JPS63307866A - Production of 1,5-benzothiazepine derivative - Google Patents
Production of 1,5-benzothiazepine derivativeInfo
- Publication number
- JPS63307866A JPS63307866A JP62142390A JP14239087A JPS63307866A JP S63307866 A JPS63307866 A JP S63307866A JP 62142390 A JP62142390 A JP 62142390A JP 14239087 A JP14239087 A JP 14239087A JP S63307866 A JPS63307866 A JP S63307866A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- formula
- reaction
- cis
- hydrochloride
- 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.)
- Pending
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 13
- KJFRSZASZNLCDF-UHFFFAOYSA-N 1,5-benzothiazepine Chemical class S1C=CC=NC2=CC=CC=C12 KJFRSZASZNLCDF-UHFFFAOYSA-N 0.000 title description 2
- 239000000010 aprotic solvent Substances 0.000 claims abstract description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- 239000000126 substance Substances 0.000 claims 2
- 150000001875 compounds Chemical class 0.000 abstract description 40
- -1 dimethylaminoethyl group Chemical group 0.000 abstract description 7
- WQMAANNAZKNUDL-UHFFFAOYSA-N 2-dimethylaminoethyl chloride Chemical compound CN(C)CCCl WQMAANNAZKNUDL-UHFFFAOYSA-N 0.000 abstract description 2
- 229960005316 diltiazem hydrochloride Drugs 0.000 abstract description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 abstract 3
- 229910052593 corundum Inorganic materials 0.000 abstract 3
- 229910001845 yogo sapphire Inorganic materials 0.000 abstract 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 2
- 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 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- 230000000304 vasodilatating effect Effects 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 13
- 239000013078 crystal Substances 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 238000001914 filtration Methods 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
- 238000007796 conventional method Methods 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- PPQXADXGECUTFI-UHFFFAOYSA-N 5h-1,5-benzothiazepin-4-one Chemical compound S1C=CC(=O)NC2=CC=CC=C21 PPQXADXGECUTFI-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000003218 coronary vasodilator agent Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000009958 sewing Methods 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
Landscapes
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
【発明の詳細な説明】
本発明は、たとえば冠血管拡張作用を有する公知の医薬
化合物である塩酸ツルチアゼムの製造に有用な公知の合
成中間体化合物の新規な製法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing a known synthetic intermediate compound useful for the production of, for example, tultiazem hydrochloride, a known pharmaceutical compound with coronary vasodilator activity.
とくには、従来法に比して、取扱い及び反応操作上、遡
かに安全な試薬を用いて且つ従来法に比して有利に短縮
された一段階反応操作をもって、更に従来法に比して高
純度ならびに高収率をもって、該公知中間体化合物を工
業的に有利にｓｌ造できる改善製法に関する。In particular, it uses reagents that are safer in handling and reaction operations than the conventional method, and has a one-step reaction procedure that is advantageously shortened compared to the conventional method. The present invention relates to an improved production method that enables industrially advantageous SL production of the known intermediate compound with high purity and high yield.
更に詳しくは、本発明は下記式（Ｉ［［）で表わされる
ｄ−シス−３−ヒドロキシ−２，３−ジヒドロ−２−（
４−メトキシフェニル）−１，５−ベンゾチアゼピン−
４（５Ｈ）−オンを、非プロトン性溶媒中でＫＦ−Ａｌ
２Ｏ２の共存下に、下記式（ＩＩ）
ＣＩＧＨｚＣＨ２Ｎ（Ｃ１ｌｓ）２（ＩＩ ）で表わさ
れる２−クロロ−Ｎ、Ｎ−ツメチルエチルアミンと反応
させることを特徴とする下記式で表わされるｄ−シス−
３−ヒドロキシ−２，３−ノヒドロー５−［２−（ツメ
チルアミ７）エチル−２−（４−メトキシフェニル）−
１，５−ベンゾチアゼピン−４（５Ｈ）−オン又はその
塩酸塩の製法に関する。More specifically, the present invention relates to d-cis-3-hydroxy-2,3-dihydro-2-(
4-methoxyphenyl)-1,5-benzothiazepine-
4(5H)-one in KF-Al in an aprotic solvent
d-cis- represented by the following formula, characterized by reacting with 2-chloro-N,N-tumethylethylamine represented by the following formula (II) CIGHzCH2N(C1ls)2(II) in the coexistence of 2O2.
