JPS6152150B2 - - Google Patents
Info
- Publication number
- JPS6152150B2 JPS6152150B2 JP15790281A JP15790281A JPS6152150B2 JP S6152150 B2 JPS6152150 B2 JP S6152150B2 JP 15790281 A JP15790281 A JP 15790281A JP 15790281 A JP15790281 A JP 15790281A JP S6152150 B2 JPS6152150 B2 JP S6152150B2
- Authority
- JP
- Japan
- Prior art keywords
- benzene
- methoxyphenyl
- added
- compound
- yield
- 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
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 6
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical class CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 125000005853 β-dimethylaminoethyl group Chemical group 0.000 claims description 5
- KJFRSZASZNLCDF-UHFFFAOYSA-N 1,5-benzothiazepine Chemical class S1C=CC=NC2=CC=CC=C12 KJFRSZASZNLCDF-UHFFFAOYSA-N 0.000 claims description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 3
- 239000005749 Copper compound Substances 0.000 claims description 3
- 150000001880 copper compounds Chemical class 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 150000007657 benzothiazepines Chemical class 0.000 claims description 2
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 107
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 34
- 150000001875 compounds Chemical class 0.000 description 32
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 28
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- 239000000203 mixture Substances 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- 239000002904 solvent Substances 0.000 description 17
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- 229910000027 potassium carbonate Inorganic materials 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 229910052739 hydrogen Inorganic materials 0.000 description 11
- 239000001257 hydrogen Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 125000003118 aryl group Chemical group 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- -1 p-methoxyphenyl glycide ester Chemical class 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 150000001408 amides Chemical class 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 230000000397 acetylating effect Effects 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 244000309464 bull Species 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940116318 copper carbonate Drugs 0.000 description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 2
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 2
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 2
- GEZOTWYUIKXWOA-UHFFFAOYSA-L copper;carbonate Chemical compound [Cu+2].[O-]C([O-])=O GEZOTWYUIKXWOA-UHFFFAOYSA-L 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- ZFPGARUNNKGOBB-UHFFFAOYSA-N 1-Ethyl-2-pyrrolidinone Chemical compound CCN1CCCC1=O ZFPGARUNNKGOBB-UHFFFAOYSA-N 0.000 description 1
- ZFFBIQMNKOJDJE-UHFFFAOYSA-N 2-bromo-1,2-diphenylethanone Chemical compound C=1C=CC=CC=1C(Br)C(=O)C1=CC=CC=C1 ZFFBIQMNKOJDJE-UHFFFAOYSA-N 0.000 description 1
- QZOCQWGVJOPBDK-UHFFFAOYSA-N 2-iodobenzenethiol Chemical compound SC1=CC=CC=C1I QZOCQWGVJOPBDK-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- JJLJMEJHUUYSSY-UHFFFAOYSA-L Copper hydroxide Chemical compound [OH-].[OH-].[Cu+2] JJLJMEJHUUYSSY-UHFFFAOYSA-L 0.000 description 1
- 239000005750 Copper hydroxide Substances 0.000 description 1
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 description 1
- 239000005751 Copper oxide Substances 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- 229910021590 Copper(II) bromide Inorganic materials 0.000 description 1
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001339 alkali metal compounds Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 229940079895 copper edta Drugs 0.000 description 1
- 229910001956 copper hydroxide Inorganic materials 0.000 description 1
- 229910000431 copper oxide Inorganic materials 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 1
