JPH07258251A - Production of tizanidine - Google Patents
Production of tizanidineInfo
- Publication number
- JPH07258251A JPH07258251A JP6071309A JP7130994A JPH07258251A JP H07258251 A JPH07258251 A JP H07258251A JP 6071309 A JP6071309 A JP 6071309A JP 7130994 A JP7130994 A JP 7130994A JP H07258251 A JPH07258251 A JP H07258251A
- Authority
- JP
- Japan
- Prior art keywords
- tizanidine
- benzothiadiazole
- compound
- amino
- imidazole derivative
- 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.)
- Granted
Links
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
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Catalysts (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は次の式（I）、The present invention relates to the following formula (I),
【化４】 で表されるチザニジンの製造方法に関し、さらに詳細に
は中枢性反射抑制作用を有し、筋弛緩薬として有用なチ
ザニジンの製造方法に関する。[Chemical 4] Relates to a method for producing tizanidine, more specifically to a method for producing tizanidine having a central reflex suppressing action and useful as a muscle relaxant.
【０００２】[0002]
【従来の技術】式（I）で表されるチザニジンは、中枢
性反射抑制作用を有し、筋弛緩薬として、筋の不随意収
縮による疼痛等を緩和する他、収縮による脳血管障害、
外傷後遺症、スモン、脊髄障害等による痙性痳痺等の治
療に臨床で使用されているものである。BACKGROUND OF THE INVENTION Tizanidine represented by the formula (I) has a central reflex inhibitory action and, as a muscle relaxant, relieves pain and the like due to involuntary contraction of muscles, and cerebrovascular disorders due to contraction,
It is clinically used for the treatment of traumatic sequelae, SMON, spastic itch, etc. due to spinal cord injury.
【０００３】このチザニジンの製造方法については、例
えば特公昭５４−４２９８３号公報、特公昭５５−３３
７１８号等においていくつかの方法が開示されている。Regarding the method for producing this tizanidine, for example, Japanese Patent Publication No. 54-29883 and Japanese Patent Publication No. 55-33.
No. 718, etc., some methods are disclosed.
【０００４】[0004]
【発明が解決しようとする課題】しかし、従来知られて
いるチザニジンの製造方法は、チザニジンのイミダゾー
ル環を閉環反応により形成せしめる方法であるため、収
率があまり高くなく、製造コストが高くなり、経済性が
劣る等必ずしも十分に満足のいくものではなかった。し
たがって、より入手が容易で、しかも安価な化合物を原
料として用いた新しいチザニジンの製造方法の開発が望
まれていた。However, the conventionally known method for producing tizanidine is a method in which the imidazole ring of tizanidine is formed by a ring-closing reaction, so that the yield is not so high and the production cost is high. The economy was not always satisfactory, for example. Therefore, it has been desired to develop a new method for producing tizanidine using a compound that is more easily available and cheaper as a raw material.
【０００５】[0005]
【課題を解決するための手段】本発明者らは上記実情に
鑑み、チザニジン（I）の新しい製造方法を開発すべく
検討を重ねた結果、下式に従い、入手の容易な式（II
I）で表されるベンゾチアジアゾール化合物と式（IV）
で表されるイミダゾール誘導体とを反応させて、Ｎ−保
護チザニジン（II）とし、これから保護基を脱離せしめ
ることによりチザニジン（I）を容易に製造しうること
を見いだした。In view of the above circumstances, the present inventors have conducted extensive studies to develop a new method for producing tizanidine (I), and as a result, according to the following formula, an easily available formula (II
A benzothiadiazole compound represented by I) and the formula (IV)
It was found that Tizanidine (I) can be easily produced by reacting it with an imidazole derivative represented by the formula to give N-protected Tizanidine (II), and removing the protecting group from this.
【０００６】[0006]
【化５】 （式中、Ｒは、アミノ保護基を示し、Ｘは酸素原子また
はイオウ原子を示す）[Chemical 5] (In the formula, R represents an amino protecting group, and X represents an oxygen atom or a sulfur atom.)
【０００７】すなわち、本発明は、ベンゾチアジアゾー
ル化合物（III）と、イミダゾール誘導体（IV）とを反
応させ、次いで脱保護化することを特徴とするチザニジ
ン（I）の製造方法である。That is, the present invention is a method for producing tizanidine (I), which comprises reacting a benzothiadiazole compound (III) with an imidazole derivative (IV) and then deprotecting the compound.