3-Hydroxy-2,3-nohydro5-[2-(tumethylami7)ethyl-2-(4-methoxyphenyl)-
The present invention relates to a method for producing 1,5-benzothiazepin-4(5H)-one or its hydrochloride.
従来、上記式（１）化合物またはその酸塩の製法として
例えば特公昭４６−１６７４９号の提案が知られている
。この従来提案によれば、上記式（ＩＩＩ）で表わされ
る１、５−ベンゾチアゼピン誘導体を、その５位窒素部
位におけるアルカリ金属塩の形の化合物に一旦転化した
後、これと式（Ｉ［）で示される化合物とを縮合反応さ
せる二段階反応により上記式（１）化合物を製造するこ
とが記載されている。そして、この従来法においては、
そして、上記式（ＩＩＩ）化合物のアルカリ金属塩は、
化合物（■）を例えば金属ナトリウム、水素化ナトリウ
ム、ナ（リウムアミドの如き試薬と適当な溶媒中２０〜
４０℃に概ね１時間程度反応させることによりＩｎされ
ることが記載されている。しかしながら、上記従来法に
おいて用いるこれらの金属す） １７ウム、水素化ナト
リウム、ナトリウム７ミドの如き試薬は、その取扱い及
び反応操作上に非常に危険を伴うものであり、これを工
業的規模で使用する事は作業の安全性を確保することが
非常に困難な方法である。その上、この従来提案の実施
例３に示される上うに、式（１）化合物の収率（臭化水
素酸塩の形で）は１２．４％と低く、満足なものではな
い。Hitherto, the proposal of Japanese Patent Publication No. 16749/1984 has been known as a method for producing the compound of formula (1) or its acid salt. According to this conventional proposal, the 1,5-benzothiazepine derivative represented by the above formula (III) is once converted into a compound in the form of an alkali metal salt at its 5-nitrogen site, and then this is combined with the formula (I[ ) It is described that the compound of formula (1) is produced by a two-step reaction of condensation reaction with the compound represented by formula (1). In this conventional method,
And the alkali metal salt of the above formula (III) compound is:
Compound (■) is mixed with a reagent such as sodium metal, sodium hydride, sodium amide in a suitable solvent for 20~
It is described that In can be obtained by reacting at 40° C. for about 1 hour. However, the reagents used in the above-mentioned conventional method, such as sodium chloride, sodium hydride, and sodium chloride, are extremely dangerous in their handling and reaction operations, and they cannot be used on an industrial scale. This is a very difficult way to ensure work safety. Moreover, as shown in Example 3 of this prior proposal, the yield of the compound of formula (1) (in the form of hydrobromide salt) is as low as 12.4%, which is not satisfactory.
かように、従来法においては取扱い及び反応操作上の危
険を伴う試薬を用いて式（１）化合物の５位−窒素部位
におけるアルカリ金属塩を形成する工業的実施に不適な
第一段階反応が必要であるという欠陥及１式（１）化合
物の製造には二段階操作を要する不利益があり、更に、
収率の点でも不満足である。As described above, in the conventional method, the first step reaction, which is unsuitable for industrial implementation, involves forming an alkali metal salt at the 5-nitrogen site of the compound of formula (1) using reagents that involve risks in handling and reaction operations. There are disadvantages in that the production of compounds of formula (1) requires a two-step operation, and furthermore,
The yield is also unsatisfactory.