- BDXBEDXBWNPQNP-UHFFFAOYSA-L copper;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate;hydron Chemical compound [Cu+2].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O BDXBEDXBWNPQNP-UHFFFAOYSA-L 0.000 description 1
- CZZBXGOYISFHRY-UHFFFAOYSA-N copper;hydroiodide Chemical compound [Cu].I CZZBXGOYISFHRY-UHFFFAOYSA-N 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 229960003280 cupric chloride Drugs 0.000 description 1
- 229940045803 cuprous chloride Drugs 0.000 description 1
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 description 1
- 229940112669 cuprous oxide Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 150000002484 inorganic compounds Chemical class 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 150000002736 metal compounds Chemical class 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Description
この発明は１・５−ベンゾチアゼピン誘導体の
製造方法に係るものである。
本発明によれば次に示すごとくして、１・５−
ベンゾチアゼピン誘導体が得られる。
即ち、
〔式中R1は水素原子またはアセチル基を、R2は水
素原子またはβ−ジメチルアミノエチル基を、Ｘ
はハロゲン原子を示す〕
ここにおいて、式（）で示される化合物を適
宜溶媒中、銅粉または銅化合物及び塩基の存在下
加熱することによつて反応は進められる。
尚、式（）で示される化合物は新規化合物で
あり、かつ、この反応は、この種の縮合環化合物
の合成方法としては新規なものである。
式（）で示される化合物におけるＸとしては
Cl、Br、Ｉであり、銅化合物としては酸化銅、
塩化第一銅、臭化第一銅、沃化第一銅、塩化第二
銅、臭化第二銅、炭酸銅、水酸化銅などの無機化
合物、酢酸銅、EDTA銅などの有機化合物があげ
られる。また、用いられる溶媒としては反応に関
与しない溶媒であれば何でも良いが、好ましい溶
媒としてはジメチルホルムアミド、ジメチルスル
ホキシド、ヘキサメチルホスホルアミド、Ｎ−エ
チル−２−ピロリドン、アミルアルコールなどが
あげられる。更に、これらと芳香族溶媒、例えば
ベンゼン、トルエン、キシレン、又はこれらのハ
ロゲン化化合物などとの混合物も使用できる。こ
こで使用される塩基としては例えば、炭酸ナトリ
ウム、炭酸カリウムなどの無機塩基、トリエチル
アミン、Ｎ−メチルモルホリンなどの有機塩基が
あげられる。
本発明において用いられる化合物（）は（
ａ）、（ｂ）で示され、例えば次の様にして合成
される。
〔式中Ｘはハロゲン原子を、R2は水素原子または
β−ジメチルアミノエチル基を、R3は低級アル
キル基を示す〕
(1) ｏ−ハロゲノチオフエノールとｐ−メトキシ
フエニルグリシドエステルを無溶媒もしくは適
宜溶媒中で反応させる。
(2) 得られた化合物（）を稀アルカリ水溶液で
加水分解して化合物（）を得る。
(3) 得られた化合物（）をアセチル化すること
によつて化合物（）を得る。
(4) 化合物（）を縮合剤の存在下またはカルボ
ン酸の反応性誘導体に変換して、アンモニア或
いはβ−ジメチルアミノエチルアミンと反応さ
せ化合物（ｂ）を得る。
(5) 化合物（）をアンモニアまたはβ−ジメチ
ルアミノエチルアミンとカルボジイミド縮合剤
（例えばD.C.C.）の存在下反応させ化合物（
ａ）を得る。
(6) 化合物（ｂ）を加水分解して、化合物（
ａ）を得る。又は、逆に化合物（ａ）をアセ
チル化して化合物（ｂ）を得る。
本発明によれば１・５−ベンゾチアゼピン誘導
体、とりわけＮ−置換体を造る場合に、従来技術
で使用されていたアルカリ金属化合物、例えばナ
トリウム、カリウム、水素化ナトリウム、水素化
カリウム、ナトリウムアミド、カリウムアミドな
どの危険な金属化合物を使用しないので、従来技
術では避けることのできなかつた工業的製造の場
における危険性を回避できる利点がある。
尚、本発明によつて得られる化合物は心蔵疾患
治療薬として有用なものである。
尚、本明細書の記載において、使用されている
「エリトロ」なる表示は、化合物の立体配置を定
めるに際し、フイツシヤーの投影図法に倣つて、
下に図示する構造の化合物に対する表示である。
（参考文献Chem.Pharm.Bull.、18 2284（1970））
This invention relates to a method for producing 1,5-benzothiazepine derivatives. According to the present invention, as shown below, 1.5-
A benzothiazepine derivative is obtained. That is, [In the formula, R 1 is a hydrogen atom or an acetyl group, R 2 is a hydrogen atom or a β-dimethylaminoethyl group,
represents a halogen atom] Here, the reaction proceeds by heating the compound represented by formula () in an appropriate solvent in the presence of copper powder or a copper compound and a base. The compound represented by formula () is a new compound, and this reaction is new as a method for synthesizing this type of fused ring compound. As X in the compound represented by formula (),
Cl, Br, I, and copper compounds include copper oxide,
Examples include inorganic compounds such as cuprous chloride, cuprous bromide, cuprous iodide, cupric chloride, cupric bromide, copper carbonate, and copper hydroxide, and organic compounds such as copper acetate and copper EDTA. It will be done. Further, any solvent may be used as long as it does not participate in the reaction, but preferred solvents include dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, N-ethyl-2-pyrrolidone, and amyl alcohol. Furthermore, mixtures of these with aromatic solvents such as benzene, toluene, xylene, or halogenated compounds thereof can also be used. Examples of the base used here include inorganic bases such as sodium carbonate and potassium carbonate, and organic bases such as triethylamine and N-methylmorpholine. The compound () used in the present invention is (