【０００８】本発明方法において、出発原料として用い
られるベンゾチアジアゾール化合物（III）は、既に公
知の化合物であり、また例えば、下式にしたがい、クロ
ルフェニレンジアミン化合物（VII）にチオニルクロラ
イド等を作用させ、得られたクロルベンゾチアゾール
（VI）をニトロ化してそのニトロ置換体（V）とし、最
後にアミノ化することにより調製される化合物である。In the method of the present invention, the benzothiadiazole compound (III) used as a starting material is a known compound, and, for example, chlorphenylenediamine compound (VII) is reacted with thionyl chloride according to the following formula. Is a compound prepared by nitrating the obtained chlorobenzothiazole (VI) to its nitro-substituted product (V), and finally aminating it.
【化６】 [Chemical 6]
【０００９】また、他方の原料であるイミダゾール誘導
体（IV）のＲで示されるアミノ保護基としては、アセチ
ル基、ベンゾイル基等のアシル基や、メトキシカルボニ
ル基、エトキシカルボニル基、２,２,２−トリクロロエ
トキシカルボニル基、ベンジルオキシカルボニル基等の
アルコキシカルボニル基等が挙げられる。As the amino protecting group represented by R of the imidazole derivative (IV) which is the other raw material, an acyl group such as an acetyl group and a benzoyl group, a methoxycarbonyl group, an ethoxycarbonyl group, 2,2,2 -Alkoxycarbonyl groups such as trichloroethoxycarbonyl group and benzyloxycarbonyl group.
【００１０】このイミダゾール誘導体（IV）のうち、Ｘ
が酸素原子でＲがアセチルである化合物は、ジャーナル
・アメリカン・ケミカル・ソサエティ（J. Chem. Am. S
oc.）、第８０巻、第６４０９〜１３頁（１９５８）
に、また、Ｘが酸素でＲがエトキシカルボニルである化
合物は、ジャーナル・オブ・ファーマシューティカル・
サイエンス（J. Pharm. Sci.）、第５３巻、第１３７〜
１４３頁（１９６４）それぞれ記載されており、更に、
Ｘが硫黄原子でＲがメトキシカルボニルである化合物
は、ジャーナル・アメリカン・ケミカル・ソサエティ、
第９８巻、第３６９０〜９４頁（１９７６）に記載され
ている。上記以外のイミダゾール誘導体（III）も、こ
れらの文献に準じて容易に調製することができる。Of these imidazole derivatives (IV), X
Compounds in which R is acetyl and R is acetyl are available from Journal American Chemical Society (J. Chem. Am. S.
oc.), vol. 80, pp. 6409-13 (1958).
In addition, a compound in which X is oxygen and R is ethoxycarbonyl is described in Journal of Pharmaceuticals.
Science (J. Pharm. Sci.), Volume 53, Volume 137-
143 (1964), respectively, and
The compounds where X is a sulfur atom and R is methoxycarbonyl are available from Journal American Chemical Society,
Vol. 98, pp. 3690-94 (1976). Imidazole derivatives (III) other than the above can be easily prepared according to these documents.
【００１１】これらのベンゾチアジアゾール化合物（II
I）およびイミダゾール誘導体（IV）を用いてＮ−保護
チザニジン（II）を得るには、オキシ塩化リン、三塩化
リン等のリン化合物の存在下でこれら化合物を反応さ
せ、水を加えてリン化合物を分解した後、アルカリ水溶
液を加えて結晶化させれば良い。These benzothiadiazole compounds (II
In order to obtain N-protected tizanidine (II) using I) and imidazole derivative (IV), these compounds are reacted in the presence of a phosphorus compound such as phosphorus oxychloride and phosphorus trichloride, and water is added to the phosphorus compound. After decomposing, the solution may be crystallized by adding an alkaline aqueous solution.
【００１２】この反応はベンゾチアジアゾール化合物
（III）とイミダゾール誘導体（IV）のモル比は、１：
１〜１：１.５程度とし、また、リン化合物は、イミダ
ゾール誘導体（IV）に対して等量以上とすれば良く、溶
媒を兼ねて使用しても良い。更に、上記反応は室温〜還
流温度で、１〜３５時間程度実施すれば良い。In this reaction, the molar ratio of the benzothiadiazole compound (III) to the imidazole derivative (IV) is 1:
The amount is about 1 to 1: 1.5, and the phosphorus compound may be used in an amount equal to or more than the imidazole derivative (IV), and may also be used as a solvent. Further, the above reaction may be carried out at room temperature to reflux temperature for about 1 to 35 hours.
