodium sulfate and remove the solvent. Recrystallize with ethyl alcohol to obtain 2-(4-methoxyphenyl)-5-methoxymethyl-1,5-benzothiazepine 3,4-(2H,5H)-dione.
Obtain 5.73g. Melting point: 124.5-125.5℃ IR spectrum: (Nujol, cm -1 ) 1720, 1670,
1610, 1585 NMR spectrum: (CDCl 3 , ppm) 3.54 (s,
3H), 3.79 (s, 3H), 5.06 (s, 1H), 5.42 (q,
2H), 6.76-7.80 (m, 8H) Elemental analysis value (%) C 18 H 17 NO 4 As S Theoretical value C, 62.97; H, 4.99; N, 4.08 Actual value C, 62.75; H, 4.93; N, 4.06 Example 4 2-(4-methoxyphenylmethylene)-4-
Using (2-hydroxyethyl)-2H-1,4-benzothiazin-3(4H)-one, 2-(4-methoxyphenyl)-5-(2 -hydroxyethyl)-1,5-
An oil of benzothiazepine-3,4(2H,5H)-dione is obtained.
I.R.スペクトル：（Neat，cm-1）3425，1725，
1660，1610，1585，
N.M.R.スペクトル：（CDCl3，ppm）3.18（broad
ｓ，1H），3.80（ｓ，3H），3.88−420（ｍ，4H），
5.50（broad ｓ，1H），6.80−7.85（ｍ，8H）
元素分析値（％） C18H17NO4Sとして
理論値 Ｃ，62.97；Ｈ，4.99；Ｎ，4.08
実測値 Ｃ，63.14；Ｈ，5.02；Ｎ，3.97
実施例 ５
２−（４−メトキシフエニルメチレン）−４−
（２−クロロエチル）−2H−１，４−ベンゾチア
ジン−３（4H）−オンを実施例３と同様の反応工
程を経て２−（４−メトキシフエニル）−５−（２
−クロロエチル）−１，５−ベンゾチアゼピン−
３，４（2H，5H）−ジオンの油状物を得る。IR spectrum: (Neat, cm -1 ) 3425, 1725,
1660, 1610, 1585, NMR spectrum: (CDCl 3 , ppm) 3.18 (broad
s, 1H), 3.80 (s, 3H), 3.88-420 (m, 4H),
5.50 (broad s, 1H), 6.80-7.85 (m, 8H) Elemental analysis value (%) As C 18 H 17 NO 4 S Theoretical value C, 62.97; H, 4.99; N, 4.08 Actual value C, 63.14; H , 5.02; N, 3.97 Example 5 2-(4-methoxyphenylmethylene)-4-
(2-Chloroethyl)-2H-1,4-benzothiazin-3(4H)-one was subjected to the same reaction steps as in Example 3, and 2-(4-methoxyphenyl)-5-(2
-chloroethyl)-1,5-benzothiazepine-
An oil of 3,4(2H,5H)-dione is obtained.
I.R.スペクトル（：（Neat，cm-1）3350，1725，
1660，1600，1580
N.M.R.スペクトル：（CDCl3，ppm）3.71（ｓ，
3H），4.10−4.60（ｍ，4H），5.44（broad ｓ，
1H），6.76−8.46（ｍ，8H）
元素分析値（％） C18H16ClNO3Sとして
理論値 Ｃ，59.75；Ｈ，4.42；Ｎ，3.87
実測値 Ｃ，60.02；Ｈ，4.38；Ｎ，3.77
実施例 ６
２−（４−メトキシフエニルメチレン）−４−
（２−ブロモエチル）−2H−１，４−ベンゾチア
ジン−３（4H）−オンを実施例３と同様の反応工
程を経て、２−（４−メトキシフエニル）−５−
（２−ブロモエチル）−１，５−ベンゾチアゼピン
−３，４（2H，5H）−ジオンの油状物を得る。IR spectrum (: (Neat, cm -1 ) 3350, 1725,
1660, 1600, 1580 NMR spectrum: (CDCl 3 , ppm) 3.71 (s,
3H), 4.10-4.60 (m, 4H), 5.44 (broad s,
1H), 6.76-8.46 (m, 8H) Elemental analysis value (%) As C 18 H 16 ClNO 3 S Theoretical value C, 59.75; H, 4.42; N, 3.87 Actual value C, 60.02; H, 4.38; N, 3.77 Example 6 2-(4-methoxyphenylmethylene)-4-
2-(4-methoxyphenyl)-5-
An oil of (2-bromoethyl)-1,5-benzothiazepine-3,4(2H,5H)-dione is obtained.
