JPS62205087A - Production of ticlopidine - Google Patents
Production of ticlopidineInfo
- Publication number
- JPS62205087A JPS62205087A JP4641786A JP4641786A JPS62205087A JP S62205087 A JPS62205087 A JP S62205087A JP 4641786 A JP4641786 A JP 4641786A JP 4641786 A JP4641786 A JP 4641786A JP S62205087 A JPS62205087 A JP S62205087A
- Authority
- JP
- Japan
- Prior art keywords
- pyridine
- acid
- tetrahydro
- acidic
- chloro
- 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
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 5
- PHWBOXQYWZNQIN-UHFFFAOYSA-N ticlopidine Chemical compound ClC1=CC=CC=C1CN1CC(C=CS2)=C2CC1 PHWBOXQYWZNQIN-UHFFFAOYSA-N 0.000 title claims abstract 3
- 239000005528 B01AC05 - Ticlopidine Substances 0.000 title 1
- 229960005001 ticlopidine Drugs 0.000 title 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 30
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000012279 sodium borohydride Substances 0.000 claims abstract description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 claims abstract description 8
- 230000002378 acidificating effect Effects 0.000 claims abstract description 7
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229940098779 methanesulfonic acid Drugs 0.000 claims abstract description 5
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229940092714 benzenesulfonic acid Drugs 0.000 claims abstract description 3
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims abstract description 3
- 239000000126 substance Substances 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 abstract description 6
- ARHVQOBKFAPHQP-UHFFFAOYSA-N (2-chlorophenyl)-(6,7-dihydro-4h-thieno[3,2-c]pyridin-5-yl)methanone Chemical compound ClC1=CC=CC=C1C(=O)N1CC(C=CS2)=C2CC1 ARHVQOBKFAPHQP-UHFFFAOYSA-N 0.000 abstract description 2
- 210000001772 blood platelet Anatomy 0.000 abstract 2
- LKRVCRUZMZLMCE-UHFFFAOYSA-N 2,3,3a,4-tetrahydrothieno[3,2-b]pyridin-2-yl-(2-chlorophenyl)methanone Chemical compound ClC1=CC=CC=C1C(=O)C1SC2=CC=CNC2C1 LKRVCRUZMZLMCE-UHFFFAOYSA-N 0.000 abstract 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 abstract 1
- 239000000701 coagulant Substances 0.000 abstract 1
- 108010081580 platelet adhesion inhibitor Proteins 0.000 abstract 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 11
- 239000000243 solution Substances 0.000 description 9
- -1 lithium aluminum hydride Chemical compound 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 239000012280 lithium aluminium hydride Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 238000000921 elemental analysis Methods 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- KDDNKZCVYQDGKE-UHFFFAOYSA-N (2-chlorophenyl)methanamine Chemical compound NCC1=CC=CC=C1Cl KDDNKZCVYQDGKE-UHFFFAOYSA-N 0.000 description 1
- 125000006282 2-chlorobenzyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- RBIGKSZIQCTIJF-UHFFFAOYSA-N 3-formylthiophene Chemical compound O=CC=1C=CSC=1 RBIGKSZIQCTIJF-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 101100507312 Invertebrate iridescent virus 6 EF1 gene Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- VRZVPALEJCLXPR-UHFFFAOYSA-N ethyl 4-methylbenzenesulfonate Chemical compound CCOS(=O)(=O)C1=CC=C(C)C=C1 VRZVPALEJCLXPR-UHFFFAOYSA-N 0.000 description 1
- 150000002366 halogen compounds Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-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】
（産業上の利用分野）
本発明は、５−（２−クロロ−ベンジル）−４，５，６
，７−テトラヒドローチエノ（５，２−Ｃ）ピリジンの
新規な製造方法に関する。本発明の目的は、血小板凝集
および血小板粘着能の抑制作用を有する５−（２−クロ
ロ−ベンジル） −４，５，６，７−テトラヒドローチ
エノ（５，２−Ｃ）ピリジンおよびその塩を工業的に、
かつ、高収率で製造することにある。Detailed Description of the Invention (Industrial Application Field) The present invention provides 5-(2-chloro-benzyl)-4,5,6
, 7-tetrahydrothieno(5,2-C)pyridine. The object of the present invention is to provide 5-(2-chloro-benzyl)-4,5,6,7-tetrahydrothieno(5,2-C)pyridine and its salts, which have inhibitory effects on platelet aggregation and platelet adhesion. industrially,
Moreover, it is to be produced at high yield.