【００１３】更に、反応は、溶媒を使用しなくても進行
するが、必要に応じてクロロホルム、ベンゼン等の溶媒
を使用しても良い。なお、結晶化は水酸化ナトリウム等
を用い、反応系のｐＨを１０程度にすることにより行わ
れる。Further, the reaction proceeds without using a solvent, but a solvent such as chloroform or benzene may be used if necessary. The crystallization is performed by using sodium hydroxide or the like and adjusting the pH of the reaction system to about 10.
【００１４】上記のようにして得られたＮ−保護チザニ
ジン（II）の保護基を脱離し、目的のチザニジン（I）
を得るには、保護基に応じた適切な方法を利用すれば良
い。例えば、保護基がアセチル基の場合は、アルカリ加
水分解もしくは水中で加熱すれば良く、また、保護基が
エトキシカルボニル基の場合は、アルカリ加水分解すれ
ば良い。The protective group of the N-protected tizanidine (II) thus obtained is eliminated to give the desired tizanidine (I).
In order to obtain the above, an appropriate method depending on the protecting group may be used. For example, when the protecting group is an acetyl group, it may be alkali-hydrolyzed or heated in water, and when the protecting group is an ethoxycarbonyl group, it may be alkali-hydrolyzed.
【００１５】如上のごとくして得られたチザニジン
（I）は、必要に応じて公知の精製手段、例えばカラム
クロマトグラフィー等により更に精製すればよい。The tizanidine (I) obtained as described above may be further purified, if necessary, by a known purification means such as column chromatography.
【００１６】また、公知の有機酸や無機酸を作用させて
薬学的に許容される各種の塩、例えば、酢酸塩、プロピ
オン酸塩、グリコール酸塩、乳酸塩、シュウ酸塩、マロ
ン酸塩、酒石酸塩、クエン酸塩、スルファミン酸塩、ア
スコルビン酸塩等の有機酸塩や塩酸塩、臭化水素酸塩、
ヨウ化水素酸塩、硫酸塩等の無機酸塩とすることができ
る。これらの塩のなかでも、特に塩酸塩とすることが好
ましい。Further, various pharmaceutically acceptable salts by reacting known organic acids and inorganic acids, such as acetate, propionate, glycolate, lactate, oxalate, malonate, Tartrate, citrate, sulfamate, ascorbate and other organic acid salts and hydrochlorides, hydrobromide,
Inorganic acid salts such as hydroiodide and sulfate can be used. Among these salts, the hydrochloride salt is particularly preferable.
【００１７】[0017]
【発明の効果】本発明の製造方法は、反応工程で原料化
合物としてベンゾチアジアゾール化合物やイミダゾール
誘導体等、入手が容易で、比較的安価な化合物を使用
し、また、反応も単なる縮合反応であるため、従来の方
法に比べ経済性に優れており、工業的にも有利な方法で
ある。INDUSTRIAL APPLICABILITY In the production method of the present invention, a readily available and relatively inexpensive compound such as a benzothiadiazole compound or an imidazole derivative is used as a raw material compound in the reaction step, and the reaction is a mere condensation reaction. The method is more economical than the conventional method and is industrially advantageous.
【００１８】[0018]
【実施例】次に、実施例を挙げ、本発明を更に詳しく説
明するが、本発明はこれら実施例になんら制約されるも
のでない。なお、以下の実施例中、ＩＲスペクトルは日
本分光ＦＴ−ＩＲ７０００型を使用し測定した。 ま
た、1Ｈ−ＮＭＲスペクトルは、テトラメチルシランを
内部標準物質とし、日本電子ＥＸ−９０型を使用して測
定し、化学シフトはδ（ｐｐｍ）で示した。EXAMPLES Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples. In addition, in the following Examples, IR spectrum was measured using JASCO FT-IR7000 type. Further, the 1 H-NMR spectrum was measured by using JEOL EX-90 type with tetramethylsilane as an internal standard substance, and the chemical shift was shown by δ (ppm).