a) and (b), and can be synthesized, for example, as follows. [In the formula, X represents a halogen atom, R 2 represents a hydrogen atom or a β-dimethylaminoethyl group, and R 3 represents a lower alkyl group] (1) o-halogenothiophenol and p-methoxyphenyl glycide ester The reaction is carried out without a solvent or in an appropriate solvent. (2) The obtained compound () is hydrolyzed with a dilute alkaline aqueous solution to obtain the compound (). (3) Compound () is obtained by acetylating the obtained compound (). (4) Compound () is reacted with ammonia or β-dimethylaminoethylamine in the presence of a condensing agent or converted into a reactive derivative of carboxylic acid to obtain compound (b). (5) Compound () is reacted with ammonia or β-dimethylaminoethylamine in the presence of a carbodiimide condensing agent (e.g. DCC) to form compound (
obtain a). (6) Compound (b) is hydrolyzed to form compound (
obtain a). Alternatively, compound (b) can be obtained by acetylating compound (a). According to the invention, when preparing 1,5-benzothiazepine derivatives, especially N-substituted derivatives, alkali metal compounds used in the prior art, such as sodium, potassium, sodium hydride, potassium hydride, sodium amide Since dangerous metal compounds such as potassium amide and the like are not used, there is an advantage that dangers in industrial manufacturing sites that cannot be avoided with conventional techniques can be avoided. The compounds obtained by the present invention are useful as therapeutic agents for cardiac diseases. In addition, in the description of this specification, the expression "erythro" used in determining the steric configuration of a compound is based on the projection projection method of Fischer.
This is a representation for a compound with the structure illustrated below.
(Reference Chem.Pharm.Bull., 18 2284 (1970))
【式】又は[Formula] or
以下本発明を具体的に記述するために実施例を
示す。
実施例 １
エリトロ−２−ヒドロキシ−３−（ｐ−メトキ
シフエニル）−３−（ｏ−ヨードフエニルチオ）−
プロピオン酸アミド351.6mgをジメチルホルムア
ミド５ml、ベンゼン５mlに加え、ダーンスターク
装置を用いて内温110℃まで加熱撹拌した。ヨウ
化銅15.5mg、炭酸カリウム124.5mgを加え、更に
２時間加熱撹拌した。減圧下に溶媒を溜去し、残
渣にクロロホルムを加えた。クロロホルム層を水
洗乾燥、減圧濃縮し、残渣をシリカゲルカラムク
ロマトグラフイーで精製（ベンゼン：酢酸エチル
＝８：２で溶出）し、ベンゼンで再結晶させシス
−３−ヒドロキシ−２−（ｐ−メトキシフエニ
ル）−２・３−ジヒドロ−１・５−ベンゾチアゼ
ピン−４（5H）−オンの白色針状結晶を得た。
得量100mg（収率45％）m.p.183〜185.5℃
ΓTLC（展開溶媒クロロホルム：エタノール：
酢酸＝60：10：1V／Ｖ）；Rf値0.64に単一ス
ポツトを認め、これは別途合成した標品と一致
した。
ΓIRcm-1：3350（OH）、1680（アミド型CO）、
1600、1505（ベンゼン核）
ΓNMRδＤＭＳＯ ＴＭＳ：3.75（3H、ｓ、OCH3）、4.35
（1H、ｄ、C3−Ｈ）、4.43（1H、ｓ、OH）、
5.08（1H、ｄ、C2−Ｈ）、6.83〜7.75（8H、芳
香環水素）
C2−C3の水素のカツプリング定数（Ｊ2、3）
がシス型を示す7cpsであつた。
（Chem.Pharm.Bull.19 598（1971）参照）
実施例 ２
エリトロ−２−アセトキシ−３−（ｐ−メトキ
シフエニル）−３−（ｏ−ヨードフエニルチオ）−
プロピオン酸アミド230mgをジメチルホルムアミ
ド５ml、ベンゼン５mlに加え、ダーンスタークの
装置を用いて、内温110℃まで加熱撹拌した。ヨ
ウ化銅9.3mg、炭酸カリウム74.4mgを加え更に５
時間加熱撹拌した。溶媒溜去したのち残渣にベン
ゼンを加え、1N−塩酸、水で洗浄乾燥後、実施
例１と同様に処理して、シス−３−アセトキシ−
２−（ｐ−メトキシフエニル）−２・３−ジヒドロ
−１・５−ベンゾチアゼピン−４（5H）−オンを
得た。
ΓTLC（展開溶媒クロロホルム：エタノール：
酢酸＝18：１：0.1V／Ｖ）；Rf0.62に単一スポ
ツトを認め、これは別途合成した標品と一致し
た。
ΓIRcm-1：1735（アセチルCO）、1685（アミド
CO）、1240（メトキシＣ−Ｏ−Ｃ）
ΓNMRδＣＤＣｌ３ ＴＭＳ：1.90（3H、ｓ、CO−CH3）、
3.8
（3H、ｓ、Ｏ−CH3）、5.15（1H、ｄ、C2−
Ｈ）、5.38（1H、ｄ、C3−Ｈ）、6.75〜7.75
（8H、芳香環水素）、Ｊ2、3＝7cpsであつた。
実施例 ３
エリトロ−Ｎ−〔β−ジメチルアミノエチル〕−
２−ヒドロキシ−３−（ｐ−メトキシフエニル）−
３−（ｏ−ヨードフエニルチオ）−プロピオン酸ア
ミド200mgを、ジメチルホルムアミド５ml、ベン
ゼン５mlに加え、ダーンスタークの装置を用いて
内温110℃まで加熱撹拌した。ヨウ化銅７mg、炭
酸カリウム56mgを加え更に2.5時間加熱撹拌し
た。溶媒を溜去し、残渣にベンゼンを加え1N−
塩酸を加えた。水層を取り出し炭酸カリウムを用
いてアルカリ性としたのち、ベンゼン抽出を行つ
た。ベンゼン層を水洗、乾燥し、ベンゼンを溜去
して、シス−３−ヒドロキシ−２・３−ジヒドロ
−５−（β−ジメチルアミノエチル）−２−（ｐ−
メトキシフエニル）１・５−ベンゾチアゼピン−
４（5H）−オンを得た。
ΓTLC（展開溶媒エタノール：クロロホルム：
水：酢酸＝12：10：３：1V／Ｖ）：Rf0.70
ΓNMRδＣＤＣｌ３ ＴＭＳ：2.25（6H、ｓ、Ｎ（CH3）2
）、
3.75（3H、ｓ、Ｏ−CH3）、4.68（1H、ｄ、C3
−Ｈ）、4.83（1H、ｄ、C2−Ｈ）、6.68〜7.75
（8H、芳香環水素）
Ｊ2、3＝7cpsであつた。
実施例 ４
エリトロ−Ｎ−（β−ジメチルアミノエチル）−
２−アセトキシ−３−（ｐ−メトキシフエニル）−
３−（ｏ−ヨードフエニルチオ）−プロピオン酸ア
ミド１ｇをジメチルスルホキシド20ml、ベンゼン
2.0mlに加え、ダーンスタークの装置を用い、内
温110℃まで加熱撹拌した。ヨカ化銅33.5mg、炭
酸カリウム280.0mgを加え、更に５時間加熱撹拌
した。溶媒を溜去し、残渣にベンゼンを加え水洗
乾燥後減圧濃縮し、黒色オイル状物650mgを得
た。これをシリカゲルカラムクロマトグラフイー
で精製（酢酸エチルで溶出）し、シス−３−アセ
トキシ−２・３−ジヒドロ−５−（β−ジメチル