（従来の技術）
４．５，６．７−テトラしドローチェノ（５，２−Ｃ）
ヒリジン誘導体の製造方法には、以下の三つの方法があ
る。(Prior art) 4.5,6.7-tetra-drowcheno (5,2-C)
There are the following three methods for producing hyridine derivatives.
ｆｉｌ特公昭５２−５１５５７号公報に記載されている
方法は、次式（ｒ［Ｉ ）
で示されるチェノ（５，２−Ｃ）ピリジンを、（式中、
Ｈａｌはハロゲン原子を表わす。）で示されるハロゲン
化合物と縮合させ、次式Ｍ（式中、）Ｉａｌは前記と同
じ意味を有する。）で示されるピリジニウム塩を得て、
次いで、該ピリジニウム塩を水素化して、前記の式（Ｉ
Ｉ）で示される化合物を得ることからなる。In the method described in Japanese Patent Publication No. 52-51557, cheno(5,2-C)pyridine represented by the following formula (r[I) is converted into
Hal represents a halogen atom. ) is condensed with a halogen compound represented by the following formula M (in the formula, )Ial has the same meaning as above. ) to obtain the pyridinium salt shown in
The pyridinium salt is then hydrogenated to give the formula (I
It consists of obtaining a compound of I).
（２１特開昭５１−１０１９９６号および特開昭５４−
１９９４号公報に記載されている方法は、次式（ＶＩ）
（式中、Ｒ＋ｔｉ置換されたアルキル、アリールま次は
アルキル基を表わす。）
で示されるアミンと縮合させ、次式（■）で示される化
合物を得て、次いで、ホルムアルデヒドτ還化して、前
記の式（ｎ）で示される化合物を得ることからなる。(21 Japanese Unexamined Patent Publication No. 101996/1983 and Japanese Unexamined Patent Publication No. 54/1989)
The method described in the 1994 publication involves condensation with an amine represented by the following formula (VI) (in the formula, R + ti-substituted alkyl, aryl and the following represent an alkyl group), and the following formula (■) The compound represented by formula (n) is then obtained by formaldehyde τ reduction to obtain the compound represented by formula (n) above.
（３１ヨーロピアン・ジャーナルｅオブ・メディカルφ
ケミストリー、−キミカ・テラベラティ力（Ｅｕｒ、
Ｊ、 Ｍｅｄ、 Ｃｈｅｍ、、 −Ｃｈｉｍｃａ Ｔｈ
ｅｒａｐｅｕｔｉｃａ ）９．４８５（１９７４）に記
載されている方法は、次式〇）
で示される化合物を水素化リチウムアルミニウムで還元
して、前記の式（ｎ）で示される化合物を得−Ｃ）ピリ
ジン（ＩＩＩ）の公知の製造方法の一例を挙げると、３
−チオフェンアルデヒドをジエチルアミノアセタール化
し、その後、速比して合成されるが、次式（ＩＸ）
で示されるジエチル−５−チェニリデンアミノアセター
ルからの収率は、ジャーナル・オブ・ザ・アメリカン・
ケミカル・ソサイアテイ（Ｊ、 Ａｍ。(31 European Journal e of Medical φ
Chemistry, - Kimica Terrabellati Power (Eur,
J, Med, Chem, -Chimca Th
erapeutica) 9.485 (1974), a compound represented by the following formula 〇) is reduced with lithium aluminum hydride to obtain a compound represented by the above formula (n) -C) pyridine An example of a known manufacturing method for (III) is 3
- Thiophenaldehyde is converted into diethylaminoacetal and then synthesized by rapid ratio.
Chemical Society (J, Am.
Ｃｈｅｍ、 Ｓｏｃ、） ７５．５１２２ （１９５Ｓ
）によれば１０％にすぎず、経済的かつ工業的実施プ
ロセスとはいいが交い。Chem, Soc, ) 75.5122 (195S
), it is only 10%, which is at odds with the economical and industrial implementation process.
