JPH02256680A - Production of 5-(3754/24)2-chloro-benzyl)-4,5,6,7-tetrahydrothieno(3,2-c)pyridine or salt thereof - Google Patents
Production of 5-(3754/24)2-chloro-benzyl)-4,5,6,7-tetrahydrothieno(3,2-c)pyridine or salt thereofInfo
- Publication number
- JPH02256680A JPH02256680A JP3325189A JP3325189A JPH02256680A JP H02256680 A JPH02256680 A JP H02256680A JP 3325189 A JP3325189 A JP 3325189A JP 3325189 A JP3325189 A JP 3325189A JP H02256680 A JPH02256680 A JP H02256680A
- Authority
- JP
- Japan
- Prior art keywords
- pyridine
- tetrahydrothieno
- formula
- salt
- ammonium salt
- 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 4
- 150000003839 salts Chemical class 0.000 title claims description 4
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims abstract description 4
- OGUWOLDNYOTRBO-UHFFFAOYSA-N 4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1NCCC2=C1C=CS2 OGUWOLDNYOTRBO-UHFFFAOYSA-N 0.000 claims abstract 3
- 125000000217 alkyl group Chemical group 0.000 claims abstract 2
- 125000005843 halogen group Chemical group 0.000 claims abstract 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 abstract description 9
- 150000001875 compounds Chemical class 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000002904 solvent Substances 0.000 abstract description 3
- 239000002798 polar solvent Substances 0.000 abstract description 2
- 208000010110 spontaneous platelet aggregation Diseases 0.000 abstract description 2
- 210000001772 blood platelet Anatomy 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 239000003112 inhibitor Substances 0.000 abstract 1
- 238000000034 method Methods 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 229910052785 arsenic Inorganic materials 0.000 description 1
- RQNWIZPPADIBDY-UHFFFAOYSA-N arsenic atom Chemical compound [As] RQNWIZPPADIBDY-UHFFFAOYSA-N 0.000 description 1
- 101150117004 atg18 gene Proteins 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- KEOKHDKWKYGPGO-UHFFFAOYSA-N n-[(2-chlorophenyl)methyl]-2-thiophen-2-ylethanamine Chemical compound ClC1=CC=CC=C1CNCCC1=CC=CS1 KEOKHDKWKYGPGO-UHFFFAOYSA-N 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 229960002961 ticlopidine hydrochloride Drugs 0.000 description 1
- MTKNGOHFNXIVOS-UHFFFAOYSA-N ticlopidine hydrochloride Chemical compound [H+].[Cl-].ClC1=CC=CC=C1CN1CC(C=CS2)=C2CC1 MTKNGOHFNXIVOS-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
Description
【発明の詳細な説明】
技 術 分 野
本発明は血小板凝集抑制作用を有する塩酸チクロピジン
の製造方法に関するものである。DETAILED DESCRIPTION OF THE INVENTION Technical Field The present invention relates to a method for producing ticlopidine hydrochloride, which has an inhibitory effect on platelet aggregation.
従来技術
本化合物の製造方法として多くの方法が知られているが
、中でも工業的に最も有利と目されている方法は、チェ
ノ（３，２−Ｃ）ピリジンをＮ−ベンジル化して生成し
た４級アンモニウム塩を還元し、目的物を得る方法であ
る（特公昭５２−３１３５７）。しかし、この方法では
収率が６０％と低く、かつ高価な還元剤を用いなければ
ならない欠点がある。PRIOR ART Many methods are known for producing the present compound, but the method considered to be the most industrially advantageous is the production of 4-benzylated cheno(3,2-C)pyridine. This is a method for obtaining the desired product by reducing a grade ammonium salt (Japanese Patent Publication No. 31357/1983). However, this method has the disadvantage that the yield is as low as 60% and that an expensive reducing agent must be used.
Ｎ−（２−クロロベンジル）−２−（２−チエニル）エ
チルアミンにホルムアルデヒドを加え、これを塩酸水溶
液中で加熱して環１ヒさせる方法（特公昭５９−３１５
１３）も提案されているが、高価な薬品や工業的に取り
扱いが困難な段階が多数ある。A method of adding formaldehyde to N-(2-chlorobenzyl)-2-(2-thienyl)ethylamine and heating it in an aqueous hydrochloric acid solution to form a ring (Japanese Patent Publication No. 59-315
13) has also been proposed, but it requires expensive chemicals and many steps that are difficult to handle industrially.
また、［Ｊ、Ｐ、Ｍａｆｆｒａｎｄ、Ｆ、Ｅｌｏｙ、Ｅ
ｕｒ、Ｊ、Ｍｅｄ、Ｃｈｅｍ。Also, [J., P., Maffrand, F., Eloy, E.
ur, J, Med, Chem.
Ｃｈｅｍ、−Ｔｈｅｒ、９．４８３（１９７４）］に記
載の方法は収率２５？６と低収率である。Chem, -Ther, 9.483 (1974)] has a low yield of 25-6.
発明が解決しようとする問題点
そこで複雑な精製工程を必要とぜず、高収率で高純度の
５−〈２−クロロベンジル）−４，５゜６．７−チトラ
ヒドロチエノＣ３，２−Ｃ）ピリジン塩酸塩（塩酸チク
口とジン）を工業的に安全で且つ容易に製造することの
できる方法の開発が要望されており、かかる課題に応え
ることが本発明目的である。Problems to be Solved by the Invention Therefore, 5-(2-chlorobenzyl)-4,5°6.7-titrahydrothienoC3,2- can be produced in high yield and in high purity without the need for complicated purification steps. C) There is a need for the development of a method that can industrially safely and easily produce pyridine hydrochloride (hydrochloric acid chikuguchi and gin), and it is an object of the present invention to meet this problem.