アミノエチル）−２−（ｐ−メトキシフエニル）−
１・５−ベンゾチアゼピン−４（5H）−オンを得
た。
得量200mg（収率26.1％）m.p.139〜141℃
ΓTLC（展開溶媒エタノール：クロロホルム：
水：酢酸＝２：10：１：1V／Ｖ）Rf0.49別途
合成した標品と一致した。
ΓIRcm-1：1740（アセチルＣ＝Ｏ）、1680（アミ
ドＣ＝Ｏ）、1600、1510（ベンゼン核）1250、
1030（メトキシＣ−Ｏ−Ｃ）
ΓNMRδＣＤＣｌ３ ＴＭＳ：1.90（3H、ｓ、CO−CH3）、
2.33（6H、ｓ、Ｎ＜ＣＨ３ ＣＨ３）、3.83（3H、ｓ、Ｏ
−CH3）、5.0（1H、ｄ、C2−Ｈ）、5.2（1H、
ｄ、C3−Ｈ）、6.88（8H、芳香環水素）
Ｊ2、3＝7cpsであつた。
参考例
(1) ｐ−メトキシフエニルグリシド酸メチルエス
テル4.0ｇをアセトニトリル６mlに加え、これ
にｏ−ヨードチオフエノール40ｇを８mlのアセ
トニトリルにとかした溶液を滴加した。室温で
４日間反応させ析出した結晶を取し、エリト
ロ−２−ヒドロキシ−３−（ｐ−メトキシフエ
ニル）−３−（ｏ−ヨードフエニルチオ）−プロ
ピオン酸メチルエステルを得た。
得量4.8ｇ（収率60.4％）m.p.133〜134℃
ΓTLC（ベンゼン：アセトン＝95：５）：
Rf0.43
ΓIRcm-1：3500（OH）、1720（エステルＣ＝
Ｏ）、1600、1510（ベンゼン環）、1240、1025
（Ｃ−Ｏ−Ｃ）、
ΓNMRδＣＤＣｌ３ ＴＭＳ：3.30（1H、ｄ、OH）、3.5
5
（3H、ｓ、−CO−OCH3）、3.71（3H、ｓ、Ｏ
−CH3）、4.48（1H、ｍ、C3−Ｈ）、4.65
（1H、ｄ、C2−Ｈ）、6.7〜7.9（8H、芳香環
水素）
(2) (1)で得たエリトロ−２−ヒドロキシ−３−
（ｐ−メトキシフエニル）−３−（ｏ−ヨードフ
エニルチオ）−プロピオン酸メチルエステル2.7
ｇを稀苛性ソーダ水溶液中室温で１時間撹拌し
た。
反応混合物をエーテルで洗浄したのち、水層
を塩酸酸性とし、エーテル抽出した。エーテル
層を集め、水洗乾燥後、エーテル溜去してエリ
トロ−２−ヒドロキシ−３−（ｐ−メトキシフ
エニル）−３−（ｏ−ヨードフエニルチオ）−プ
ロピオン酸を得た。
ベンゼンから再結晶した。
得量2.24ｇ（収率85.4％）m.p.131〜132℃
ΓTCL（クロロホルム：エタノール：酢酸＝
60：10：１）：Rf0.38
ΓIRcm-1：3500（OH）、3200〜2000（カルボン
酸OH）、1710（カルボン酸−Ｃ＝Ｏ）、
1600、1510（ベンゼン環）
ΓNMRδＣＤＣｌ３ ＴＭＳ：3.73（3H、ｓ、Ｏ−CH3）
、
4.55（1H、ｄ、C3−Ｈ）、4.75（1H、ｄ、C2
−Ｈ）、5.51（1H、ブロード、OH）、6.68〜
7.85（8H、芳香環水素）
(3) (2)で得た化合物600mgに無水酢酸３ｇを加
え、60℃で２時間反応させた。
濃縮後、シリカゲルクロマトグラフイーにて
精製（ベンゼン：酢酸エチル＝４：１で溶出）
し、エリトロ−２−アセトキシ−３−（ｐ−メ
トキシフエニル）−３−（ｏ−ヨードフエニルチ
オ）−プロピオン酸を得た。
得量560mg（収率84.0％）
ΓTLC（クロロホルム：エタノール：酢酸＝
60：10：１）：Rf0.61
ΓIRcm-1：3600〜2400（COOH）、1750（エス
テル＝CO）、1720（カルボン酸＝CO）、
1600、1520（ベンゼン環）
ΓNMRδＣＤＣｌ３ ＴＭＳ：2.1（3H、ｓ、−CO−CH3
）、
3.73（3H、ｓ、Ｏ−CH3）、4.83（1H、ｄ、
C2−Ｈ）、5.5（1H、ｄ、C3−Ｈ）、6.68〜
7.98（8H、芳香環水素）
(4) (3)で得た化合物6.1ｇをクロロホルム20mlに
とかし、これに塩化チオニル3.07ｇを加え２時
間加熱還流した。減圧濃縮して、エリトロ−２
−アセトキシ−３−（ｐ−メトキシフエニル）−
３−（ｏ−ヨードフエニルチオ）−プロピオン酸
クロライドを得た。
得量6.21ｇ（収率94.9％）
ΓIRcm-1：1790（−CO−Cl）、1750（エステル
＞Ｃ＝Ｏ）、1600、1510（ベンゼン環）
(5) Ｎ・Ｎ−ジメチルエチルアミン1.24ｇ、トリ
エチルアミン1.57ｇをクロロホルム８mlにとか
し、これに(4)で得た化合物6.21ｇをクロロホル
ム25mlにとかした溶液を加えた。反応後、減圧
濃縮し、残渣をベンゼンにとかし稀塩酸を加え
た。得られた稀塩酸層を炭酸カリウムでアルカ
リ性とし、ベンゼンで抽出した。
ベンゼン層を後処理して、エリトロ−Ｎ−
（β−ジメチルアミノエチル）−２−アセトキシ
−３−（ｐ−メトキシフエニル）−３−（ｏ−ヨ
ードフエニル）−ブロピオン酸アミドを得た。
得量4.98ｇ（収率75.0％）
ΓTLC（エタノール：クロロホルム：水：酢
酸
＝２：10：１：１）：Rf0.50
ΓIRcm-1：3300（NH）、1730（エステル＞Ｃ＝
Ｏ）、1670（アミド＞Ｃ＝Ｏ）、1600、1510
（ベンゼン環）
ΓNMRδＣＤＣｌ３ ＴＭＳ：2.1（3H、ｓ、−CO−CH3
）、
2.25（6H、ｓ、Ｎ（CH3）2）、2.45（2H、
ｔ、Ｃβ−H2）、3.3（2H、ｑ、Ｃα−H2）、
3.78（3H、ｓ、Ｏ−CH3）、4.93（1H、ｄ、
C2−Ｈ）、5.50（1H、ｄ、C3−Ｈ）、6.75〜
7.93（8H、芳香環水素）
(6) (5)で得た化合物4.48ｇをエタノール20mlにと
かし、炭酸カリウム17ｇを含む水溶液20mlを加
えた。50℃で２時間撹拌した。減圧濃縮し、残
渣にクロロホルムを加えた。クロロホルム層に
1N−塩酸を加えた。塩酸層を取り炭酸カリウ
ムで中和した。次にクロロホルムで抽出し、水
洗乾燥溶媒溜去して、エリトロ−Ｎ−（β−ジ
メチルアミノエチル）−２−ヒドロキシ−３−
（ｐ−メトキシフエニル）−３−（ｏ−ヨードフ
エニルチオ）−プロピオン酸アミドを得た。
ベンゼンから再結晶した。
得量2.87ｇ（収率69.45％）m.p.124〜127℃
ΓTLC（エタノール：クロロホルム：水：
酢酸＝２：10：１：１）：Rf0.31
ΓIRcm-1：1660（アミド＞Ｃ＝Ｏ）、1240、
1035（Ｃ−Ｏ−CH3）
ΓNMRδＣＤＣｌ３ ＴＭＳ：2.15（6H、ｓ、Ｎ（CH3）
2）、
2.4（2H、ｔ、Ｃβ−H2）、3.33（2H、ｑ、
Ｃα−H2）、3.78（3H、ｓ、Ｏ−CH3）、4.53
（1H、ｄ、C3−Ｈ）、5.0（1H、ｄ、C2−
Ｈ）、6.83〜7.95（8H、芳香環水素）
(7) (4)において得た化合物2.37ｇをベンゼン10ml
にとかし、これを氷冷下28％アンモニア水に滴
加した。徐々に室温にもどしベンゼンで抽出、
水洗乾燥濃縮し、残渣をベンゼンから再結晶
し、融点150〜153℃の白色結晶であるエリトロ
−２−ヒドロキシ−３−（ｐ−メトキシフエニ
ル）−３−（ｏ−ヨードフエニルチオ）−プロピ
オン酸アミドを得た。
ΓTLC（クロロホルム：エタノール：酢酸＝
60：10：１）：Rr0.62
ΓIRcm-1：3450〜3170（OH、NH）、1670（ア
ミドCO）
ΓNMRδＤＭＳＯ ＴＭＳ：3.70（3H、ｓ、Ｏ−CH3）、
4.20（1H、ｑ、C3−Ｈ）、4.90（1H、ｄ、C2
−Ｈ）、6.08（1H、ｄ、OH）、6.75〜7.90
（8H、芳香環水素）、7.33（2H、ｓ、NH2）
実施例 ５
エリトロ−Ｎ−（β−ジメチルアミノエチル）−
２−アセトキシ−３−（ｐ−メトキシフエニル）−
３−（ｏ−ヨードフエニルチオ）−プロピオン酸ア
ミド200mgをジメチルスルホキシド５ml、ベンゼ
ン５mlに加え、ダーンスタークの装置を用いて内
温110℃まで加熱撹拌した。銅粉４mg、炭酸カリ
ウム56mgを加えて５時間加熱撹拌した。溶媒を留
去し、実施例４と同様に処理し、黒色オイル状物
150mgを得た。これをシリカゲルカラムクロマト
グラフイーで精製し、シス−３−アセトキシ−
２・３−ジヒドロ−５−（β−ジメチルアミノエ
チル）−２−（ｐ−メトキシフエニル）−１・５−
ベンゾチアゼピン−４（5H）−オンを得た。
得量36mg（収率23.6％）m.p.137〜139℃。得ら
れた化合物は実施例４で得られたものと一致し
た。
実施例 ６
エリトロ−Ｎ−（β−ジメチルアミノエチル）−
２−ヒドロキシ−３−（ｐ−メトキシフエニル）−
３−（ｏ−ヨードフエニルチオ）−プロピオン酸ア
ミド250mgをジメチルホルムアミド５ml、ベンゼ
ン５mlに加え、ダーンスタークの装置を用いて内
温110℃まで加熱撹拌した。酸化第一銅５mg、炭
酸カリウム70mgを加えて３時間加熱撹拌した。溶
媒を留去し、実施例３と同様に処理した。ベンゼ
ンを留去してシス−３−ヒドロキシ−２・３−ジ
ヒドロ−５−（β−ジメチルアミノエチル）−２−
（ｐ−メトキシフエニル）−１・５−ベンゾチアゼ
ピン−４（5H）−オンを得た。
得られた化合物は実施例３で得られたものと一