ま次、＋２１の方法では、２−（２−チェニル）エチル
トシレートと２−クロロベンジルアミンとの反応におい
て、三級アミン等の副生物が生ずるため、精製分離に非
常に煩雑な操作が必要である。Secondly, in method +21, by-products such as tertiary amines are produced in the reaction of 2-(2-chenyl)ethyl tosylate and 2-chlorobenzylamine, so very complicated operations are required for purification and separation. It is.
三級以上のアミン体の副生をさけようとすると、該アミ
ンをトシレートに対して２倍モル以上用いなければなら
ず、これでも副生物の生成はさけられない。さらに、速
比の段階においても、二級アミンから三級アミンへの変
換であり、分離精製が非常に難しい。In order to avoid the by-product of tertiary or higher class amines, the amine must be used in an amount of at least twice the mole of tosylate, and even with this, the formation of by-products cannot be avoided. Furthermore, even at the speed ratio stage, secondary amines are converted to tertiary amines, which is extremely difficult to separate and purify.
（３）の方法では、還元剤として水素化リチウムアルミ
ニウムを使用しており、取り扱い上非常に危険性があり
、工業的実施プロセスとしては好ましくない。Method (3) uses lithium aluminum hydride as a reducing agent, which is extremely dangerous to handle and is not suitable for industrial implementation.
（問題点を解決するための手段および作用）本発明者は
、上記の問題点を解決するため鋭意検討し次結果、次式
（Ｉ）
４．５，６．７−テトラヒドローチエノ（３，２−Ｃ）
ピリジンを、酸性ジメチルスルホキシド中、水素イヒホ
ウ素ナトリウムで還元することによる、次式（ＩＩ）ｔ
で示される５−（２−りａローベンジル）−４゜５．６
．７−テトラヒドローチエノ（ｓ、ｚ −Ｃ）ピリジン
の製造方法を見い出し友。(Means and effects for solving the problems) The present inventor has made extensive studies to solve the above problems, and as a result, the following formula (I) 4.5,6.7-tetrahydrothieno(3, 2-C)
5-(2-r-alobenzyl)-4゜5.6 of the following formula (II)t by reducing pyridine with sodium dihydroborate in acidic dimethyl sulfoxide.
．． A friend who discovered a method for producing 7-tetrahydrothieno(s,z-C)pyridine.
反応は、チェノピリジン誘導体（Ｉ）と水素化ホウ素ナ
トリウムを１対１〜１０倍モル、望ましくは１対１〜４
倍モルの割合で溶解し、その溶液に、酸性物質としてメ
タンスルホン酸、エタンスルホン酸、ベンゼンスルホン
酸ｔｅｕノくラドルエンスルホン酸を、チェノピリジン
誘導体（Ｉ）に対して１〜１５倍モル、望ましくは２〜
５倍モルを添加しｆｃＤＭＳＯ溶液ヲ０．５〜１時間で
滴下し、滴下終了袋、５０〜１００Ｃで１〜３時間加熱
して行われる。目的物５−（２−クロａ−ベンジル）−
４，５，６，７−テトラヒドローチエノ（５，２−Ｃ：
１ピリジンは塩基性物質であり、公知の精製操作により
容易に単離することができる。The reaction is carried out using chenopyridine derivative (I) and sodium borohydride in a ratio of 1:1 to 10 times the molar ratio, preferably 1:1 to 4 times the molar ratio.
Dissolve in a ratio of 1 to 15 times the molar ratio of the chenopyridine derivative (I), and add methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, radruenesulfonic acid as an acidic substance to the solution, preferably in a molar ratio of 1 to 15 times the mole of the chenopyridine derivative (I). is 2~
After adding 5 times the mole, the fcDMSO solution is added dropwise over 0.5 to 1 hour, and after the dropping is finished, the bag is heated at 50 to 100C for 1 to 3 hours. Target product 5-(2-chloroa-benzyl)-
4,5,6,7-tetrahydrothieno(5,2-C:
1Pyridine is a basic substance and can be easily isolated by known purification procedures.
