JPH0585549B2 - - Google Patents
Info
- Publication number
- JPH0585549B2 JPH0585549B2 JP59009496A JP949684A JPH0585549B2 JP H0585549 B2 JPH0585549 B2 JP H0585549B2 JP 59009496 A JP59009496 A JP 59009496A JP 949684 A JP949684 A JP 949684A JP H0585549 B2 JPH0585549 B2 JP H0585549B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- methoxyphenyl
- acetyl chloride
- formula
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 10
- 239000012346 acetyl chloride Substances 0.000 claims description 10
- KHQWPNQLSKDWAR-UHFFFAOYSA-N 3-(2-aminophenyl)sulfanyl-2-hydroxy-3-(4-methoxyphenyl)propanoic acid Chemical compound C1=CC(OC)=CC=C1C(C(O)C(O)=O)SC1=CC=CC=C1N KHQWPNQLSKDWAR-UHFFFAOYSA-N 0.000 claims description 5
- 229910052783 alkali metal Inorganic materials 0.000 claims description 5
- -1 alkali metal salt Chemical class 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- WKLRIRQZTCFCSE-UHFFFAOYSA-N [2-(4-methoxyphenyl)-4-oxo-3,5-dihydro-2h-1,5-benzothiazepin-3-yl] acetate Chemical compound C1=CC(OC)=CC=C1C1C(OC(C)=O)C(=O)NC2=CC=CC=C2S1 WKLRIRQZTCFCSE-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- 150000001875 compounds Chemical class 0.000 description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 239000000243 solution Substances 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000013078 crystal Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- KJFRSZASZNLCDF-UHFFFAOYSA-N 1,5-benzothiazepine Chemical group S1C=CC=NC2=CC=CC=C12 KJFRSZASZNLCDF-UHFFFAOYSA-N 0.000 description 1
- FEDJGPQLLNQAIY-UHFFFAOYSA-N 2-[(6-oxo-1h-pyridazin-3-yl)oxy]acetic acid Chemical compound OC(=O)COC=1C=CC(=O)NN=1 FEDJGPQLLNQAIY-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 230000000397 acetylating effect Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000003218 coronary vasodilator agent Substances 0.000 description 1
- 229960005316 diltiazem hydrochloride Drugs 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
- 239000011259 mixed solution Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229940001470 psychoactive drug Drugs 0.000 description 1
- 239000004089 psychotropic agent Substances 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Landscapes
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は式（） The present invention is based on the formula ()
【式】
で示される１，５−ベンゾチアゼピン誘導体であ
る。
２−（４−メトキシフエニル）−３−アセトキシ
−２，３−ジヒドロ−１，５−ベンゾチアゼピン
−４（5H）−オンの製造法に関する。
さらに詳しくは、式（）It is a 1,5-benzothiazepine derivative represented by the formula: The present invention relates to a method for producing 2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one. For more details, see expression ()
【式】
で示される２−ヒドロキシ−３−（２−アミノフ
エニルチオ）−３−（４−メトキシフエニル）プロ
ピオン酸を非プロトン性極性溶媒中において、ア
ルカリ金属塩の存在下に塩化アセチルを作用させ
ることを特徴とする化合物（）の製法に関する
ものである。
化合物（）は冠血管拡張剤或は向精神薬とし
て有用な医薬品である塩酸ジルチアゼムの合成中
間体として有用である。
化合物（）のアセチル化と同時に閉環して化
合物（）を製造する方法はすでに特開昭57−
136581号が公知である。しかし、この方法はやゝ
反応性に乏しい酸無水物を用いるため、あらかじ
め化合物（）をピリジン類等の塩を形成させる
必要があり、また反応に不必要な２ないし３分子
の酸残基を消費する。上記特許はさらに化合物
（）と塩化アセチルとの反応を記載しているが、
この場合は化合物（）のアセチル体が得られる
のみで、化合物（）が生成していない。
本発明者らは、炭酸ナトリウム等のアルカリ金
属存在下、化合物（）に塩化アセチルを作用さ
せると意外にも化合物（）が高収率で得られる
ことを見出し、これにもとずいて工業的に有利な
化合物（）の製造法を完成したものである。
この方法を実施するには、例えば化合物（）
とアルカリ金属塩を溶媒中に加え、直ちに溶媒で
稀釈した塩化アセチルを上部より滴下する。反応
は瞬時に進行し、このことは反応液の薄層クロマ
トグラフ分析で追跡することができ、同時に重炭
酸塩、塩と思われる沈殿が生成してくる。加える
塩化アセチルは化合物（）に対し２〜2.5当量
でよく、反応温度としては20℃ないし55℃が好ま
しい。用いるアルカリ金属塩としては、炭酸ナト
リウム及び炭酸カリウム、重炭酸ナトリウム等が
良く、必須ではないがピリジン、トリエチルアミ
ン等の有機塩基を添加する事も反応に好結果をも
たらす。用いる溶媒はジメチルホルムアミド、ジ
メチルスルホキシド、HMPA等の非プロトン性
極性溶媒が好ましい。滴下終了後は反応液を水に
あけ、酢酸エチル又はクロロホルムの溶媒で抽出
後溶媒を留去することにより化合物（）を結晶
として単離することができる。
以下に実施例を挙げて具体的に説明する。
実施例 １
２−ヒドロキシ−３−（２−アミノフエニルチ