本発明者らは、取扱い及び操作上の危険性がなくて工業
的規模の実施に適した且つ高純度の式（１）目的化合物
又はその塩酸塩を高収率で製造でさる式（１）化合物又
はその塩酸塩の新しい製法を開発すべ（研究を行って米
な。その結果、従来、式（ＩＩＩ）化合物から式（Ｉ）
化合物のＷＪＩ造に有用であることの全く未知であった
それ自体公知の化合物ＫＦ−ＡＩ□０３（弗化カリ担持
アルミナ）を、アルキレーション促進剤として利用する
ことによって式（Ｉ［［）化合物と式（ＩＩ）化合物と
から、−１２階反応によって一挙ｌこ式（１）化合物が
製造できることを発見した。The present inventors have proposed a method for producing the target compound of formula (1) or its hydrochloride in high yield, which is free from handling and operational hazards, suitable for implementation on an industrial scale, and of high purity. A new method for producing the compound or its hydrochloride should be developed (research should be carried out).As a result, it has been found that
The compound of formula (I [[) It has been discovered that a compound of formula (1) can be produced at once from a compound of formula (II) and a compound of formula (II) by a -12-step reaction.
斯（で、本発明方法によれば、取扱い及び操作上の危険
性から完全に解放された一段階反応捏作という工業的に
顕著に有利な捏作によって高純度の式（１５目的物また
はその塩酸塩な高収率で一挙に製造できることがわかっ
た。According to the method of the present invention, highly pure formula (15 target products or their It was found that the hydrochloride salt can be produced all at once with high yield.
従って、本発明の目的は式（１）化合物を工業的に有利
に製造できる新しい製法を提供するにある。Therefore, an object of the present invention is to provide a new method for producing the compound of formula (1) industrially and advantageously.
本発明の上記目的及び更に多くの池の目的ならびに利点
は、以下の記載から一層明らかとなるであろう。The above objects and further objects and advantages of the present invention will become more apparent from the following description.
本発明方法によれば、式（Ｉｌｌ）化合物を非プロトン
性溶媒中でＫ Ｆ −Ａ Ｉ２０ 、の共存下に式（Ｉ
Ｉ）化合物と反応させることにより、一段反応操作で一
挙に式（１）目的化合物を製造することができる。According to the method of the present invention, a compound of formula (Ill) is converted into a compound of formula (Ill) in an aprotic solvent in the coexistence of K F -A I20 .
By reacting with compound I), the target compound of formula (1) can be produced all at once in a single reaction operation.
反応は室温でも進行するのでとくに冷却もしくは加熱す
る必要はないが、例えば約２０” 〜３０℃程度の反応
温度及び約１日〜約４日の如き反応時間を例示すること
ができる。Since the reaction proceeds at room temperature, there is no need for particular cooling or heating; however, for example, a reaction temperature of about 20'' to 30°C and a reaction time of about 1 day to about 4 days can be used.
反応成分式（ＩＩＩ）化合物は公知化合物であって、例
えば特公昭４５−９３８３号に開示された方法を利用又
は応用して製造することができる６式（ＩＩ）化合物も
公知化合物であり、たとえばその塩酸塩として市販され
ている０反応に用いるＫＦ−Ａ Ｉ ２０３も公知化合
物であって、例えば、Ｃｈｅｍｉｓｔｒｙ Ｌｅｔｔ
ｅｒｓ＊ ７５５ （１９７９）に記載の公知方法で、
Ａｌ２０ｉとＫＦ水溶液を接触させ例えばロータリー蒸
発器巾約５０〜６０℃の如き条件で水分を除去し、更に
乾燥する手法によって製造することができる。この際、
水分除去後、減圧乾燥もしくは加熱条件下の減圧乾燥を
行うことができ、例えば約７５℃前後或は約１５０℃前
後の温度条件下の減圧乾燥を例示することができる。好
ましい乾燥条件の一例として、約１５０℃前後の温度条
件下の減圧乾燥を例示することができる。The reaction component formula (III) compound is a known compound, and the formula (II) compound, which can be produced by using or applying the method disclosed in Japanese Patent Publication No. 45-9383, is also a known compound, for example. KF-A I 203 used in the 0 reaction, which is commercially available as its hydrochloride, is also a known compound, for example, Chemistry Lett.
ers* 755 (1979),
It can be produced by bringing Al20i and a KF aqueous solution into contact, removing moisture under conditions such as a rotary evaporator width of about 50 to 60° C., and further drying. On this occasion,
After removing moisture, drying under reduced pressure or drying under reduced pressure under heated conditions can be performed, for example, drying under reduced pressure at a temperature of about 75° C. or about 150° C. can be exemplified. As an example of preferable drying conditions, vacuum drying at a temperature of about 150° C. can be exemplified.