I.R.スペクトル：（Neat，cm-1）3350，1720，
1660，1600，1580
N.M.R.スペクトル：（CDCl3，ppm）3.56（ｍ，
2H），3.76（ｓ，3H），4.28（ｍ，2H），5.42
（broad ｓ，1H），6.76−8.80（ｍ，8H）
元素分析値（％） C18H16BrNO3Sとして
理論値 Ｃ，53.20；Ｈ，3.94；Ｎ，3.44
実測値 Ｃ，53.47；Ｈ，4.01；Ｎ，3.50
実施例 ７
(1) ２−（４−メトキシフエニルメチレン）−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8.2ｇを氷酢酸
30mlとベンゼン100mlの混合溶媒に溶解し、四
酢酸鉛21.3ｇを添加して、内温55〜60℃で２時
間加熱攪拌する。反応終了後、冷却して100ml
の水を加え攪拌しながら重炭酸ソーダ75ｇを
徐々に添加して液性を中性にする。析出物を
去後有機溶媒層を分取し、数回水洗して無水芒
硝で乾燥した後溶媒を減圧下で留去すると２−
〔アセトキシ（４−メトキシフエニル）メチル〕
−２−アセトキシ−４−（２−ジメチルアミノ
エチル）−2H−１，４−ベンゾチアジン−３
（4H）−オンの油状物９ｇを得る。IR spectrum: (Neat, cm -1 ) 3350, 1720,
1660, 1600, 1580 NMR spectrum: (CDCl 3 , ppm) 3.56 (m,
2H), 3.76 (s, 3H), 4.28 (m, 2H), 5.42
(broad s, 1H), 6.76-8.80 (m, 8H) Elemental analysis value (%) As C 18 H 16 BrNO 3 S Theoretical value C, 53.20; H, 3.94; N, 3.44 Actual value C, 53.47; H, 4.01; N, 3.50 Example 7 (1) 2-(4-methoxyphenylmethylene)-4-
(2-dimethylaminoethyl)-2H-1,4-
8.2 g of benzothiazin-3(4H)-one in glacial acetic acid
Dissolve in a mixed solvent of 30 ml and benzene 100 ml, add 21.3 g of lead tetraacetate, and heat and stir at an internal temperature of 55 to 60°C for 2 hours. After the reaction is complete, cool to 100ml.
of water and gradually add 75 g of bicarbonate of soda while stirring to make the liquid neutral. After removing the precipitate, the organic solvent layer was separated, washed several times with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 2-
[Acetoxy(4-methoxyphenyl)methyl]
-2-acetoxy-4-(2-dimethylaminoethyl)-2H-1,4-benzothiazine-3
9 g of (4H)-one oil are obtained.