オ）−３−（４−メトキシフエニル）プロピオン酸
638mg、炭酸ナトリウム424mgおよびＮ，Ｎ−ジメ
チルホルムアミド10mlの混合物に塩化アセチル
390mgを５mlのＮ，Ｎ−ジメチルホルムアミドに
溶かした溶液を20分で滴下した。その後反応液に
酢酸エチル20mlを加えて攪拌し、次いで炭酸ナト
リウム水溶液、水、飽和食塩水で順次洗浄後乾燥
し、濃縮すると２−（４−メトキシフエニル）−３
−アセトキシ−２，３−ジヒドロ−１，５−ベン
ゾチアゼピン−４（5H）−オンの結晶523mgが得ら
れた。
m.p.183〜188℃
実施例 ２
２−ヒドロキシ−３−（２−アミノフエニルチ
オ）−３−（４−メトキシフエニル）プロピオン酸
1.276g、ピリジン0.474g、炭酸カリウム1.14gおよ
びＮ，Ｎ−ジメチルホルムアミド10mlの混合物を
攪拌し、これに塩化アセチル0.624gのＮ，Ｎ−ジ
メチルホルムアミド10ml溶液を20分で滴下した。
以下実施例１と同様に処理して1.112gの２−（４
−メトキシフエニル）−３−アセトキシ−２，３
−ジヒドロ−１，５−ベンゾチアゼピン−４
（5H）−オンを得た。
実施例 ３
２−ヒドロキシ−３−（2′−アミノフエニルチ
オ）−３−（4′−メトキシフエニル）−プロピオン
酸638mg、ピリジン237mg、炭酸ナトリウム424mg
をＮ，Ｎ−ジメチルホルムアミド10mlに加え、こ
の溶液に、塩化アセチル0.4gをＮ，Ｎ−ジメチル
ホルムアミド５mlに溶解した溶液を室温下30分を
要して滴下し、更に５分攪拌した。
以下実施例１と同様に処理して２−（4′−メト
キシフエニル）−３−アセトキシ−２，３−ジヒ
ドロ−１，５−ベンゾチアゼピン−４（5H）−オ
ンの結晶613mgが得られた。
実施例 ４2-Hydroxy-3-(2-aminophenylthio)-3-(4-methoxyphenyl)propionic acid represented by the formula is mixed with acetyl chloride in the presence of an alkali metal salt in an aprotic polar solvent. The present invention relates to a method for producing the compound (2), which is characterized by causing the compound (2) to act on the compound (2). Compound () is useful as a synthetic intermediate for diltiazem hydrochloride, a pharmaceutical useful as a coronary vasodilator or psychotropic drug. A method for producing compound () by simultaneously acetylating and ring-closing compound () has already been disclosed in JP-A-57-
No. 136581 is publicly known. However, since this method uses an acid anhydride with relatively little reactivity, it is necessary to form a salt such as pyridine with the compound () in advance, and it is also necessary to remove two or three molecules of acid residues that are unnecessary for the reaction. Consume. The above patent further describes the reaction of compound () with acetyl chloride,
In this case, only the acetyl form of compound () is obtained, and compound () is not produced. The present inventors have unexpectedly found that compound () can be obtained in high yield when compound () is reacted with acetyl chloride in the presence of an alkali metal such as sodium carbonate, and based on this finding, industrial This is a completed method for producing compound () which is advantageous for To carry out this method, for example the compound ()
and an alkali metal salt are added to the solvent, and immediately acetyl chloride diluted with the solvent is added dropwise from the top. The reaction proceeds instantaneously, and this can be tracked by thin-layer chromatographic analysis of the reaction solution, with the formation of a precipitate that appears to be bicarbonate or salt. The amount of acetyl chloride added may be 2 to 2.5 equivalents based on the compound (), and the reaction temperature is preferably 20°C to 55°C. Preferred alkali metal salts include sodium carbonate, potassium carbonate, and sodium bicarbonate.Although not essential, addition of an organic base such as pyridine or triethylamine also brings about good results in the reaction. The solvent used is preferably an aprotic polar solvent such as dimethylformamide, dimethylsulfoxide, or HMPA. After completion of the dropwise addition, the reaction solution is poured into water, extracted with a solvent such as ethyl acetate or chloroform, and the solvent is distilled off, thereby allowing compound (2) to be isolated as crystals. This will be specifically explained below with reference to Examples. Example 1 2-hydroxy-3-(2-aminophenylthio)-3-(4-methoxyphenyl)propionic acid
638 mg, acetyl chloride in a mixture of 424 mg sodium carbonate and 10 ml N,N-dimethylformamide.