致した。
実施例 ７
エリトロ−Ｎ−（β−ジメチルアミノエチル）−
２−アセトキシ−３−（ｐ−メトキシフエニル）−
３−（ｏ−ヨードフエニルチオ）−プロピオン酸ア
ミド500mgをジメチルスルホキシド10ml、ベンゼ
ン10mlに加え、ダーンスタークの装置を用いて内
温110℃まで加熱撹拌した。臭化第一銅13mg、炭
酸カリウム140mgを加えて５時間加熱撹拌した。
溶媒を留去し、実施例４と同様に処理しシス−３
−アセトキシ−２・３−ジヒドロ−５−（β−ジ
メチルアミノエチル）−２−（ｐ−メトキシフエニ
ル）−１・５−ベンゾチアゼピン−４（5H）−オ
ンを得た。
得量94mg（収率24.6％）m.p.138〜140℃。得ら
れた化合物は実施例４で得られたものと一致し
た。
実施例 ８
エリトロ−２−ヒドロキシ−３−（ｐ−メトキ
シフエニル）−３−（ｏ−ヨードフエニルチオ）−
プロピオン酸アミド200mgをジメチルホルムアミ
ド５ml、ベンゼン５mlに加え、ダーンスタークの
装置を用いて内温110℃まで加熱撹拌した。炭酸
銅10mg、炭酸カリウム80mgを加えて３時間加熱撹
拌した後、実施例１と同様に処理して、シス−３
−ヒドロキシ−２・３−ジヒドロ−２−（ｐ−メ
トキシフエニル）−１・５−ベンゾチアゼピン−
４（5H）−オンの白色針状結晶を得た。
得量50mg（収率35.6％）。得られた化合物は実
施例１で得られたものと一致した。
実施例 ９
エリトロ−２−ヒドロキシ−３−（ｐ−メトキ
シフエニル）−３−（ｏ−ヨードフエニルチオ）−
プロピオン酸アミド350mgをジメチルホルムアミ
ド５ml、ベンゼン５mlに加え、ダーンスタークの
装置を用いて内温110℃まで加熱撹拌した。
EDTA−銅35mg、炭酸カリウム120mgを加え更に
２時間加熱撹拌した。実施例１と同様に処理し
て、シス−３−ヒドロキシ−２・３−ジヒドロ−
２−（ｐ−メトキシフエニル）−１・５−ベンゾチ
アゼピン−４（5H）−オンを得た。
得量95mg（収率38.6％）。得られた化合物は実
施例１で得られたものと一致した。
Examples will be shown below to specifically describe the present invention. Example 1 Erythro-2-hydroxy-3-(p-methoxyphenyl)-3-(o-iodophenylthio)-
351.6 mg of propionic acid amide was added to 5 ml of dimethylformamide and 5 ml of benzene, and the mixture was heated and stirred using a Dern-Stark apparatus to an internal temperature of 110°C. 15.5 mg of copper iodide and 124.5 mg of potassium carbonate were added, and the mixture was further heated and stirred for 2 hours. The solvent was distilled off under reduced pressure, and chloroform was added to the residue. The chloroform layer was washed with water, dried, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with benzene:ethyl acetate = 8:2) and recrystallized from benzene to give cis-3-hydroxy-2-(p-methoxy). White needle-like crystals of phenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one were obtained. Yield 100 mg (yield 45%) mp183-185.5℃ ΓTLC (developing solvent chloroform: ethanol: acetic acid = 60:10:1 V/V); A single spot was observed at an Rf value of 0.64, which was different from the separately synthesized standard. Agreed. ΓIRcm -1 : 3350 (OH), 1680 (amide type CO),
1600, 1505 (benzene nucleus) ΓNMRδ DMSO TMS : 3.75 (3H, s, OCH 3 ), 4.35
(1H, d, C3 -H), 4.43 (1H, s, OH),
5.08 (1H, d, C2 -H), 6.83-7.75 (8H, aromatic ring hydrogen) C2 - C3 hydrogen coupling constant ( J2 , 3 )
was 7 cps, indicating cis type. (See Chem.Pharm.Bull. 19 598 (1971)) Example 2 Erythro-2-acetoxy-3-(p-methoxyphenyl)-3-(o-iodophenylthio)-
230 mg of propionic acid amide was added to 5 ml of dimethylformamide and 5 ml of benzene, and the mixture was heated and stirred using a Dernstark apparatus to an internal temperature of 110°C. Add 9.3 mg of copper iodide and 74.4 mg of potassium carbonate and add 5 more
The mixture was heated and stirred for hours. After distilling off the solvent, benzene was added to the residue, washed with 1N hydrochloric acid and water, dried, and treated in the same manner as in Example 1 to obtain cis-3-acetoxy-
2-(p-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one was obtained. ΓTLC (developing solvent chloroform: ethanol: acetic acid = 18:1:0.1 V/V); a single spot was observed at Rf0.62, which coincided with a separately synthesized sample. ΓIRcm -1 : 1735 (acetyl CO), 1685 (amide
CO), 1240 (methoxyC-O-C) ΓNMRδ CDCl3 TMS : 1.90 (3H, s, CO-CH 3 ),
3.8
(3H, s, O-CH 3 ), 5.15 (1H, d, C 2 -
H), 5.38 (1H, d, C3 -H), 6.75-7.75
(8H, aromatic ring hydrogen), J 2 , 3 = 7 cps. Example 3 Erythro-N-[β-dimethylaminoethyl]-
2-hydroxy-3-(p-methoxyphenyl)-
200 mg of 3-(o-iodophenylthio)-propionic acid amide was added to 5 ml of dimethylformamide and 5 ml of benzene, and the mixture was heated and stirred using a Dernstark apparatus to an internal temperature of 110°C. 7 mg of copper iodide and 56 mg of potassium carbonate were added, and the mixture was further heated and stirred for 2.5 hours. The solvent was distilled off, and benzene was added to the residue to give a 1N