I.R.スペクトル：（Neat，cm-1）2925，2810，
2755，1750，1680，1604，1580，1503，1220，
1033
N.M.R.スペクトル：（CDCl3，ppm）1.98（ｓ，
3H），2.03（ｓ，3H），2.26（ｓ，6H），2.52（ｍ，
2H），3.71（ｓ，3H），3.98（ｍ，2H），6.43（ｓ，
1H），6.6−7.5（ｍ，8H）
元素分析値（％） C24H28N2O6Sとして
理論値 Ｃ，61.01；Ｈ，5.90；Ｎ，5.93
実測値 Ｃ，61.28；Ｈ，5.89；Ｎ，6.05
(2) ２−〔アセトキシ（４−メトキシフエニル）
メチル〕−２−アセトキシ−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4.2ｇをメタノール60mlにとか
し５℃に冷却して10％水酸化ナトリウム水溶液
を12ml添加し、５℃で１時間攪拌後、酢酸エチ
ル50mlで抽出、水洗、無水芒硝で乾燥して減圧
下で溶媒を留去すると、２−〔ヒドロキシ（４
−メトキシフエニル）メチル〕−２−ヒドロキ
シ−４−（２−ジメチルアミノエチル）−2H−
１，４−ベンゾチアジン−３（4H）−オンの油
状物3.1ｇを得る。IR spectrum: (Neat, cm -1 ) 2925, 2810,
2755, 1750, 1680, 1604, 1580, 1503, 1220,
1033 NMR spectrum: (CDCl 3 , ppm) 1.98 (s,
3H), 2.03 (s, 3H), 2.26 (s, 6H), 2.52 (m,
2H), 3.71 (s, 3H), 3.98 (m, 2H), 6.43 (s,
1H), 6.6-7.5 (m, 8H) Elemental analysis value (%) As C 24 H 28 N 2 O 6 S Theoretical value C, 61.01; H, 5.90; N, 5.93 Actual value C, 61.28; H, 5.89; N, 6.05 (2) 2-[acetoxy(4-methoxyphenyl)
Dissolve 4.2 g of methyl]-2-acetoxy-4-(2-dimethylaminoethyl)-2H-1,4-benzothiazin-3(4H)-one in 60 ml of methanol, cool to 5°C, and prepare a 10% aqueous sodium hydroxide solution. After stirring at 5℃ for 1 hour, extraction with 50 ml of ethyl acetate, washing with water, drying with anhydrous sodium sulfate, and distilling off the solvent under reduced pressure yielded 2-[hydroxy(4
-methoxyphenyl)methyl]-2-hydroxy-4-(2-dimethylaminoethyl)-2H-
3.1 g of 1,4-benzothiazin-3(4H)-one as an oil are obtained.
I.R.スペクトル：（Neat，cm-1）3380，2940，
2820，1657，1602，1585，1505，1243，1026
N.M.R.スペクトル：（CDCl3，ppm）2.24（ｓ，
6H），3.75（ｓ，3H），4.73（ｓ，1H），6.64−7.48
（ｍ，8H）
なお、この油状物をイソプロピルアルコールに溶
解し、濃塩酸を加えると対応する塩酸塩が晶出す
る。融点187−189℃
I.R.スペクトル：（KBr.cm-1）3395，3260，2953，
2698，1663，1243，1121
N.M.R.スペクトル：（DMSO−d6，ppm）2.83
（ｓ，6H），3.08−3.52（ｍ，2H），4.24−4.64（ｍ，
2H），5.02（ｓ），4.79（ｓ），6.46−7.76（ｍ，8H）
元素分析値（％） C20H24N2O4S・HClとして
理論値 Ｃ，56.53；Ｈ，5.88；Ｎ，6.59
実測値 Ｃ，56.94；Ｈ，6.02；Ｎ，6.68
(3) ２−〔ヒドロキシ（４−メトキシフエニル）
メチル〕−２−ヒドロキシ−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３ｇをテトラヒドロフラン25
mlにとかし５℃に冷却して攪拌しながら塩化チ
オニル１ｇを滴下後、５℃で１時間攪拌する。
反応後溶媒を減圧下で留去し、重炭酸ナトリウ
ム水溶液で弱塩基性にして酢酸エチルで抽出、
水洗、無水芒硝で乾燥後減圧留去すると２−
（４−メトキシフエニル）−５−（２−ジメチル
アミノエチル）−１，５−ベンゾチアゼピン−
３，４（2H，5H）−ジオンの油状物2.5ｇを得
る。IR spectrum: (Neat, cm -1 ) 3380, 2940,
2820, 1657, 1602, 1585, 1505, 1243, 1026 NMR spectrum: (CDCl 3 , ppm) 2.24 (s,
6H), 3.75 (s, 3H), 4.73 (s, 1H), 6.64-7.48
(m, 8H) If this oil is dissolved in isopropyl alcohol and concentrated hydrochloric acid is added, the corresponding hydrochloride will crystallize. Melting point 187-189℃ IR spectrum: (KBr.cm -1 ) 3395, 3260, 2953,
2698, 1663, 1243, 1121 NMR spectrum: (DMSO-d 6 , ppm) 2.83
(s, 6H), 3.08-3.52 (m, 2H), 4.24-4.64 (m,
2H), 5.02 (s), 4.79 (s), 6.46-7.76 (m, 8H) Elemental analysis value (%) C 20 H 24 N 2 O 4 As S・HCl Theoretical value C, 56.53; H, 5.88; N , 6.59 Actual value C, 56.94; H, 6.02; N, 6.68 (3) 2-[Hydroxy(4-methoxyphenyl)
methyl]-2-hydroxy-4-(2-dimethylaminoethyl)-2H-1,4-benzothiazin-3(4H)-one (3 g) in tetrahydrofuran 25
ml, cool to 5°C, add 1 g of thionyl chloride dropwise with stirring, and stir at 5°C for 1 hour.
