JPH0426690A - New production of thienopyridine derivative - Google Patents
New production of thienopyridine derivativeInfo
- Publication number
- JPH0426690A JPH0426690A JP12944290A JP12944290A JPH0426690A JP H0426690 A JPH0426690 A JP H0426690A JP 12944290 A JP12944290 A JP 12944290A JP 12944290 A JP12944290 A JP 12944290A JP H0426690 A JPH0426690 A JP H0426690A
- Authority
- JP
- Japan
- Prior art keywords
- producing
- dioxolane
- acid
- formula
- new production
- 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 6
- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical class C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 title claims 2
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 claims abstract description 7
- HVLUYXIJZLDNIS-UHFFFAOYSA-N 2-thiophen-2-ylethanamine Chemical compound NCCC1=CC=CS1 HVLUYXIJZLDNIS-UHFFFAOYSA-N 0.000 claims abstract description 4
- 150000003839 salts Chemical class 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 10
- 150000001875 compounds Chemical class 0.000 abstract description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 abstract description 4
- 239000002253 acid Substances 0.000 abstract description 4
- 229960002961 ticlopidine hydrochloride Drugs 0.000 abstract description 4
- MTKNGOHFNXIVOS-UHFFFAOYSA-N ticlopidine hydrochloride Chemical compound [H+].[Cl-].ClC1=CC=CC=C1CN1CC(C=CS2)=C2CC1 MTKNGOHFNXIVOS-UHFFFAOYSA-N 0.000 abstract description 4
- 229940127218 antiplatelet drug Drugs 0.000 abstract description 2
- 229940098779 methanesulfonic acid Drugs 0.000 abstract description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000000034 method Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 description 2
- 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
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229940061627 chloromethyl methyl ether Drugs 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ZZLKPFGLOQUCNC-UHFFFAOYSA-N 2-thiophen-2-ylethanamine;hydrochloride Chemical compound Cl.NCCC1=CC=CS1 ZZLKPFGLOQUCNC-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- XKTYXVDYIKIYJP-UHFFFAOYSA-N 3h-dioxole Chemical compound C1OOC=C1 XKTYXVDYIKIYJP-UHFFFAOYSA-N 0.000 description 1
- 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
- 206010061218 Inflammation Diseases 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- LNZVDLUCJVLNLA-UHFFFAOYSA-N n-(2-thiophen-2-ylethyl)methanimine Chemical compound C=NCCC1=CC=CS1 LNZVDLUCJVLNLA-UHFFFAOYSA-N 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 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】 Ａ。[Detailed description of the invention] A.
産業上の利用分野
本発明は、
式
で表わされるチェノピリジン誘導体およびその塩の新規
な製造法に関する。INDUSTRIAL APPLICATION FIELD The present invention relates to a novel method for producing a chenopyridine derivative represented by the formula and a salt thereof.
本発明により製造することができる化合物（１）は、抗
血小板剤として広（臨床的に使用されている塩酸チクロ
ピジンを製造するための中間体である。チクロピジンは
Ｉより１工程で簡便にしかも高収率で製造することがで
きる。Compound (1) that can be produced according to the present invention is an intermediate for producing ticlopidine hydrochloride, which is widely used clinically as an antiplatelet agent. It can be produced with high yield.
Ｂ、 従来の技術
式
で表わされる２−（２−チエニル）エチルアミンよりＩ
を製造する方法はいくつか知られている（特開昭５４−
１９９９４； 特開昭６２−＋０３０８７；特開昭６２
−１０３０８８などを参照。）。B, I from 2-(2-thienyl)ethylamine represented by the conventional technical formula
There are several known methods for producing
19994; JP-A-62-+03087; JP-A-62
See, for example, -103088. ).
例えば、ジメチルホルムアミド中ＩＩにクロロメチルメ
チルエーテルを作用させた時、１工程でＩの塩酸塩が３
１％の収率で得られる（特開昭５４１９９９４ヲ参照）
。クロロメチルメチルエーテルは反応性が極めて高く、
また刺激性も極めて強く、取扱いには特別の注意を要す
る。同様に、ＴＩにジメチルホルムアミド中、 １．
３． ５−トリブチル−１，３，５−バーハイドロド
ＩＪアジノを作用させた時、 Ｉの塩酸塩が６５％の収
率で得られる（特開昭５４−１９９９４を参照）。また
ＩＩにホルムアルデヒドの水溶液を作用させ、Ｎメチレ
ン−２−（２−チエニル）エチルアミンを抽出単離した
後、 ジメチルホルムアミド中テ。For example, when chloromethyl methyl ether is allowed to react with II in dimethylformamide, 3 hydrochlorides of I are produced in one step.