【００１９】実 施 例 １ ４−（１−アセチル−２−イミダゾリン−２−イル−ア
ミノ）−５−クロロ−２,１,３−ベンゾチアジアゾール
の合成：１−アセチル−２−イミダゾリドン ４.１４ｇ
（３２.３ｍｍｏｌ）をオキシ塩化リン ２５ｍｌに懸濁
させ、激しく撹拌しながら、４−アミノ−５−クロロ−
２,１,３−ベンゾチアジアゾール ５.０ｇ（２６.９ｍ
ｍｏｌ）を室温で加えた後、６０℃で１０時間撹拌し
た。 反応液を減圧濃縮し、得られた残渣に氷水を加え
た。 これに２５％−ＮａＯＨ水溶液をｐＨ１０になる
まで徐々に加えた。 析出した結晶を濾取し、黄色結晶
として標題化合物 ７.５２ｇを得た。Example 1 Synthesis of 4- (1-acetyl-2-imidazolin-2-yl-amino) -5-chloro-2,1,3-benzothiadiazole: 1-acetyl-2-imidazolidone 4.14 g
(32.3 mmol) was suspended in 25 ml of phosphorus oxychloride, and 4-amino-5-chloro- was added with vigorous stirring.
2,1,3-Benzothiadiazole 5.0g (26.9m
(mol) was added at room temperature, and then the mixture was stirred at 60 ° C. for 10 hours. The reaction solution was concentrated under reduced pressure, and ice water was added to the obtained residue. A 25% -NaOH aqueous solution was gradually added to this until pH 10 was reached. The precipitated crystals were collected by filtration to give the title compound (7.52 g) as yellow crystals.
【００２０】ＩＲνmaxＫＢｒ（ｃｍ-1）：３３８４,
２８９４, １６７６, １５２２, １４７７, １４０８,
１３８６, １３４４, ８３５ ＮＭＲ（ＣＤＣｌ3）δ：２.７９（ｓ,３Ｈ,ＮＡｃ）、
３.４１−４.１８（ｍ,４Ｈ,（ＣＨ2）2） ４.５６（ｂｒｓ,１Ｈ,ＮＨ）、７.６１（ｓ,２Ｈ,アロ
マティック）IRν max KBr (cm -1 ): 3384,
2894, 1676, 1522, 1477, 1408,
1386, 1344, 835 NMR (CDCl 3 ) δ: 2.79 (s, 3H, NAc),
3.41-4.18 (m, 4H, (CH 2) 2) 4.56 (brs, 1H, NH), 7.61 (s, 2H, aromatic)
【００２１】実 施 例 ２ ４−（１−エトキシカルボニル−２−イミダゾリン−２
−イル−アミノ）−５−クロロ−２,１,３−ベンゾチア
ジアゾールの合成： （１）１−エトキシカルボニル−２−イミダゾリドン
４.６７ｇ（２９.５ｍｍｏｌ）をオキシ塩化リン ２５
ｍｌに懸濁させ、激しく撹拌しながら、４−アミノ−５
−クロロ−２,１,３−ベンゾチアジアゾール ５.０ｇ
（２６.９ｍｍｏｌ）を室温で加えた後、６０℃で１時
間半撹拌した。 反応液を減圧濃縮し、得られた残渣に
氷水を加えた。 これに２５％−ＮａＯＨ水溶液をｐＨ
１０になるまで徐々に加えた。 析出した結晶を濾取し
黄色結晶として標題化合物 ８.５０ｇを得た。Example 2 4- (1-Ethoxycarbonyl-2-imidazoline-2
Synthesis of 5-yl-amino) -5-chloro-2,1,3-benzothiadiazole: (1) 1-ethoxycarbonyl-2-imidazolidone
4.67 g (29.5 mmol) of phosphorus oxychloride 25
4-amino-5 with vigorous stirring.
-Chloro-2,1,3-benzothiadiazole 5.0 g
(26.9 mmol) was added at room temperature, and then the mixture was stirred at 60 ° C. for 1 hour and a half. The reaction solution was concentrated under reduced pressure, and ice water was added to the obtained residue. Add 25% -NaOH aqueous solution to pH
Gradually added until 10. The precipitated crystals were collected by filtration to give the title compound (8.50 g) as yellow crystals.