After the reaction, the solvent was distilled off under reduced pressure, made weakly basic with an aqueous sodium bicarbonate solution, and extracted with ethyl acetate.
After washing with water, drying with anhydrous sodium sulfate, and distilling under reduced pressure, 2-
(4-methoxyphenyl)-5-(2-dimethylaminoethyl)-1,5-benzothiazepine-
2.5 g of 3,4(2H,5H)-dione oil are obtained.
I.R.スペクトル：（Neat，cm-1）3300，2900，
2825，2750，1716，1658，1598，1577，1502，
1245，1172，1022
N.M.R.スペクトル：（CDCl3，ppm）2.22（ｓ，
6H），2.60（ｍ，2H），3.79（ｓ，3H），4.06（ｍ，
2H），5.44（broad，1H），6.76−7.80（ｍ，8H）
元素分析値（％） C20H22N2O3Sとして
理論値 Ｃ，64.85；Ｈ，5.99；Ｎ，7.56
実測値 Ｃ，64.78；Ｈ，6.06；Ｎ，7.62
実施例 ８
(1) ２−（４−メトキシフエニルメチレン）−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20ｇを塩化メ
チレン300mlにとかし、トリメチルクロロシラ
ン19.5ｇを加え、−５℃〜−10℃に冷却して30
％過酸化水素水6.38ｇを徐々に滴下した後、同
温度にて30分攪拌、これを冷却した10％食塩水
500mlで２回洗浄する。洗浄した塩化メチレン
を無水硫酸マグネシウムで乾燥後、室温下減圧
にて留去すると２−〔クロロ（４−メトキシフ
エニル）メチル〕−２−ヒドロキシ−2H−４−
（２−ジメチルアミノエチル）−１，４−ベンゾ
チアジン−３（4H）−オン・塩酸塩の淡黄色粉
末24ｇを得る。IR spectrum: (Neat, cm -1 ) 3300, 2900,
2825, 2750, 1716, 1658, 1598, 1577, 1502,
1245, 1172, 1022 NMR spectrum: (CDCl 3 , ppm) 2.22 (s,
6H), 2.60 (m, 2H), 3.79 (s, 3H), 4.06 (m,
2H), 5.44 (broad, 1H), 6.76-7.80 (m, 8H) Elemental analysis value (%) C 20 H 22 N 2 O 3 S Theoretical value C, 64.85; H, 5.99; N, 7.56 Actual value C , 64.78; H, 6.06; N, 7.62 Example 8 (1) 2-(4-methoxyphenylmethylene)-4-
(2-dimethylaminoethyl)-2H-1,4-
Dissolve 20 g of benzothiazin-3(4H)-one in 300 ml of methylene chloride, add 19.5 g of trimethylchlorosilane, and cool to -5°C to -10°C.
After gradually dropping 6.38g of % hydrogen peroxide solution, stirred at the same temperature for 30 minutes, and cooled it to 10% saline solution.
Wash twice with 500ml. After drying the washed methylene chloride over anhydrous magnesium sulfate and distilling it off under reduced pressure at room temperature, 2-[chloro(4-methoxyphenyl)methyl]-2-hydroxy-2H-4-
24 g of pale yellow powder of (2-dimethylaminoethyl)-1,4-benzothiazin-3(4H)-one hydrochloride is obtained.