Obtained with a yield of 1% (see JP-A-5419994)
. Chloromethyl methyl ether is extremely reactive;
It is also extremely irritating and requires special care when handling. Similarly, TI in dimethylformamide, 1.
3. When treated with 5-tributyl-1,3,5-barhydrodo IJ azino, the hydrochloride of I is obtained in a yield of 65% (see JP-A-54-19994). Further, II was treated with an aqueous formaldehyde solution to extract and isolate N-methylene-2-(2-thienyl)ethylamine, and then extracted and isolated in dimethylformamide.
塩化水素を作用させることによりＩの塩酸塩が得られる
（特開昭６２−１０３０８７； 特開昭６２１０３０８
８を参照）。２工程の通算収率は６５％に過ぎない。し
かもホルムアルデヒドは刺激性であり、炎症等を引き起
こす恐れがあるので。Hydrochloride of I can be obtained by reacting with hydrogen chloride (JP-A-62-103087; JP-A-6210308)
8). The total yield of the two steps is only 65%. Moreover, formaldehyde is an irritant and may cause inflammation.
その取扱いには特別の注意を要する。Special care is required when handling it.
その他、 １１を出発原料としないＩの製造法も知ら
れている［例えば、 Ｅｕｒ、 Ｊ、 Ｍｅｄ、
Ｃｈ ｅ ｍ、 ９． ４８３ （＋ ９７４
）などを参照］。In addition, methods for producing I that do not use 11 as a starting material are also known [for example, Eur, J., Med.
Chem, 9. 483 (+974
), etc.].
Ｃ１発明が解決しようとする問題点
前述したように、いくつかの■の製造法が知られている
が、工程が長い、収率が低い、あるいは反応試薬が刺激
性であるなどの問題点を有している。本発明は安価なし
かも刺激性の無い原料を用い、工程数も短く９反応は簡
便で容易であり、 しかも高収率なＩの製造法を提供す
るものである。C1 Problems to be Solved by the Invention As mentioned above, several methods for producing (2) are known, but they suffer from problems such as long steps, low yields, and irritating reaction reagents. have. The present invention provides a method for producing I that uses inexpensive and non-irritating raw materials, has a short number of steps, is simple and easy to perform 9 reactions, and has a high yield.
Ｄ、 問題点を解決するための手段と作用本発明者ら
は、 ＩＩに、酸存在下、１，３−ジオキソランを作
用させることにより、簡便に。D. Means and Actions for Solving the Problems The present inventors simply reacted II with 1,3-dioxolane in the presence of an acid.
工程で、 しかも高収率で目的化合物（Ｉ）を製造でき
ることを見いだし２本発明を完結するに至った。It was discovered that the target compound (I) could be produced in a high yield in a simple process, and the present invention was completed.
１１および１，３−ジオキソランの反応は、酸存在下、
１，３−ジオキソランを溶媒として、あるいはその他の
反応に不活性な溶媒２例えば、 ジオキサン、エタノー
ル等を用い、さらには無溶媒で 加熱下に行なうことが
できる。酸きしては塩酸、臭化水素酸等の無機酸、メタ
ンスルホン酸等の有機酸を使用することができる。酸の
使用量は。The reaction of 11 and 1,3-dioxolane is carried out in the presence of an acid,
The reaction can be carried out using 1,3-dioxolane as a solvent, or using other solvents inert to the reaction, such as dioxane, ethanol, etc., or without a solvent under heating. For acidification, inorganic acids such as hydrochloric acid and hydrobromic acid, and organic acids such as methanesulfonic acid can be used. What is the amount of acid used?
１１に対して当量に触媒量を加えた量、 ＴＩの塩を
使用する場合は触媒量が適当である。The amount equivalent to 11 plus the catalytic amount is appropriate, and when using a TI salt, the catalytic amount is appropriate.
本発明により、 ＩＩより１工程で簡便に容易に。According to the present invention, it is simpler and easier than II in one step.
しかも高収率で目的化合物（１）を製造することができ
る。Furthermore, the target compound (1) can be produced in high yield.
本発明は塩酸チクロピジン製造のための中間体Ｉの製造
法として産業上極めて有用である。The present invention is industrially extremely useful as a method for producing Intermediate I for producing ticlopidine hydrochloride.
Ｅ、 実施例
２−（２−チエニル）エチルアミン塩酸塩（１０、０ｇ
）、 １． ３−ジオキソラン（ａＯ，Ｏｇ）の混合
物に、濃塩酸（０，１ｍ１）を加え。E, Example 2-(2-thienyl)ethylamine hydrochloride (10.0 g
), 1. Concentrated hydrochloric acid (0.1 ml) was added to the mixture of 3-dioxolane (aO, Og).