問題点を解決するための手段
本発明に従えば、上記発明目的が、
で示される４、５．６．７−チトラヒドロチエノＣ３，
２−Ｃ）ピリジンを
（式中、前述と同じ）
で示される四級アンモニウム塩と反応させることにより
達成せられる。使用せられる原料はいずれも入手容易で
あり、両者を適当な溶剤中で加熱反応せしめるど、目的
物である式（ＩＩＩ）が高収率で、しかも高純度で得れ
られることが見出された。本反応で使用せられる好まし
い溶剤は、ジメチルホルムアミドのような極性溶媒であ
り、好ましい温度は１４０〜１５０℃である。本発明方
法はその実施が容易であるばかりか、目的物を高純度高
収率で得ることができ、複雑な精製工程を必要とせず、
工業的に極めて有用な５−（２−クロロベンジル）−４
，５，６，７−チトラヒドロチエノ（３，２−Ｃ）ピリ
ジンまたはその塩の製法を提供するものである。Means for Solving the Problems According to the present invention, the above-mentioned object of the invention is achieved by the following: 4,5.6.7-titrahydrothieno C3,
2-C) This can be achieved by reacting pyridine with a quaternary ammonium salt represented by (wherein the formula is the same as above). All of the raw materials used are easily available, and it has been found that the target product, formula (III), can be obtained in high yield and with high purity by subjecting them to a heating reaction in an appropriate solvent. Ta. The preferred solvent used in this reaction is a polar solvent such as dimethylformamide, and the preferred temperature is 140-150°C. The method of the present invention is not only easy to implement, but also can obtain the target product with high purity and high yield, does not require complicated purification steps,
Industrially extremely useful 5-(2-chlorobenzyl)-4
, 5,6,7-titrahydrothieno(3,2-C)pyridine or a salt thereof.
以下実施例により本発明を説明する。The present invention will be explained below with reference to Examples.
夾１目生
４．５．６．７−チトラヒドロチエノ〔３，２−Ｃ）ピ
リジンＩｇ、Ｏ−クロロベンジルトリメチルアンモニウ
ムクロリド１．９ｇにジメチルホルムアミド１２戯を加
え、１３０〜１４０℃で１０時間撹拌する９反応終了後
、水を加え、トルエンにて抽出。トルエン層を水洗。乾
燥（ＭｇＳＯ４）、濃縮し、２ｇの５−（２−クロロベ
ンジル）−４゜５．６．７−チトラヒドロチエノ（３，
２−Ｃ）ピリジンを得た０次にこの化合物にエタノール
１２〜を加え、無水塩ｆヒ水素を吹き込んだ後、反応液
を冷却し、５−（２−クロロベンジル）−４゜５．６．
７−チトラヒドロチエノ（３，２−Ｃ）ピリジンの塩酸
塩１゜７ｇ （収率７８，８％）を得た。4.5.6.7-Titrahydrothieno[3,2-C)pyridine Ig, add dimethylformamide 12 to 1.9 g of O-chlorobenzyltrimethylammonium chloride and heat at 130 to 140°C for 10 hours. Stir 9 After the reaction is complete, add water and extract with toluene. Wash the toluene layer with water. Dry (MgSO4) and concentrate to give 2 g of 5-(2-chlorobenzyl)-4°5.6.7-titrahydrothieno(3,
2-C) Pyridine was obtained. Next, 12~ of ethanol was added to this compound, and after blowing in anhydrous salt f arsenic, the reaction solution was cooled and 5-(2-chlorobenzyl)-4゜5.6 ．．
1.7 g (yield 78.8%) of 7-titrahydrothieno(3,2-C)pyridine hydrochloride was obtained.
ＮＭＲ１薄層クロマトグラフィー、ＩＲ測測定結果、標
品と同一であることを確認した。The results of NMR1 thin layer chromatography and IR measurement confirmed that it was the same as the standard product.
特許出願代理人patent application agent
Claims (1)
２−Ｃ〕ピリジンを 式 ▲数式、化学式、表等があります▼…（II） （式中Ｘはハロゲン原子、Ｒ＿１Ｒ＿２Ｒ＿３は低級ア
ルキル基で、同一あるいは異なってもよい）で示される
四級アンモニウム塩と反応させることを特徴とする 式 ▲数式、化学式、表等があります▼…（III） で示される５−（２−クロロベンジル）−４，５，６，
７−テトラヒドロチエノ〔３，２−Ｃ〕ピリジン又はそ
の塩の製造方法。[Claims] 4,5,6,7-tetrahydrothieno [3,
2-C] Pyridine is a quaternary ammonium salt represented by the formula ▲ Numerical formula, chemical formula, table, etc.▼...(II) (In the formula, X is a halogen atom, R_1R_2R_3 is a lower alkyl group, and they may be the same or different) Formulas characterized by the reaction with
A method for producing 7-tetrahydrothieno[3,2-C]pyridine or a salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3325189A JPH02256680A (en) | 1989-02-13 | 1989-02-13 | Production of 5-(3754/24)2-chloro-benzyl)-4,5,6,7-tetrahydrothieno(3,2-c)pyridine or salt thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3325189A JPH02256680A (en) | 1989-02-13 | 1989-02-13 | Production of 5-(3754/24)2-chloro-benzyl)-4,5,6,7-tetrahydrothieno(3,2-c)pyridine or salt thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH02256680A true JPH02256680A (en) | 1990-10-17 |
Family
ID=12381277
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3325189A Pending JPH02256680A (en) | 1989-02-13 | 1989-02-13 | Production of 5-(3754/24)2-chloro-benzyl)-4,5,6,7-tetrahydrothieno(3,2-c)pyridine or salt thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH02256680A (en) |
-
1989
- 1989-02-13 JP JP3325189A patent/JPH02256680A/en active Pending
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