【００２２】ＩＲνmaxＫＢｒ（ｃｍ-1）：３３４４,
２９８６, ２９０６, １７５６, １６５７, １５２２,
１４７９, １４１２, １３７５, １３１９, ７６８ ＮＭＲ（ＣＤＣｌ3）δ：１.３６（ｔ,Ｊ=７.０Ｈｚ,３
Ｈ,ＣＨ3）、３.６６−４.０１（ｍ,４Ｈ,（Ｃ
Ｈ2）2）、４.３３（ｑ,Ｊ=７.０Ｈｚ,２Ｈ,ＣＨ2）、
７.６２（ｄ,Ｊ=９.２Ｈｚ,１Ｈ,アロマティック）、
７.７２（ｄ,Ｊ=９.２Ｈｚ,１Ｈ,アロマティック）IRν max KBr (cm -1 ): 3344,
2986, 2906, 1756, 1657, 1522,
1479, 1412, 1375, 1319, 768 NMR (CDCl 3 ) δ: 1.36 (t, J = 7.0 Hz, 3
H, CH 3), 3.66-4.01 ( m, 4H, (C
H 2 ) 2 ), 4.33 (q, J = 7.0 Hz, 2H, CH 2 ),
7.62 (d, J = 9.2Hz, 1H, aromatic),
7.72 (d, J = 9.2Hz, 1H, aromatic)
【００２３】（２）１−エトキシカルボニル−２−イミ
ダゾリチオン ５１６ｍｇ（２.９６ｍｍｏｌ）をオキシ
塩化リン ５ｍｌに懸濁させ、激しく撹拌しながら、４
−アミノ−５−クロロ−２,１,３−ベンゾチアジアゾー
ル ５００ｍｇ（２.６９ｍｍｏｌ）を室温で加えた。
６０℃で３２時間撹拌した後、反応液を減圧濃縮し、得
られた残渣に氷水を加えた。 これに２５％−ＮａＯＨ
水溶液をｐＨ１０になるまで徐々に加えた。 析出した
結晶を濾取し、黄色結晶として標題化合物 ７９５ｍｇ
を得た。(2) 1-Ethoxycarbonyl-2-imidazolithione (516 mg, 2.96 mmol) was suspended in phosphorus oxychloride (5 ml).
500 mg (2.69 mmol) of -amino-5-chloro-2,1,3-benzothiadiazole was added at room temperature.
After stirring at 60 ° C. for 32 hours, the reaction solution was concentrated under reduced pressure, and ice water was added to the obtained residue. 25% NaOH
The aqueous solution was added slowly until pH 10. The precipitated crystals were collected by filtration to give the title compound as yellow crystals (795 mg)
Got
【００２４】（３）１−エトキシカルボニル−２−イミ
ダゾリドン ４７ｍｇ（０.２９ｍｍｏｌ）を三塩化リン
１ｍｌに懸濁させ、激しく撹拌しながら、４−アミノ
−５−クロロ−２,１,３−ベンゾチアジアゾール ５０
ｍｇ（０.２６ｍｍｏｌ）を室温で加え、６０℃で２２
時間撹拌した。 反応液を減圧濃縮し、得られた残渣に
氷水を加えた。 これに２５％−ＮａＯＨ水溶液をｐＨ
１０になるまで徐々に加えた。 析出した結晶を濾取
し、黄色結晶として標題化合物 ６３ｍｇを得た。(3) 1-Ethoxycarbonyl-2-imidazolidone (47 mg, 0.29 mmol) was suspended in phosphorus trichloride (1 ml), and 4-amino-5-chloro-2,1,3-benzoic acid was stirred under vigorous stirring. Thiadiazole 50
mg (0.26 mmol) was added at room temperature, and 22 at 60 ° C.
Stir for hours. The reaction solution was concentrated under reduced pressure, and ice water was added to the obtained residue. Add 25% -NaOH aqueous solution to pH
Gradually added until 10. The precipitated crystals were collected by filtration to give the title compound (63 mg) as yellow crystals.
【００２５】実 施 例 ３ ５−クロロ−４−（２−イミダゾリン−２−イル−アミ
ノ）−２,１,３−ベンゾチアジアゾール（チザニジン）
の合成： （１）１.２５Ｎ−ＮａＯＨ／４０％エタノール水溶液
５ｍｌに、４−（１−アセチル−２−イミダゾリン−２
−イル−アミノ）−５−クロロ−２,１,３−ベンゾチア
ジアゾール １.０ｇ（３.８５ｍｍｏｌ）を加え、還流
下３時間撹拌した。 反応液を冷却し、析出した結晶を
濾取し、黄色粉末結晶として標題化合物 ６３４ｍｇを
得た。Example 3 5-Chloro-4- (2-imidazolin-2-yl-amino) -2,1,3-benzothiadiazole (tizanidine)
Synthesis of (1) 1.25N-NaOH / 40% ethanol aqueous solution
4- (1-acetyl-2-imidazoline-2) in 5 ml
-Yl-amino) -5-chloro-2,1,3-benzothiadiazole 1.0 g (3.85 mmol) was added, and the mixture was stirred under reflux for 3 hours. The reaction solution was cooled, and the precipitated crystals were collected by filtration to give the title compound (634 mg) as yellow powder crystals.