（発明の効果）
本発明により、温和な還元剤である水素化ホウ素ナトリ
ウム′ｔ−酸性ＤＭＳＯ中で使用することで、取り扱い
上危険である水素化リチウムアルミニウムを使用せずに
、アミド体で多るチェノピリジン誘導体を還元して、水
素化リチウムアルミニウムを用ｔｎ７ｉ時と同じくらい
の効率で、目的物５−（２−クロロ−ベンジル） −４
，５，６，７−テトラヒドローチエノ（Ｓ、Ｚ −Ｃ）
ピリジンを製造することが可能となつ友。さらに、中性
′＃Ｉ質から塩基性物質へという、原料と生成物の関係
がある友め、分離′！ｆＩＪ！！！が容易でおり、工業
的かつ経済的実施プロセスである。(Effects of the invention) By using the present invention in sodium borohydride't-acidic DMSO, which is a mild reducing agent, it is possible to use amide derivatives without using lithium aluminum hydride, which is dangerous to handle. The desired product 5-(2-chloro-benzyl)-4 was obtained by reducing the chenopyridine derivative using lithium aluminum hydride with the same efficiency as in tn7i.
,5,6,7-tetrahydrothieno(S,Z-C)
Natsutomo is able to produce pyridine. Furthermore, separation from neutral substances to basic substances, a relationship between raw materials and products! fIJ! ! ! It is an easy, industrial and economical process to implement.
（実施例）
次に、本発明の実施例を挙げるが、この実施例によって
本発明が限定されるものではない。(Example) Next, an example of the present invention will be given, but the present invention is not limited to this example.
実施例１
５−（２−クロロ−ベンジル） −４，５，６，７−テ
トラヒドローチエノ（３，２−Ｃ）ピリジン水素化ホウ
素ナトリウＡ Ｌ９ ｆ （４５ｍｍｏｌ ）と５−（
２−クロロ−ベンゾイル） ４，５，６．７−テトラ
ヒドロ−チェノ（５，２−Ｃ）ピリジン５．Ｏｙ （１
ａ ｍｍｏｌ ） ｔ−含むＤＭＳＯ溶液３０−に、メ
タンスルホン酸３．８ ｍｌ （６５ｍｍｏｆ ）を含
むＤ ＭＳＯ溶液３０ｒｎｌを３０分で滴下し、ｙａＣ
で２時間反応を行った。反応終了後、ＩＱ％水酸化ナト
ＩＪウム水溶液５０−を添加し、エーテル５０−で３回
抽出し几。さらに、そのエーテル層を０．１Ｎ水酸化ナ
トリウムＢＯｒｎｔで５回洗浄し、ＤＭＳＯを除去し友
。そのエーテル層を１０％塩酸５０−で３回抽出し友。Example 1 5-(2-chloro-benzyl)-4,5,6,7-tetrahydrothieno(3,2-C)pyridine sodium borohydride A L9 f (45 mmol) and 5-(
2-chloro-benzoyl) 4,5,6.7-tetrahydro-cheno(5,2-C)pyridine5. Oy (1
30 rnl of a DMSO solution containing 3.8 ml (65 mmof) of methanesulfonic acid was added dropwise over 30 minutes to 30 rnl of a DMSO solution containing 3.8 ml (65 mmof) of methanesulfonic acid.
The reaction was carried out for 2 hours. After the reaction was completed, 50% of IQ% sodium hydroxide aqueous solution was added, and the mixture was extracted three times with 50% of ether. Furthermore, the ether layer was washed five times with 0.1N sodium hydroxide to remove DMSO. The ether layer was extracted three times with 10% hydrochloric acid.
その水層を１０係水酸化ナトリウムでｐ）（１２とし、
エーテル１００−で５回抽出し次。エーテル層を乾燥後
、エーテルを留去して、５−（ｚ−クロロ−ベンジル）
−４，５，６，７−テトラヒドローチエノ（３，２−
Ｃ）ピリジン３．４ｆ（収率７２憾）を得几。The aqueous layer was made p) (12 with 10% sodium hydroxide,
Extracted 5 times with 100% ether. After drying the ether layer, the ether was distilled off to give 5-(z-chloro-benzyl)
-4,5,6,7-tetrahydrothieno(3,2-
C) Pyridine 3.4f (yield 72) was obtained.