本発明方法の実施に際しで、Ｋ Ｆ −Ａ Ｉ２０ 、
の使用量は適宜に選択できるが、式（ＩＩＩ）化合物に
対して例えば約２〜約５倍当量（ＫＦとして）の使用量
を例示することがで軽る。ＫＦ−Ａｌ□０．におけるＫ
Ｆの含量として約４０重１％程度が普通であるが、適宜
に選択することができる０式（ＩＩ）化合物の使用量は
適宜に選択できるが、式（ＩＩＩ）化合物に対して約１
〜約２倍当量の如き使用量を例示することができる。When carrying out the method of the present invention, K F -A I20,
The amount to be used can be selected as appropriate, but for example, the amount to be used is about 2 to about 5 times equivalent (as KF) to the compound of formula (III). KF-Al□0. K in
The content of F is usually about 40% by weight, but can be selected as appropriate.The amount of the compound of formula (II) to be used can be selected as appropriate, but it is about 1% by weight based on the compound of formula (III).
An example of the amount used is about 2 to about 2 equivalents.
反応は非プロトン性溶媒中で行われ、このような溶媒の
具体例としては、例えば、アセトニトリル、１，２−ジ
メトキシエタン、テトラヒドロ７２ンなとの如き非プロ
トン性溶媒を例示できる。The reaction is carried out in an aprotic solvent, and specific examples of such solvents include acetonitrile, 1,2-dimethoxyethane, tetrahydro-72, and the like.
その使用量にもと（べつな制約はないが、例えば、式（
ＩＩＩ）化合物に対して約１０〜約５０倍容量の如き使
用量を例示することができる１反応は不活性雰囲気下で
行うのが好ましくは、例えばアルゴン、窒素などを例示
できる。Its usage is based on (there are no other restrictions, but for example, the expression (
III) The amount used can be exemplified by about 10 to about 50 times the volume of the compound. The reaction is preferably carried out under an inert atmosphere, such as argon, nitrogen, etc.
本発明方法で得られる式（１）化合物は、塩化水素と接
触させることにより容易にその塩酸塩に転化できる。The compound of formula (1) obtained by the method of the present invention can be easily converted into its hydrochloride by contacting it with hydrogen chloride.
本発明方法で得られる式（１）化合物は・例えばトルエ
ン等の反応溶媒中で塩化アセチルとトリエチルアミンと
を用いるアセチル化反応に付した後、必要により塩化水
素と接触せしめて公知医薬化合物である塩酸ツルチアゼ
ムに変換することができる。The compound of formula (1) obtained by the method of the present invention is subjected to an acetylation reaction using acetyl chloride and triethylamine in a reaction solvent such as toluene, and then, if necessary, brought into contact with hydrogen chloride to form a compound of hydrochloric acid, which is a known pharmaceutical compound. It can be converted to tultiazem.
以下、実施例により本発明方法を更に詳しく説明する。Hereinafter, the method of the present invention will be explained in more detail with reference to Examples.