【００２６】ＩＲνmaxＫＢｒ（ｃｍ-1）：３３６８,
３１７６, ２８７８, １６５５, １５１８, １４７７,
８３０,８１０ ＮＭＲ（ＣＤＣｌ3）δ：３.７１（ｓ,４Ｈ,（Ｃ
Ｈ2）2）、５.４２ （ｂｒｓ,１Ｈ,ＮＨ）、７.５８
（ｄ,Ｊ=９.２Ｈｚ,１Ｈ,アロマティック）、７.６８
（ｄ,Ｊ=９.２Ｈｚ,１Ｈ,アロマティック）IRν max KBr (cm -1 ): 3368,
3176, 2878, 1655, 1518, 1477,
830,810 NMR (CDCl 3 ) δ: 3.71 (s, 4H, (C
H 2) 2), 5.42 ( brs, 1H, NH), 7.58
(D, J = 9.2Hz, 1H, aromatic), 7.68
(D, J = 9.2Hz, 1H, aromatic)
【００２７】（２）１.２５Ｎ−ＮａＯＨ／４０％エタ
ノール水溶液 ５ｍｌに、４−（１−エトキシカルボニ
ル−２−イミダゾリン−２−イル−アミノ）−５−クロ
ロ−２,１,３−ベンゾチアジアゾール １.０ｇ（３.１
２ｍｍｏｌ）を加え、室温で３時間撹拌した。 反応液
を水冷し、析出した結晶を濾取し、黄色粉末結晶として
標題化合物 ７７３ｍｇを得た。(2) 4- (1-ethoxycarbonyl-2-imidazolin-2-yl-amino) -5-chloro-2,1,3-benzothiadiazole was added to 5 ml of 1.25N-NaOH / 40% ethanol aqueous solution. 1.0 g (3.1
2 mmol) was added and the mixture was stirred at room temperature for 3 hours. The reaction solution was cooled with water, and the precipitated crystals were collected by filtration to give the title compound (773 mg) as yellow powder crystals.
【００２８】（３）上記（１）または（２）で得られた
チザニジンをメタノールに懸濁し、適量の塩酸を加え溶
解した後、減圧濃縮し残渣をメタノールから再結晶する
と、塩酸チザニジンを淡黄色結晶として得た。 以 上(3) The tizanidine obtained in (1) or (2) above was suspended in methanol, dissolved in an appropriate amount of hydrochloric acid, dissolved, and then concentrated under reduced pressure, and the residue was recrystallized from methanol. Obtained as crystals. that's all
─────────────────────────────────────────────────────
─────────────────────────────────────────────────── ───
【手続補正書】[Procedure amendment]
【提出日】平成７年２月２２日[Submission date] February 22, 1995
【手続補正１】[Procedure Amendment 1]
【補正対象書類名】明細書[Document name to be amended] Statement
【補正対象項目名】請求項１[Name of item to be corrected] Claim 1
【補正方法】変更[Correction method] Change
【補正内容】[Correction content]
【手続補正２】[Procedure Amendment 2]
【補正対象書類名】明細書[Document name to be amended] Statement
【補正対象項目名】請求項２[Name of item to be corrected] Claim 2
【補正方法】変更[Correction method] Change
【補正内容】[Correction content]
【手続補正３】[Procedure 3]
【補正対象書類名】明細書[Document name to be amended] Statement
【補正対象項目名】０００３[Name of item to be corrected] 0003
【補正方法】変更[Correction method] Change
【補正内容】[Correction content]
【０００３】このチザニジンの製造方法については、例
えば特公昭５４−４２９８３号公報、特公昭５５−３３
７１８号公報等においていくつかの方法が開示されてい
る。Regarding the method for producing this tizanidine, for example, Japanese Patent Publication No. 54-29883 and Japanese Patent Publication No. 55-33.
Several methods have been disclosed in 718 Patent Publication.