Hydrochloric acid was added. The aqueous layer was taken out and made alkaline using potassium carbonate, and then extracted with benzene. The benzene layer was washed with water, dried, and the benzene was distilled off to give cis-3-hydroxy-2,3-dihydro-5-(β-dimethylaminoethyl)-2-(p-
methoxyphenyl)1,5-benzothiazepine-
4(5H)-one was obtained. ΓTLC (developing solvent ethanol: chloroform: water: acetic acid = 12:10:3:1 V/V): Rf0.70 ΓNMRδ CDCl3 TMS : 2.25 (6H, s, N(CH 3 ) 2
),
3.75 (3H, s, O-CH 3 ), 4.68 (1H, d, C 3
-H), 4.83 (1H, d, C2 - H), 6.68-7.75
(8H, aromatic ring hydrogen) J 2 , 3 = 7 cps. Example 4 Erythro-N-(β-dimethylaminoethyl)-
2-acetoxy-3-(p-methoxyphenyl)-
Add 1 g of 3-(o-iodophenylthio)-propionic acid amide to 20 ml of dimethyl sulfoxide and benzene.
The mixture was added to 2.0 ml and heated and stirred using a Dernstark apparatus until the internal temperature reached 110°C. 33.5 mg of copper iodine and 280.0 mg of potassium carbonate were added, and the mixture was further heated and stirred for 5 hours. The solvent was distilled off, benzene was added to the residue, washed with water, dried, and concentrated under reduced pressure to obtain 650 mg of a black oily substance. This was purified by silica gel column chromatography (eluted with ethyl acetate), and cis-3-acetoxy-2,3-dihydro-5-(β-dimethylaminoethyl)-2-(p-methoxyphenyl)-
1,5-benzothiazepin-4(5H)-one was obtained. Yield 200 mg (yield 26.1%) mp 139-141°C ΓTLC (developing solvent ethanol: chloroform: water: acetic acid = 2:10:1:1 V/V) Rf0.49 Consistent with the separately synthesized standard. ΓIRcm -1 : 1740 (acetyl C=O), 1680 (amide C=O), 1600, 1510 (benzene nucleus) 1250,
1030 (methoxy C-O-C) ΓNMRδ CDCl3 TMS : 1.90 (3H, s, CO-CH 3 ),
2.33 (6H, s, N < CH3 CH3 ), 3.83 (3H, s, O
-CH 3 ), 5.0 (1H, d, C 2 -H), 5.2 (1H,
d, C3 -H), 6.88 (8H, aromatic ring hydrogen) J2,3 = 7 cps. Reference Example (1) 4.0 g of p-methoxyphenyl glycidic acid methyl ester was added to 6 ml of acetonitrile, and a solution of 40 g of o-iodothiophenol dissolved in 8 ml of acetonitrile was added dropwise thereto. The reaction was carried out for 4 days at room temperature, and the precipitated crystals were collected to obtain erythro-2-hydroxy-3-(p-methoxyphenyl)-3-(o-iodophenylthio)-propionic acid methyl ester. Yield 4.8g (yield 60.4%) mp133-134℃ ΓTLC (benzene: acetone = 95:5):
Rf0.43 ΓIRcm -1 : 3500 (OH), 1720 (ester C=
O), 1600, 1510 (benzene ring), 1240, 1025
(C-O-C), ΓNMRδ CDCl3 TMS : 3.30 (1H, d, OH), 3.5
Five
(3H, s, -CO-OCH 3 ), 3.71 (3H, s, O
−CH 3 ), 4.48 (1H, m, C 3 −H), 4.65
(1H, d, C 2 -H), 6.7-7.9 (8H, aromatic ring hydrogen) (2) Erythro-2-hydroxy-3- obtained in (1)
(p-methoxyphenyl)-3-(o-iodophenylthio)-propionic acid methyl ester 2.7
g was stirred in dilute aqueous caustic soda solution at room temperature for 1 hour. After washing the reaction mixture with ether, the aqueous layer was acidified with hydrochloric acid and extracted with ether. The ether layer was collected, washed with water, dried, and then distilled off with ether to obtain erythro-2-hydroxy-3-(p-methoxyphenyl)-3-(o-iodophenylthio)-propionic acid. Recrystallized from benzene. Yield 2.24g (yield 85.4%) mp131-132℃ ΓTCL (chloroform: ethanol: acetic acid = 60:10:1): Rf0.38 ΓIRcm -1 : 3500 (OH), 3200-2000 (carboxylic acid OH), 1710 (carboxylic acid -C=O),
1600, 1510 (benzene ring) ΓNMRδ CDCl3 TMS : 3.73 (3H, s, O-CH 3 )
,
4.55 (1H, d, C 3 −H), 4.75 (1H, d, C 2
-H), 5.51 (1H, Broad, OH), 6.68~
7.85 (8H, aromatic ring hydrogen) (3) 3 g of acetic anhydride was added to 600 mg of the compound obtained in (2), and the mixture was reacted at 60°C for 2 hours. After concentration, purification by silica gel chromatography (eluted with benzene:ethyl acetate = 4:1)
This gave erythro-2-acetoxy-3-(p-methoxyphenyl)-3-(o-iodophenylthio)-propionic acid. Yield 560 mg (yield 84.0%) ΓTLC (chloroform: ethanol: acetic acid = 60:10:1): Rf0.61 ΓIRcm -1 : 3600-2400 (COOH), 1750 (ester = CO), 1720 (carboxylic acid = CO),