本品はアセトンから再結晶すると融点189−194
℃の無色粉末晶となる。 This product has a melting point of 189-194 when recrystallized from acetone.
It becomes a colorless powder crystal at ℃.
I.R.スペクトル：（Nujol，cm-1）3350（br.）2580，
2450，1690，16608，1580，1485，1250，1175，
1065，765
N.M.R.スペクトル：（DMSO−d6，ppm）2.95
（br.s.6H），3.64−3.30（ｍ，2H），3.88（ｓ，3H）
，
4.90−4.50（ｍ，2H），6.07（ｓ，1H），8.17−6.96
（ｍ，8H）
(2) ２−〔クロロ（４−メトキシフエニル）メチ
ル〕−２−ヒドロキシ−2H−４−（２−ジメチ
ルアミノエチル）−１，４−ベンゾチアジン−
３（4H）−オン・塩酸塩１ｇを水10mlにとかし、
25〜30℃で１時間攪拌後、飽和炭酸水素ナトリ
ウムを加えてアルカリ性としたのち、クロロホ
ルム10mlで２回抽出する。クロロホルム層は水
洗後無水芒硝で乾燥し、減圧下で溶媒を留去す
ると２−（４−メトキシフエニル）−５−（２−
ジメチルアミノエチル）−１，５−ベンゾチア
ゼピン−３，４（2H，5H）−ジオンの油状物１
ｇを得る。IR spectrum: (Nujol, cm -1 ) 3350 (br.) 2580,
2450, 1690, 16608, 1580, 1485, 1250, 1175,
1065,765 NMR spectrum: (DMSO−d 6 , ppm) 2.95
(br.s.6H), 3.64-3.30 (m, 2H), 3.88 (s, 3H)
，
4.90-4.50 (m, 2H), 6.07 (s, 1H), 8.17-6.96
(m, 8H) (2) 2-[chloro(4-methoxyphenyl)methyl]-2-hydroxy-2H-4-(2-dimethylaminoethyl)-1,4-benzothiazine-
Dissolve 1 g of 3(4H)-one hydrochloride in 10 ml of water,
After stirring at 25-30°C for 1 hour, the mixture was made alkaline by adding saturated sodium bicarbonate, and then extracted twice with 10 ml of chloroform. The chloroform layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 2-(4-methoxyphenyl)-5-(2-
Dimethylaminoethyl)-1,5-benzothiazepine-3,4(2H,5H)-dione oil 1
get g.
本品は通常の方法、たとえばアセトンに溶解後
濃塩酸を加えると２−（４−メトキシフエニル）−
５−（２−ジメチルアミノエチル）−１，５−ベン
ゾチアゼピン−３，４（2H，5H）．ジオン・塩酸
塩を得る。本品をアセトンで精製すると融点197
−201℃の無色粉末晶となる。 This product can be obtained by the usual method, for example, by dissolving it in acetone and adding concentrated hydrochloric acid.
5-(2-dimethylaminoethyl)-1,5-benzothiazepine-3,4(2H,5H). Obtain dione hydrochloride. When this product is purified with acetone, the melting point is 197.
It becomes a colorless powder crystal at -201℃.