【手続補正４】[Procedure amendment 4]
【補正対象書類名】明細書[Document name to be amended] Statement
【補正対象項目名】００１０[Correction target item name] 0010
【補正方法】変更[Correction method] Change
【補正内容】[Correction content]
【００１０】このイミダゾール誘導体（ＩＶ）のうち、
Ｘが酸素原子でＲがアセチルである化合物は、ジャーナ
ル・アメリカン・ケミカル・ソサエティ（Ｊ．Ａｍ．Ｃ
ｈｅｍ．Ｓｏｃ．）、第８０巻、第６４０９〜１３頁
（１９５８）に、また、Ｘが酸素でＲがエトキシカルボ
ニルである化合物は、ジャーナル・オブ・ファーマシュ
ーティカル・サイエンス（Ｊ．Ｐｈａｒｍ．Ｓｃ
ｉ．）、第５３巻、第１３７〜１４３頁（１９６４）そ
れぞれ記載されており、更に、Ｘが硫黄原子でＲがメト
キシカルボニルである化合物は、ジャーナル・アメリカ
ン・ケミカル・ソサエティ、第９８巻、第３６９０〜９
４頁（１９７６）に記載されている。上記以外のイミダ
ゾール誘導体（ＩＩＩ）も、これらの文献に準じて容易
に調製することができる。Of the imidazole derivative (IV),
Compounds in which X is an oxygen atom and R is acetyl are available from Journal American Chemical Society ( J. Am. C.
hem. Soc. ), 80, 6409-13 (1958), and compounds in which X is oxygen and R is ethoxycarbonyl are described in Journal of Pharmaceutical Science (J. Pharm. Sc).
i. ), Vol. 53, pp. 137-143 (1964), and further, compounds wherein X is a sulfur atom and R is methoxycarbonyl are described in Journal American Chemical Society, Vol. 98, 3690. ~ 9
4 pages (1976). Imidazole derivatives (III) other than the above can be easily prepared according to these documents.
Claims (2)
V） 【化２】 （式中、Ｒは、アミノ保護基を示し、Ｘは酸素原子また
はイオウ原子を示す）で表されるイミダゾール誘導体と
を反応させ、次いで脱保護化することを特徴と次の式
（I） 【化３】 で表されるチザニジンの製造方法。1. The following formula (III): A benzothiadiazole compound represented by the following formula (I
V) [Chemical 2] (Wherein R represents an amino-protecting group, and X represents an oxygen atom or a sulfur atom), and then the compound is reacted with an imidazole derivative, followed by deprotection. Chemical 3] A method for producing tizanidine represented by.
イミダゾール誘導体（IV）の反応を、リン化合物の存在
下行う請求項１記載のチザニジンの製造方法。2. The method for producing tizanidine according to claim 1, wherein the reaction of the benzothiadiazole compound (III) and the imidazole derivative (IV) is carried out in the presence of a phosphorus compound.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6071309A JP2681873B2 (en) | 1994-03-17 | 1994-03-17 | Method for producing tizanidine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6071309A JP2681873B2 (en) | 1994-03-17 | 1994-03-17 | Method for producing tizanidine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH07258251A true JPH07258251A (en) | 1995-10-09 |
| JP2681873B2 JP2681873B2 (en) | 1997-11-26 |
Family
ID=13456901
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP6071309A Expired - Lifetime JP2681873B2 (en) | 1994-03-17 | 1994-03-17 | Method for producing tizanidine |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2681873B2 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2599844C1 (en) * | 2015-10-05 | 2016-10-20 | Войсковая Часть 41598 | Agent for prevention of acute radiation disease |
| CN107778307A (en) * | 2016-08-24 | 2018-03-09 | 四川科瑞德制药股份有限公司 | A kind of preparation method of the adrenoceptor agonists of central α 2 |
| CN110563715A (en) * | 2018-06-05 | 2019-12-13 | 四川科瑞德制药股份有限公司 | Process for preparing imidazoline-diazacyclopentene derivatives |
| CN113135908A (en) * | 2021-04-01 | 2021-07-20 | 杭州泓友医药科技有限公司 | Preparation method of tizanidine hydrochloride |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS528833A (en) * | 1975-07-10 | 1977-01-24 | Olympus Optical Co Ltd | Latent image forming device of a screen drum type |
| JPS5442983A (en) * | 1977-04-26 | 1979-04-05 | Handotai Kenkyu Shinkokai | Semiconductor ic |
| JPS5533718A (en) * | 1978-09-01 | 1980-03-10 | Toshiba Corp | Straight advancing type klystron |
| JPH0782268A (en) * | 1993-09-09 | 1995-03-28 | Permachem Asia Ltd | Production of benzothiadiazole derivative |
-
1994
- 1994-03-17 JP JP6071309A patent/JP2681873B2/en not_active Expired - Lifetime
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS528833A (en) * | 1975-07-10 | 1977-01-24 | Olympus Optical Co Ltd | Latent image forming device of a screen drum type |