実施例１
ｄ−シス−２，３−ジヒドロ−３−ヒドロキシー−２−
（４−メトキシフェニル）−１，５−ベンゾチアゼピン
−４（５Ｈ）−オン２０ｇ５ＫＦ−ＡＩ□０３ ３２、
Ｉｇ、７セトニトリル３００＋ｌ及び水０．５１の混合
物を２０〜３０℃で２０分攪拌しり０次いで２−クロロ
−Ｎ、Ｎ−ジメチルエチルアミンのトルエン溶液（１，
０８８Ｎ）７４．５ｍｌを約２０℃にて加えた。１５〜
２２℃で４７時間攪拌した後、さらにＫ Ｆ −Ａ １
．０１ ８ｇを加えて１２１１’Ｔ間攪袢した。不溶物
をろ去し、得られたろ液を減圧にて濃縮した。得られた
残留物にＦルエン１００ｍ１と水３０ｍ１を加えて攪拌
した後、分液した。有ｆｉ層を分取し、水３０−１で洗
浄した後、炭酸カリウム４ｇを用いて乾燥した。炭酸カ
リウムをろ去して得られたろ液を減圧にて濃縮した後、
得られた残留物にインプロパツール１００鋤１を加えて
加熱溶解した５次いで水にて冷却し、接種して１６時間
攪拌した。析出した結晶をろ取し乾燥してｄ−シス−２
，３−ジヒドロ−５−［２−（ジメチルアミノ）エチル
１−３−ヒドロキシ−２−（４−メトキシフェニル）−
ｉ、ｓ−ベンゾチアゼピン−４（５Ｈ）−オンの第−晶
１６．７１ｇを得た。論ｐ８６−８７℃、母液から第二
晶２．３２ｇを得た。Example 1 d-cis-2,3-dihydro-3-hydroxy-2-
(4-Methoxyphenyl)-1,5-benzothiazepine-4(5H)-one 20g5KF-AI□03 32,
A mixture of 300+l of Ig, 7cetonitrile and 0.51l of water was stirred at 20-30°C for 20 minutes, and then a toluene solution of 2-chloro-N,N-dimethylethylamine (1,
088N) was added at about 20°C. 15~
After stirring at 22°C for 47 hours, further K F -A 1
．． 018g was added and stirred for 1211'T. Insoluble materials were removed by filtration, and the resulting filtrate was concentrated under reduced pressure. After adding 100 ml of F-luene and 30 ml of water to the obtained residue and stirring, the mixture was separated. The fi layer was separated, washed with 30-1 of water, and then dried using 4 g of potassium carbonate. After filtering off potassium carbonate and concentrating the obtained filtrate under reduced pressure,
One part of Improper Tool 100 was added to the resulting residue and dissolved by heating.The mixture was then cooled with water, inoculated, and stirred for 16 hours. The precipitated crystals were collected by filtration and dried to give d-cis-2
,3-dihydro-5-[2-(dimethylamino)ethyl 1-3-hydroxy-2-(4-methoxyphenyl)-
16.71 g of crystals of i,s-benzothiazepin-4(5H)-one were obtained. 2.32 g of second crystals were obtained from the mother liquor at 86-87°C.
ｗ＋ｐ８４−８５℃０合計収１１１９．０３ｇ、収牢７
７゜０％。w+p84-85℃0 total yield 1119.03g, storage 7
7°0%.
実施例２゜
ｄ−シス−２，３−ジヒドロ−３−ヒドロキシ−２−（
４−メトキシフェニル）−１，５−ベンゾチアゼピン−
４（５１（）−オン２０ｇ、ＫＦ−Ａｔ□０゜２９．０
．、アセトニトリル４００■１及び水０．５ｌｌの混合
物を２０分攪拌した。次いで２−クロロ−Ｎ、Ｎ−ジメ
チルエチルアミン−トルエン（１．１０３Ｎ＞６６ｍｌ
を２０〜２３℃にて２０分を要して滴下した４２０〜２
５℃にて４１時間攪押した後、さらにＫ Ｆ − Ａ
１２０ ｓ ７ 、 １ ｇを加えて７時間攪拌した
．次いでラヂオライ）７，１ｇを加えて３０分攪拌した
後ラデオライ） ？，Ｉｇの層を通して吸引ろ過した．
トルエン８０１を流しこんで洗浄した後、得られたろ液
を合して減圧にてｍａｔ，た、得られた残留物にトルエ
ン１００＋ｍｌ及び水３０ｍｌを加えて３０分攪拌した
後、分液した。Example 2 d-cis-2,3-dihydro-3-hydroxy-2-(
4-methoxyphenyl)-1,5-benzothiazepine-
4(51()-one 20g, KF-At□0゜29.0
．． A mixture of 400 ml of acetonitrile and 0.5 ml of water was stirred for 20 minutes. Then 2-chloro-N,N-dimethylethylamine-toluene (1.103N>66ml
420-2 was added dropwise over 20 minutes at 20-23°C.