７（］−７５°Ｃで２．５時間加熱攪拌。放冷汲水を加
え、酢酸エチルにて洗浄。水層をＮａＯＨ−アルカリ性
とし、酢酸エチルで抽出。有機層を水洗。7 (] Heat and stir at -75°C for 2.5 hours. Add cooled water and wash with ethyl acetate. The aqueous layer is made alkaline with NaOH and extracted with ethyl acetate. The organic layer is washed with water.
硫酸マグネシウムで乾燥。溶媒留去し、油状の４゜５、
６． ７−チトラヒドロチエノ ［３，２−ｃ］ピリ
ジン（８，５ｇ、 約１００％）を得。Dry with magnesium sulfate. The solvent was distilled off, leaving an oily 4°5.
6. 7-titrahydrothieno[3,2-c]pyridine (8.5 g, approximately 100%) was obtained.
ＮＭＲ（ＣＤＣｌ２）δ： ２． ６１−２． ９２
（２Ｈ，ｍ）、 ３． １２ （２Ｈ，ｔｄ、
Ｊ＝５． ７゜Ｊ＝１． ２）、 ３． ９０（２Ｈ
，ｔ、 Ｊ＝１． ２）６、 ６８ （ＩＨ，ｄ
、 Ｊ＝５． ４）、 ７． ０１（ＩＨ
，ｄ、 Ｊ＝５． ４）。NMR (CDCl2) δ: 2. 61-2. 92
(2H, m), 3. 12 (2H, td,
J=5. 7°J=1. 2), 3. 90 (2H
,t, J=1. 2) 6, 68 (IH, d
, J=5. 4), 7. 01(IH
, d, J=5. 4).
遊離塩基をメタノール中で塩酸塩とし、メタツルを濃縮
後、アセトンをゆっくり加えて放置。Convert the free base into a hydrochloride salt in methanol, concentrate the methazuru, then slowly add acetone and leave to stand.
析出結晶を濾取し、 ４． ５． ６． ７−チトラ
ヒドロチエノ［３，２−ｃコピリジン塩酸塩の無色針状
晶、ｍｐ２２８−９° （９，１ｇ、８５％）を得。4. Collect the precipitated crystals by filtration. 5. 6. Colorless needles of 7-titrahydrothieno[3,2-c-copyridine hydrochloride, mp 228-9° (9.1 g, 85%) were obtained.
Ｆ、 効果
実施例より明かな如く１本発明により、 ＩＩより１
工程で簡便に容易に、しかも高収率で目的化合物（１）
を製造することができる。さらに２反応試薬である１、
３−ジオキソランは、溶媒として使用される化合物であ
り、刺激性もなく安全に取り扱うことができる。F. As is clear from the effect examples, 1 according to the present invention, 1 from II
Target compound (1) can be obtained easily and easily in a high yield during the process.
can be manufactured. Furthermore, 2 reaction reagents 1,
3-dioxolane is a compound used as a solvent and can be safely handled without irritation.
本発明は塩酸チクロピジン製造のための中間体の製造法
として産業上極めて有用である。The present invention is industrially extremely useful as a method for producing an intermediate for producing ticlopidine hydrochloride.
Claims (1)
−ジオキソランを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▼ で表わされるチエノピリジン誘導体およびその塩の製造
法。[Claims] 2-(2-thienyl)ethylamine represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ 1,3
- A method for producing a thienopyridine derivative and its salt represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼, characterized by reacting dioxolane.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12944290A JPH0426690A (en) | 1990-05-18 | 1990-05-18 | New production of thienopyridine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12944290A JPH0426690A (en) | 1990-05-18 | 1990-05-18 | New production of thienopyridine derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0426690A true JPH0426690A (en) | 1992-01-29 |
Family
ID=15009570
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP12944290A Pending JPH0426690A (en) | 1990-05-18 | 1990-05-18 | New production of thienopyridine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0426690A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0829482A3 (en) * | 1996-09-04 | 1998-05-20 | Poli Industria Chimica S.p.A. | Method of making thieno-pyridine derivatives |
-
1990
- 1990-05-18 JP JP12944290A patent/JPH0426690A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0829482A3 (en) * | 1996-09-04 | 1998-05-20 | Poli Industria Chimica S.p.A. | Method of making thieno-pyridine derivatives |
| US6043368A (en) * | 1996-09-04 | 2000-03-28 | Poli Industria Chimica, S.P.A. | Method of making thieno-pyridine derivatives |
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