| JPS5442983A (en) * | 1977-04-26 | 1979-04-05 | Handotai Kenkyu Shinkokai | Semiconductor ic |
| JPS5533718A (en) * | 1978-09-01 | 1980-03-10 | Toshiba Corp | Straight advancing type klystron |
| JPH0782268A (en) * | 1993-09-09 | 1995-03-28 | Permachem Asia Ltd | Production of benzothiadiazole derivative |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2599844C1 (en) * | 2015-10-05 | 2016-10-20 | Войсковая Часть 41598 | Agent for prevention of acute radiation disease |
| CN107778307A (en) * | 2016-08-24 | 2018-03-09 | 四川科瑞德制药股份有限公司 | A kind of preparation method of the adrenoceptor agonists of central α 2 |
| CN107778307B (en) * | 2016-08-24 | 2021-05-28 | 四川科瑞德制药股份有限公司 | Preparation method of central alpha 2 adrenoreceptor agonist |
| CN110563715A (en) * | 2018-06-05 | 2019-12-13 | 四川科瑞德制药股份有限公司 | Process for preparing imidazoline-diazacyclopentene derivatives |
| CN110563715B (en) * | 2018-06-05 | 2024-01-09 | 四川科瑞德制药股份有限公司 | Process for preparation of imidazoline meta-diazacyclopentene derivatives |
| CN113135908A (en) * | 2021-04-01 | 2021-07-20 | 杭州泓友医药科技有限公司 | Preparation method of tizanidine hydrochloride |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2681873B2 (en) | 1997-11-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| FI71126C (en) | PROCEDURE FOR THE FRAMSTATION OF N- (1-ALKYL-ELLER ALLYL-2-PYRROLIDINYLMETHYL) -2-METHOXY-4-AMINO--5-ALKYL SULPHONYL BENZENIDE | |
| US8518936B2 (en) | Method for preparing acid addition salts of polyacidic basic compounds | |
| JP2011518866A (en) | Process for producing 5- (2-amino-pyrimidin-4-yl) -2-aryl-lH-pyrrole-3-carboxamide | |
| US5101040A (en) | Process for the industrial preparation of 4-chloro-3-sulfamoyl-n-(2,3-dihydro-2-methyl-1h-indol-1-yl)benzamide | |
| JP2681873B2 (en) | Method for producing tizanidine | |
| JP6276894B2 (en) | Method for preparing quinazoline derivative | |
| FI95378B (en) | Process for the preparation of therapeutically useful benzoxazolones trisubstituted in the benzo ring | |
| WO2004041781A1 (en) | Preparation of 3-aminoalkyl-substituted indole derivatives from phenylhydrazines and aminoketones | |
| TWI478914B (en) | Process for the preparation of 5-(2-amino-pyrimidin-4-yl)-2-aryl-1h-pyrrole-3-carboxamides | |
| JP2639782B2 (en) | Method for producing irsogladine and its acid addition salt | |
| JPH0417195B2 (en) | ||
| CN110577520B (en) | Preparation method of 6-nitro-4-substituted amino quinazoline derivative | |
| IE912005A1 (en) | "New process for the industrial preparation of 4-chloro 3-sulphamoyl-N-(2,3-dihydro-2-methyl-1H-indol-1- yl)- benzamide from 2,3-dihydro-2-methyl-1H-indole and hydrox ylamine-O-sulphonic acid" | |
| JP2816778B2 (en) | Method for producing quinazolinone derivatives | |
| HU194193B (en) | Process for preparing new 4-/amino-methylidene/-3-aryl-5/4h/-isoxazolinone derivatives and pharmaceutical compositions containing such compounds as active ingredients | |
| KR100368895B1 (en) | A process for preparing 1,2,3,9-tetrahydro-9-methyl-3- [(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one | |
| KR100377578B1 (en) | Process for the preparation of ondansetron and pharmaceutically acceptable salts thereof | |
| JP2761677B2 (en) | Method for producing quinazolinone derivatives | |
| KR790001029B1 (en) | Process for prepaing pyrazine derivatives | |
| JPH07267950A (en) | Production of 5-chloro-n-(4,5-dihydro-1h-imidazol-2-yl)-2,1,3-benzothiadiazole-4-amine or its acid-added salt | |
| JPH05170766A (en) | Method for synthesizing 6-chloropurine | |
| CN114560862A (en) | Synthesis method of pyrrolo [1,2-A ] quinoxaline-4 (5H) -ketone and derivative thereof | |
| KR900003882B1 (en) | Process for the preparation of compounds with h2 antihistamine activity | |
| JP2004300101A (en) | Method for producing chloropyrimidine derivative | |
| KR20070087764A (en) | A process for preparing losartan |