I.R.スペクトル：（Nujol，cm-1）3350，2670，
1650，1638，1600，1580
I.R.スペクトル：（KBr，cm-1）3400，2670，
1720，1660，1610，1585
N.M.R.スペクトル：（DMSO−d6，ppm）2.80
（ｓ，6H），3.36（br.，2H），3.72（ｓ，3H），4.42
（br.，2H），6.06（br.，1H），6.40−7.90（ｍ，8H）
元素分析値（％） C20H22N2O3S・HClとして
理論値 Ｃ，59.04；Ｈ，5.65；Ｎ，6.88
実測値 Ｃ，59.17；Ｈ，5.68；Ｎ，6.91
実施例 ９
２−（４−メトキシフエニルメチレン）−（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20ｇを塩化メチレン300
mlにとかし、トリメチルクロロシラン19.5ｇを加
え、−５〜−10℃に冷却して30％過酸化水素水5.8
ｇを除々に滴下し、同温度で30分攪拌後、水10ml
を加えて、内温23℃にて２時間攪拌、これに飽和
食塩水400mlを加え塩化メチレン層を分取する。
次いで分取した塩化メチレン層を飽和食塩水400
mlと水300mlの混液にて洗浄し、硫酸マグネシウ
ムで乾燥後、減圧下室温にて留去すると２−（４
−メトキシフエニル）−５−（２−ジメチルアミノ
エチル）−１，５−ベンゾチアゼピン−３，４−
（2H，5H）−ジオン・塩酸塩の淡黄色粉末22ｇを
得る。本品はアセトンで精製すると融点197−201
℃の無色粉末晶14.8ｇを得る。IR spectrum: (Nujol, cm -1 ) 3350, 2670,
1650, 1638, 1600, 1580 IR spectrum: (KBr, cm -1 ) 3400, 2670,
1720, 1660, 1610, 1585 NMR spectrum: (DMSO−d 6 , ppm) 2.80
(s, 6H), 3.36 (br., 2H), 3.72 (s, 3H), 4.42
(br., 2H), 6.06 (br., 1H), 6.40-7.90 (m, 8H) Elemental analysis value (%) C 20 H 22 N 2 O 3 As S・HCl Theoretical value C, 59.04; H, 5.65 ;N, 6.88 Actual value C, 59.17;H, 5.68;N, 6.91 Example 9 2-(4-methoxyphenylmethylene)-(2-
20 g of dimethylaminoethyl)-2H--1,4-benzothiazin-3(4H)-one and 300 g of methylene chloride
ml, add 19.5 g of trimethylchlorosilane, cool to -5 to -10°C, and add 5.8 g of 30% hydrogen peroxide solution.
Gradually add 10ml of water, stir at the same temperature for 30 minutes, and add 10ml of water.
and stirred for 2 hours at an internal temperature of 23°C. Add 400 ml of saturated saline and separate the methylene chloride layer.
Next, the separated methylene chloride layer was diluted with 400% saturated saline solution.
ml and 300 ml of water, dried over magnesium sulfate, and distilled off at room temperature under reduced pressure to obtain 2-(4
-methoxyphenyl)-5-(2-dimethylaminoethyl)-1,5-benzothiazepine-3,4-
Obtain 22 g of pale yellow powder of (2H,5H)-dione hydrochloride. This product has a melting point of 197-201 when purified with acetone.
14.8 g of colorless powder crystals are obtained.
Claims (1)
キシ基、R2は低級アルキル基、低級アルコキシ
アルキル基、水酸基もしくはハロゲンで置換され
た低級アルキル基、または低級ジアルキルアミノ
アルキル基を表わす）で示される２−フエニル
〔または２−（４−置換フエニル）〕−５−置換−
１，５−ベンゾチアゼピン−３，４（2H，5H）−
ジオンまたはその酸付加塩。[Claims] 1 formula (In the formula, R 1 represents hydrogen, halogen or a lower alkoxy group, R 2 represents a lower alkyl group, a lower alkoxyalkyl group, a hydroxyl group, a lower alkyl group substituted with a halogen, or a lower dialkylaminoalkyl group) 2-phenyl [or 2-(4-substituted phenyl)]-5-substituted-
1,5-benzothiazepine-3,4(2H,5H)-
Diones or their acid addition salts.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP9639382A JPS58213764A (en) | 1982-06-04 | 1982-06-04 | 1,5-benzothiazepine derivative and preparation thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP9639382A JPS58213764A (en) | 1982-06-04 | 1982-06-04 | 1,5-benzothiazepine derivative and preparation thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS58213764A JPS58213764A (en) | 1983-12-12 |
| JPH0333713B2 true JPH0333713B2 (en) | 1991-05-20 |
Family
ID=14163710
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP9639382A Granted JPS58213764A (en) | 1982-06-04 | 1982-06-04 | 1,5-benzothiazepine derivative and preparation thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS58213764A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0730058B2 (en) * | 1988-05-14 | 1995-04-05 | 参天製薬株式会社 | 3-oxo-1,4-benzothiazine derivative |
-
1982
- 1982-06-04 JP JP9639382A patent/JPS58213764A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS58213764A (en) | 1983-12-12 |
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