A solution of 390 mg dissolved in 5 ml of N,N-dimethylformamide was added dropwise over 20 minutes. After that, 20 ml of ethyl acetate was added to the reaction solution and stirred, and then washed successively with aqueous sodium carbonate solution, water, and saturated brine, dried, and concentrated to produce 2-(4-methoxyphenyl)-3.
523 mg of crystals of -acetoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one were obtained. mp183-188℃ Example 2 2-hydroxy-3-(2-aminophenylthio)-3-(4-methoxyphenyl)propionic acid
A mixture of 1.276 g, 0.474 g of pyridine, 1.14 g of potassium carbonate, and 10 ml of N,N-dimethylformamide was stirred, and a solution of 0.624 g of acetyl chloride in 10 ml of N,N-dimethylformamide was added dropwise thereto over 20 minutes.
Thereafter, 1.112 g of 2-(4
-methoxyphenyl)-3-acetoxy-2,3
-dihydro-1,5-benzothiazepine-4
(5H)-one was obtained. Example 3 2-hydroxy-3-(2'-aminophenylthio)-3-(4'-methoxyphenyl)-propionic acid 638 mg, pyridine 237 mg, sodium carbonate 424 mg
was added to 10 ml of N,N-dimethylformamide, and a solution of 0.4 g of acetyl chloride dissolved in 5 ml of N,N-dimethylformamide was added dropwise to this solution over 30 minutes at room temperature, followed by stirring for an additional 5 minutes. The following treatment was carried out in the same manner as in Example 1 to obtain 613 mg of crystals of 2-(4'-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one. It was done. Example 4
【化】
プロピオン酸〔〕0.64g（１／500mol）をと
り、アセトニトリル８mlとピリジン0.2mlを入れ、
室温にて30分攪拌する（この際必要ならば、無水
硫酸ナトリウムを入れてもさしつかえない）。
更に炭酸カリウム0.83gを投入し、アセチルク
ロライド0.63mlとアセトニトリル４mlの混液を室
温にて1.5〜２時間を要して滴下する。滴下終了
後１〜２時間そのまゝ攪拌を続け、内容液を150
mlの氷冷水に注入し、15分間攪拌し、１時間放置
後、析出した結晶を取し、水洗、乾燥する。
収量 0.601g 収率 87％[Chemical] Take 0.64g (1/500mol) of propionic acid, add 8ml of acetonitrile and 0.2ml of pyridine,
Stir at room temperature for 30 minutes (anhydrous sodium sulfate may be added if necessary). Further, 0.83 g of potassium carbonate was added, and a mixed solution of 0.63 ml of acetyl chloride and 4 ml of acetonitrile was added dropwise at room temperature over a period of 1.5 to 2 hours. After dropping, continue stirring for 1 to 2 hours until the content reaches 150%
ml of ice-cold water, stirred for 15 minutes, and left to stand for 1 hour. The precipitated crystals were collected, washed with water, and dried. Yield 0.601g Yield 87%
Claims (1)
エニルチオ）−３−（4′−メトキシフエニル）プロ
ピオン酸をアルカリ金属塩の存在下に塩化アセチ
ルと反応させることを特徴とする。 式【式】 で示される。 ２−（４−メトキシフエニル）−３−アセトキシ
−２，３−ジヒドロ−１，５−ベンゾチアゼピン
−４（5H）−オンの製造法。[Claims] 1. 2-hydroxy-3-(2'-aminophenylthio)-3-(4'-methoxyphenyl)propionic acid represented by the formula [formula] in the presence of an alkali metal salt. Characterized by reaction with acetyl chloride. It is shown by the formula [formula]. A method for producing 2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP949684A JPS60155168A (en) | 1984-01-24 | 1984-01-24 | Production of 1,5-benzothiazepine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP949684A JPS60155168A (en) | 1984-01-24 | 1984-01-24 | Production of 1,5-benzothiazepine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS60155168A JPS60155168A (en) | 1985-08-15 |
| JPH0585549B2 true JPH0585549B2 (en) | 1993-12-07 |
Family
ID=11721843
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP949684A Granted JPS60155168A (en) | 1984-01-24 | 1984-01-24 | Production of 1,5-benzothiazepine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS60155168A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5863192A (en) * | 1995-04-19 | 1999-01-26 | Tokyo Gas Company, Ltd. | Low nitrogen oxides generating method and apparatus |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS57136581A (en) * | 1981-02-18 | 1982-08-23 | Nippon Kayaku Co Ltd | Preparation of 1,5-benzothiazepin derivative |
-
1984
- 1984-01-24 JP JP949684A patent/JPS60155168A/en active Granted
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS57136581A (en) * | 1981-02-18 | 1982-08-23 | Nippon Kayaku Co Ltd | Preparation of 1,5-benzothiazepin derivative |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS60155168A (en) | 1985-08-15 |
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