1600, 1520 (benzene ring) ΓNMRδ CDCl3 TMS : 2.1 (3H, s, -CO-CH 3
),
3.73 (3H, s, O-CH 3 ), 4.83 (1H, d,
C2 - H), 5.5 (1H, d, C3 - H), 6.68~
7.98 (8H, aromatic ring hydrogen) (4) 6.1 g of the compound obtained in (3) was dissolved in 20 ml of chloroform, 3.07 g of thionyl chloride was added thereto, and the mixture was heated under reflux for 2 hours. Concentrate under reduced pressure to obtain erythro-2
-acetoxy-3-(p-methoxyphenyl)-
3-(o-iodophenylthio)-propionic acid chloride was obtained. Amount obtained: 6.21 g (yield 94.9%) ΓIRcm -1 : 1790 (-CO-Cl), 1750 (ester > C=O), 1600, 1510 (benzene ring) (5) 1.24 g of N/N-dimethylethylamine, 1.57 g of triethylamine was dissolved in 8 ml of chloroform, and a solution of 6.21 g of the compound obtained in (4) dissolved in 25 ml of chloroform was added thereto. After the reaction, the mixture was concentrated under reduced pressure, and the residue was dissolved in benzene and diluted hydrochloric acid was added. The obtained dilute hydrochloric acid layer was made alkaline with potassium carbonate and extracted with benzene. After treatment of the benzene layer, erythro-N-
(β-dimethylaminoethyl)-2-acetoxy-3-(p-methoxyphenyl)-3-(o-iodophenyl)-bropionic acid amide was obtained. Yield 4.98g (yield 75.0%) ΓTLC (ethanol: chloroform: water: acetic acid = 2:10:1:1): Rf0.50 ΓIRcm -1 : 3300 (NH), 1730 (ester > C =
O), 1670 (amide > C=O), 1600, 1510
(Benzene ring) ΓNMRδ CDCl3 TMS : 2.1 (3H, s, -CO-CH 3
),
2.25 (6H, s, N(CH 3 ) 2 ), 2.45 (2H,
t, Cβ-H 2 ), 3.3 (2H, q, Cα-H 2 ),
3.78 (3H, s, O-CH 3 ), 4.93 (1H, d,
C2 - H), 5.50 (1H, d, C3 - H), 6.75~
7.93 (8H, aromatic ring hydrogen) (6) 4.48 g of the compound obtained in (5) was dissolved in 20 ml of ethanol, and 20 ml of an aqueous solution containing 17 g of potassium carbonate was added. Stirred at 50°C for 2 hours. It was concentrated under reduced pressure, and chloroform was added to the residue. to the chloroform layer
1N hydrochloric acid was added. The hydrochloric acid layer was taken and neutralized with potassium carbonate. Next, it was extracted with chloroform, washed with water, dried, and the solvent was distilled off.
(p-methoxyphenyl)-3-(o-iodophenylthio)-propionic acid amide was obtained. Recrystallized from benzene. Yield 2.87g (yield 69.45%) mp124-127℃ ΓTLC (ethanol: chloroform: water: acetic acid = 2:10:1:1): Rf0.31 ΓIRcm -1 : 1660 (amide > C=O), 1240 ,
1035 (C-O-CH 3 ) ΓNMRδ CDCl3 TMS : 2.15 (6H, s, N(CH 3 )
2 ),
2.4 (2H, t, Cβ-H 2 ), 3.33 (2H, q,
Cα-H 2 ), 3.78 (3H, s, O-CH 3 ), 4.53
(1H, d, C 3 −H), 5.0 (1H, d, C 2 −
H), 6.83-7.95 (8H, aromatic ring hydrogen) (7) Add 2.37 g of the compound obtained in (4) to 10 ml of benzene.
This was added dropwise to 28% ammonia water under ice-cooling. Gradually return to room temperature and extract with benzene.
After washing with water, drying and concentrating, the residue was recrystallized from benzene to give white crystals, erythro-2-hydroxy-3-(p-methoxyphenyl)-3-(o-iodophenylthio)-, with a melting point of 150-153°C. Propionic acid amide was obtained. ΓTLC (chloroform: ethanol: acetic acid = 60:10:1): Rr0.62 ΓIRcm -1 : 3450-3170 (OH, NH), 1670 (amide CO) ΓNMRδ DMSO TMS : 3.70 (3H, s, O-CH 3 ),
4.20 (1H, q, C 3 −H), 4.90 (1H, d, C 2
-H), 6.08 (1H, d, OH), 6.75-7.90
(8H, aromatic ring hydrogen), 7.33 (2H, s, NH2 ) Example 5 Erythro-N-(β-dimethylaminoethyl)-
2-acetoxy-3-(p-methoxyphenyl)-
200 mg of 3-(o-iodophenylthio)-propionic acid amide was added to 5 ml of dimethyl sulfoxide and 5 ml of benzene, and the mixture was heated and stirred using a Dernstark apparatus to an internal temperature of 110°C. 4 mg of copper powder and 56 mg of potassium carbonate were added, and the mixture was heated and stirred for 5 hours. The solvent was distilled off and treated in the same manner as in Example 4, leaving a black oily substance.