After stirring and pressing at 5°C for 41 hours, further KF-A
1 g of 120 s 7 was added and stirred for 7 hours. Next, add 7.1 g of radio rye) and stir for 30 minutes. , suction filtered through a layer of Ig.
After pouring toluene 801 and washing, the obtained filtrates were combined and heated under reduced pressure. To the obtained residue, 100 ml of toluene and 30 ml of water were added, stirred for 30 minutes, and then separated.
有機層を分取し、水３０−１で洗浄した後、炭酸カリウ
ム４ｅを用いて乾燥した．炭酸カリウムをろ去して得ら
れたろ液を減圧にて濃縮した後、得られた残留物にエフ
７−ル１１０鶴盈を加え加熱溶解し、次いで氷冷した，
２．４２Ｎ塩化水索−エタノール３０．５ｍｌを加えて
１５〜２０℃にで２時間３０分攪拌した．析出した結晶
をろ取し、乾燥した．第１晶２ ４．ｌ ｏｇを得た．
ｓｐ２１５ ２２５℃（分解）、収率８８．８％．母
液より第２晶０。The organic layer was separated, washed with water 30-1, and then dried using potassium carbonate 4e. The filtrate obtained by filtering off potassium carbonate was concentrated under reduced pressure, and F7-110 Tsuruei was added to the obtained residue and dissolved by heating, and then cooled on ice.
2.42N chloride water cord - 30.5 ml of ethanol was added and stirred at 15-20°C for 2 hours and 30 minutes. The precipitated crystals were collected by filtration and dried. First Crystal 2 4. I got log.
sp215 225°C (decomposition), yield 88.8%. 0 second crystals from mother liquor.
７７ｇを得た。収率２．８％。得られた合計２４。77g was obtained. Yield 2.8%. Total obtained 24.
８７ｇの結晶にエタノール１２５１を加えて２０分間還
流して洗浄した後、１５〜２５℃にて３時間攪拌した．
結晶をろ取して、乾燥しｄ−シス−２、３−ｐヒドロ−
３−ヒドロキシ−５−［２−（ジメチルアミノ）エチル
］−２−（４−メトキシ７エ二ル）−１．５−ベンゾチ
アゼピン−４（５Ｈ）−オン塩酸塩２ ２．７ ｓｇを
得た．収率８３．８％、縫ρ２１７−２２５℃（分解）
。Ethanol 1251 was added to 87 g of crystals and the mixture was washed by refluxing for 20 minutes, followed by stirring at 15 to 25°C for 3 hours.
The crystals were collected by filtration and dried to give d-cis-2,3-phydro-
3-Hydroxy-5-[2-(dimethylamino)ethyl]-2-(4-methoxy7enyl)-1.5-benzothiazepine-4(5H)-one hydrochloride 2 2.7 sg Obtained. Yield 83.8%, sewing ρ217-225℃ (decomposition)
.
参考例１［公知医薬化合物塩酸ジルチアゼムの製造１
ｄ−シス−２．３−ノヒドロー５−［２−（ジメチルア
ミノ）エチル］−３−ヒドロキシ−２−（４−ノドキシ
フェニル）−１．５−ベンゾチアゼピン−４（５Ｈ）−
オニ／１，８６．及びトルエン１９ｍ１の混合物にトリ
エチルアミン１．０５ｍｌを加え水冷した．次いで塩化
アセチル０．５４ｓ＋ｌを滴下した後、約２０℃にて９
０分攪拌した．次いで飽和炭酸水素ナトリウム水溶液１
００１と氷２０．の混合物に反応液を投入した．トルエ
ン層を分取した後、水層をトルエン２０−１で抽出した
．トルエン層を会して炭酸カリウムで乾燥した．溶媒を
蕾去した後得ら八た残留物にエタノール８ｍｌを加えて
溶解した．次いで２．８３Ｎ−塩酸−エタノール１．９
−１を加えた．３時間後、析出した結晶をろ取した。Reference Example 1 [Production of known pharmaceutical compound diltiazem hydrochloride 1 d-cis-2.3-nohydro-5-[2-(dimethylamino)ethyl]-3-hydroxy-2-(4-nodoxyphenyl)-1.5 -Benzothiazepine-4(5H)-
Oni/1,86. 1.05 ml of triethylamine was added to a mixture of 19 ml of toluene and the mixture was cooled with water. Next, 0.54 s+l of acetyl chloride was added dropwise, and the mixture was heated at about 20°C.