ＮＭＲ，元素分析値を以下に示すが、これは目的物の構
造を支持する。NMR and elemental analysis values are shown below, which support the structure of the target product.
Ｎ Ｍ Ｒ（ＣＤＣｔｓ ）
δ（ｐＰｌ） ２．９０ （ｓ、 ４８）３．６
０（ｓ、２Ｈ）
５．８５ （３，２Ｈ）
６．９０ （ｄｄ、 ２）１ ）
７．５０ （ｍ、 ４Ｈ）
元素分析
理論値 分析値
Ｃ６３，７６％ ６３．４９％
Ｈ５，３１％ ５．４７％
Ｎ ５．５１係 ５．２６％Ｃ１１３
，４７係 １３．１７％ｆ３ １２．１４％
１２．５９％実施例２
５−（２−クロロ−ベンジル） −４，５，６，７−テ
トラヒドローチエノ（５，２−Ｃ）ピリジン水素化ホウ
素ナトリウム１．９ｆ（４５ｍｍｏｌ）と５−（２−ク
ロロ−ベンゾイル） −４，５，６，７−テトラヒドロ
−チェノ［５，２−Ｃ］ピリジン５．Ｏｆ（１８ｍｍｏ
ｌ）を含むＤＭＳＯ溶液３０−に、パラトルエンスルホ
ン酸１０．８ ｆ （６３ｍｍｏｌ ）を含むＤＭＳＯ
溶液３０−を３０分で滴下し、７０Ｃで２時間反応させ
た。反応終了後は、実施例１と同様の後処理を行い、５
−＋２−クロロ−ベンジル） −４，５，６，７−テト
ラヒドローチエノ（５，２−Ｃ〕ピリジン２．８ ？
（収率５９俤）を得た。NMR(CDCts) δ(pPl) 2.90 (s, 48) 3.6
0 (s, 2H) 5.85 (3, 2H) 6.90 (dd, 2) 1) 7.50 (m, 4H) Elemental analysis theoretical value Analysis value C63,76% 63.49% H5,31% 5.47% N 5.51 section 5.26% C113
,47 section 13.17%f3 12.14%
12.59% Example 2 5-(2-chloro-benzyl)-4,5,6,7-tetrahydrothieno(5,2-C)pyridine sodium borohydride 1.9f (45 mmol) and 5-( 2-chloro-benzoyl)-4,5,6,7-tetrahydro-cheno[5,2-C]pyridine5. Of(18mmo
l) in DMSO containing 10.8 f (63 mmol) of para-toluenesulfonic acid.
Solution 30- was added dropwise over 30 minutes and reacted at 70C for 2 hours. After the reaction was completed, the same post-treatment as in Example 1 was carried out, and 5
-+2-chloro-benzyl) -4,5,6,7-tetrahydrothieno(5,2-C]pyridine2.8?
(yield: 59 yen).
ＮＭＲ，元素分析値は、目的物の構造を支持する。NMR and elemental analysis values support the structure of the target product.
参考例１
５−（２−クロロ−ベンジル） −４，５，６，７−テ
トラヒドローチエノ（５，２−Ｃ）ピリジン水素化リチ
ウムアルミニウム０．９５Ｆ（２５ｍｍｏｌ ） ｔ−
含むエーテル５０−に、５−（２−クロロ−ベンゾイル
） −４，５，６，７−テトラヒドローチエノ（５，２
−Ｃ）ビリジｙ ６，９ ｆ （２５ｍｍｏｌ ） ？
：含むエーテル溶液３０−を滴下し、室温で５時間反応
させた。反応終了後、過剰の水素化リチウムアルミニウ
ムを、水１〜２−を滴下して不活性化した。水酸化アル
ミ等の不溶物を戸別し、Ｐ液を１０４塩酸５０−で５回
抽出し次。その水層をｔＯｑ６水酸化ナトリウムでｐＨ
１２とし、エーテル５０−で３回抽出した。エーテル層
を乾燥後、ｘ−ｆルｆ留去り、、５− （２−クロロ−
ベンジル）−４，５，６，７−テトラヒドローチエノ（
５，２−Ｃ）ピリジン５．１ ？ （収率７７チ）を得
た。Reference example 1 5-(2-chloro-benzyl)-4,5,6,7-tetrahydrothieno(5,2-C)pyridine lithium aluminum hydride 0.95F (25 mmol) t-
5-(2-chloro-benzoyl)-4,5,6,7-tetrahydrothieno(5,2
-C) Viridiy 6,9 f (25 mmol)?