Obtained 150 mg. This was purified by silica gel column chromatography, and cis-3-acetoxy-
2,3-dihydro-5-(β-dimethylaminoethyl)-2-(p-methoxyphenyl)-1,5-
Benzothiazepine-4(5H)-one was obtained. Yield 36 mg (yield 23.6%) mp137-139°C. The compound obtained was consistent with that obtained in Example 4. Example 6 Erythro-N-(β-dimethylaminoethyl)-
2-hydroxy-3-(p-methoxyphenyl)-
250 mg of 3-(o-iodophenylthio)-propionic acid amide was added to 5 ml of dimethylformamide and 5 ml of benzene, and the mixture was heated and stirred using a Dernstark apparatus to an internal temperature of 110°C. 5 mg of cuprous oxide and 70 mg of potassium carbonate were added, and the mixture was heated and stirred for 3 hours. The solvent was distilled off, and the same treatment as in Example 3 was carried out. Benzene was distilled off to give cis-3-hydroxy-2,3-dihydro-5-(β-dimethylaminoethyl)-2-
(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one was obtained. The compound obtained was consistent with that obtained in Example 3. Example 7 Erythro-N-(β-dimethylaminoethyl)-
2-acetoxy-3-(p-methoxyphenyl)-
500 mg of 3-(o-iodophenylthio)-propionic acid amide was added to 10 ml of dimethyl sulfoxide and 10 ml of benzene, and the mixture was heated and stirred using a Dernstark apparatus to an internal temperature of 110°C. 13 mg of cuprous bromide and 140 mg of potassium carbonate were added, and the mixture was heated and stirred for 5 hours.
The solvent was distilled off and treated in the same manner as in Example 4 to give cis-3
-acetoxy-2,3-dihydro-5-(β-dimethylaminoethyl)-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one was obtained. Yield 94mg (yield 24.6%) mp138-140℃. The compound obtained was consistent with that obtained in Example 4. Example 8 Erythro-2-hydroxy-3-(p-methoxyphenyl)-3-(o-iodophenylthio)-
200 mg of propionic acid amide was added to 5 ml of dimethylformamide and 5 ml of benzene, and the mixture was heated and stirred using a Dernstark apparatus to an internal temperature of 110°C. After adding 10 mg of copper carbonate and 80 mg of potassium carbonate and heating and stirring for 3 hours, the same treatment as in Example 1 was carried out to obtain cis-3.
-Hydroxy-2,3-dihydro-2-(p-methoxyphenyl)-1,5-benzothiazepine-
White needle-like crystals of 4(5H)-one were obtained. Amount obtained: 50 mg (yield 35.6%). The compound obtained was consistent with that obtained in Example 1. Example 9 Erythro-2-hydroxy-3-(p-methoxyphenyl)-3-(o-iodophenylthio)-
350 mg of propionic acid amide was added to 5 ml of dimethylformamide and 5 ml of benzene, and the mixture was heated and stirred using a Dernstark apparatus to an internal temperature of 110°C.
35 mg of EDTA-copper and 120 mg of potassium carbonate were added, and the mixture was further heated and stirred for 2 hours. Treated in the same manner as in Example 1, cis-3-hydroxy-2,3-dihydro-
2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one was obtained. Amount obtained: 95 mg (yield 38.6%). The compound obtained was consistent with that obtained in Example 1.
Claims (1)
はアセチル基を、R2は水素原子またはβ−ジメ
チルアミノエチル基を示す〕 で示される２−ヒドロキシ（またはアセトキシ）
−３−（ｐ−メトキシフエニル）−３−（ｏ−ハロ
ゲノフエニルチオ）プロピオン酸アミド誘導体を
銅粉または銅化合物及び塩基の存在下縮合閉環さ
せ、 式 〔式中R1は水素原子またはアセチル基を、R2は水
素原子またはβ−ジメチルアミノエチル基を示
す〕 で示される、１・５−ベンゾチアゼピン誘導体を
得ることを特徴とする１・５−ベンゾチアゼピン
誘導体の製造方法。[Claims] 1 formula [In the formula, X represents a halogen atom, R 1 represents a hydrogen atom or an acetyl group, and R 2 represents a hydrogen atom or a β-dimethylaminoethyl group] 2-hydroxy (or acetoxy) represented by
-3-(p-methoxyphenyl)-3-(o-halogenophenylthio)propionic acid amide derivative is condensed and ring-closed in the presence of copper powder or a copper compound and a base, formula [In the formula, R 1 represents a hydrogen atom or an acetyl group, and R 2 represents a hydrogen atom or a β-dimethylaminoethyl group] 1.5, characterized by obtaining a 1,5-benzothiazepine derivative represented by - A method for producing a benzothiazepine derivative.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15790281A JPS58150579A (en) | 1981-10-02 | 1981-10-02 | Preparation of 1,5-benzothiazepine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15790281A JPS58150579A (en) | 1981-10-02 | 1981-10-02 | Preparation of 1,5-benzothiazepine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS58150579A JPS58150579A (en) | 1983-09-07 |
| JPS6152150B2 true JPS6152150B2 (en) | 1986-11-12 |
Family
ID=15659922
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP15790281A Granted JPS58150579A (en) | 1981-10-02 | 1981-10-02 | Preparation of 1,5-benzothiazepine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS58150579A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6219516U (en) * | 1985-07-18 | 1987-02-05 | ||
| JPH062950A (en) * | 1992-06-17 | 1994-01-11 | Fujitsu General Ltd | Controlling method for oil fired warm water boiler |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH01186875A (en) * | 1988-01-19 | 1989-07-26 | Tanabe Seiyaku Co Ltd | Production of benzothiazepine derivative |
-
1981
- 1981-10-02 JP JP15790281A patent/JPS58150579A/en active Granted
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6219516U (en) * | 1985-07-18 | 1987-02-05 | ||
| JPH062950A (en) * | 1992-06-17 | 1994-01-11 | Fujitsu General Ltd | Controlling method for oil fired warm water boiler |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS58150579A (en) | 1983-09-07 |
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