Stirred for 0 minutes. Then saturated aqueous sodium hydrogen carbonate solution 1
001 and ice 20. The reaction solution was added to the mixture. After separating the toluene layer, the aqueous layer was extracted with toluene 20-1. The toluene layers were combined and dried with potassium carbonate. After removing the solvent, 8 ml of ethanol was added to the resulting residue to dissolve it. Then 2.83N-hydrochloric acid-ethanol 1.9
-1 was added. After 3 hours, the precipitated crystals were collected by filtration.
得られた２．Ｏｌｇの結晶をエタノール８１から再結晶
してｄ−シス−３−７セＦキシ−２，３−ジヒドロ−５
−（２−（ジメチル７ミノ）二チル】−２−（４−ノ
ドキシフェニル）−１．５−ベンゾチアゼピン−４（５
Ｈ）−オン塩酸塩１．７３．を得た．収率７６、８％、
ｓｐ２１１−２１５℃（分解）、［（１１Ｂ ＋１ １
５．８°（ｃｌ．Ｏ、水）。Obtained 2. The crystals of Olg were recrystallized from ethanol 81 to give d-cis-3-7seFx-2,3-dihydro-5.
-(2-(dimethyl7mino)dityl)-2-(4-nodoxyphenyl)-1,5-benzothiazepine-4(5
H)-one hydrochloride 1.73. I got it. Yield 76.8%,
sp211-215℃ (decomposition), [(11B +1 1
5.8° (cl.O, water).
外１名 手続補正書 昭和６２年８月５日1 other person Procedural amendment August 5, 1986
Claims (1)
ドロ−２−（４−メトキシフェニル）−１，５−ベンゾ
チアゼピン−４（５Ｈ）−オンを、非プロトン性溶媒中
でＫＦ−Ａｌ＿２Ｏ＿３の共存下に、下記式（II） ＣｌＣＨ＿２ＣＨ＿２Ｎ（ＣＨ＿３）＿２（II）で表わ
される２−クロロ−Ｎ，Ｎ−ジメチルエチルアミンと反
応させることを特徴とする下記式（ I ） ▲数式、化学式、表等があります▼（ I ） で表わされるｄ−シス−３−ヒドロキシ−２，３−ジヒ
ドロ−５−１２−（ジメチルアミノ）エチル−２−（４
−メトキシフェニル）−１，５−ベンゾチアゼピン−４
（５Ｈ）−オン又はその塩酸塩の製法。[Claims] 1. d-cis-3-hydroxy-2,3-dihydro-2-(4-methoxyphenyl)-1 represented by the following formula (III) ▲ Numerical formula, chemical formula, table, etc. ▼ , 5-benzothiazepin-4(5H)-one in the presence of KF-Al_2O_3 in an aprotic solvent to form 2-chloro-N represented by the following formula (II) ClCH_2CH_2N(CH_3)_2(II). ,N-dimethylethylamine. d-cis-3-hydroxy-2,3-dihydro-5- represented by the following formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) 12-(dimethylamino)ethyl-2-(4
-methoxyphenyl)-1,5-benzothiazepine-4
A method for producing (5H)-one or its hydrochloride.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62142390A JPS63307866A (en) | 1987-06-09 | 1987-06-09 | Production of 1,5-benzothiazepine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62142390A JPS63307866A (en) | 1987-06-09 | 1987-06-09 | Production of 1,5-benzothiazepine derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS63307866A true JPS63307866A (en) | 1988-12-15 |
Family
ID=15314247
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62142390A Pending JPS63307866A (en) | 1987-06-09 | 1987-06-09 | Production of 1,5-benzothiazepine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS63307866A (en) |
-
1987
- 1987-06-09 JP JP62142390A patent/JPS63307866A/en active Pending
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