: An ether solution containing 30% of the solution was added dropwise and reacted at room temperature for 5 hours. After the reaction was completed, excess lithium aluminum hydride was inactivated by dropwise addition of water 1-2-. Insoluble materials such as aluminum hydroxide were removed from each house, and the P solution was extracted five times with 104-hydrochloric acid 50-. The aqueous layer was pH adjusted with tOq6 sodium hydroxide.
12 and extracted three times with ether 50. After drying the ether layer, 5-(2-chloro-
benzyl)-4,5,6,7-tetrahydrothieno(
5,2-C) Pyridine 5.1? (yield: 77 cm).
ＮＭＲ，元素分析値は、目的物の構造を支持する。゛
参考例２
水素化ホウ素ナトリウム１．９ ｆ （４５ｍｍｏｌ
）と５−（２−クロロ−ベンゾイル） −４，５，６，
７−テトラヒドローチエノ（３，２−Ｃ）ピリジンｓ
Ｏ？ （１８ｍｍｏｌ ）を含むＤＭＳＯ溶液４０１Ｒ
ｔを、７０Ｃで２時間反応させ次。反応終了後は、実施
例１と同様の後処理を行なつ几が、５−（２−クロロ−
ベンジル） −４，５，６，７−テトラヒドローチエノ
（ｓ、ｚ −Ｃ）ピリジンは得られなかった。NMR and elemental analysis values support the structure of the target product.゛Reference Example 2 Sodium borohydride 1.9 f (45 mmol
) and 5-(2-chloro-benzoyl) -4,5,6,
7-tetrahydrothieno(3,2-C)pyridine s
O? DMSO solution 401R containing (18 mmol)
t was reacted at 70C for 2 hours. After the reaction is completed, the same post-treatment as in Example 1 is carried out, and 5-(2-chloro-
benzyl)-4,5,6,7-tetrahydrothieno(s,z-C)pyridine was not obtained.
Claims (2)
６，７−テトラヒドロ−チエノ〔３，２−Ｃ〕ピリジン
を、酸性ジメチルスルホキシド中、水素化ホウ素ナトリ
ウムで還元することを特徴とする次式（II） ▲数式、化学式、表等があります▼（II） 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〕ピリジンの
製造方法。(1) The following formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) 5-(2-chloro-benzoyl)-4,5,
The following formula (II) is characterized by reducing 6,7-tetrahydro-thieno[3,2-C]pyridine with sodium borohydride in acidic dimethyl sulfoxide. II) 5-(2-chloro-benzyl)-4,5,6
, 7-tetrahydro-thieno[3,2-C]pyridine.
タンスルホン酸、エタンスルホン酸、ベンゼンスルホン
酸またはパラトルエンスルホン酸を添加する特許請求の
範囲第１項記載の製造方法。(2) The manufacturing method according to claim 1, wherein methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, or p-toluenesulfonic acid is added to prepare acidic dimethylsulfoxide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4641786A JPS62205087A (en) | 1986-03-05 | 1986-03-05 | Production of ticlopidine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4641786A JPS62205087A (en) | 1986-03-05 | 1986-03-05 | Production of ticlopidine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS62205087A true JPS62205087A (en) | 1987-09-09 |
| JPH0442395B2 JPH0442395B2 (en) | 1992-07-13 |
Family
ID=12746572
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP4641786A Granted JPS62205087A (en) | 1986-03-05 | 1986-03-05 | Production of ticlopidine |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS62205087A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6043368A (en) * | 1996-09-04 | 2000-03-28 | Poli Industria Chimica, S.P.A. | Method of making thieno-pyridine derivatives |
-
1986
- 1986-03-05 JP JP4641786A patent/JPS62205087A/en active Granted
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6043368A (en) * | 1996-09-04 | 2000-03-28 | Poli Industria Chimica, S.P.A. | Method of making thieno-pyridine derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0442395B2 (en) | 1992-07-13 |
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