JPH059435B2 - - Google Patents
Info
- Publication number
- JPH059435B2 JPH059435B2 JP9532087A JP9532087A JPH059435B2 JP H059435 B2 JPH059435 B2 JP H059435B2 JP 9532087 A JP9532087 A JP 9532087A JP 9532087 A JP9532087 A JP 9532087A JP H059435 B2 JPH059435 B2 JP H059435B2
- Authority
- JP
- Japan
- Prior art keywords
- pyridine
- tetrahydrothieno
- following formula
- chlorobenzyl
- reducing
- 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 - Fee Related
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 18
- -1 lithium halide Chemical class 0.000 claims description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 8
- 239000012279 sodium borohydride Substances 0.000 claims description 7
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 7
- 229910052744 lithium Inorganic materials 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000000034 method Methods 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 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 description 5
- 150000003512 tertiary amines Chemical class 0.000 description 5
- PHWBOXQYWZNQIN-UHFFFAOYSA-N ticlopidine Chemical compound ClC1=CC=CC=C1CN1CC(C=CS2)=C2CC1 PHWBOXQYWZNQIN-UHFFFAOYSA-N 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 4
- 239000003638 chemical reducing agent Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- KDDNKZCVYQDGKE-UHFFFAOYSA-N (2-chlorophenyl)methanamine Chemical compound NCC1=CC=CC=C1Cl KDDNKZCVYQDGKE-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- HLPRKWVEMYDPAU-UHFFFAOYSA-N 2-thiophen-2-ylethyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCCC1=CC=CS1 HLPRKWVEMYDPAU-UHFFFAOYSA-N 0.000 description 2
- 239000005528 B01AC05 - Ticlopidine Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- MKYRMMMSZSVIGD-UHFFFAOYSA-N thieno[3,2-c]pyridine Chemical compound N1=CC=C2SC=CC2=C1 MKYRMMMSZSVIGD-UHFFFAOYSA-N 0.000 description 2
- 229960005001 ticlopidine Drugs 0.000 description 2
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 1
- OJYDKYKQCVPTFG-UHFFFAOYSA-N 2,3,3a,4-tetrahydrothieno[3,2-c]pyridine Chemical compound C1N=CC=C2SCCC21 OJYDKYKQCVPTFG-UHFFFAOYSA-N 0.000 description 1
- RBIGKSZIQCTIJF-UHFFFAOYSA-N 3-formylthiophene Chemical compound O=CC=1C=CSC=1 RBIGKSZIQCTIJF-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002366 halogen compounds Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 150000003511 tertiary amides Chemical class 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 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)
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−テトラヒドロチエノ〔３，２−Ｃ〕
ピリジン（慣用名；チクロピジン）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チクロピジン
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。
（従来の技術）
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(2)の
製造方法には、以下の３つの方法がある。
１ 特公昭52−31357号に記載されている方法は、
次式(3)
で示されるチエノ〔３，２−Ｃ〕ピリジンを次
式(4)
（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(5)
（式中、Hal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、ついで該ピ
リジニウム塩を水素化して、前記(2)で示される
化合物を得ることから成る。
２ 特開昭51−101996号および特開昭54−1994号
に記載されている方法は、次式(6)
（式中、Ｒは置換されたアルキル、アリール
またはアラルキル基を表わす。）
で示される化合物を次式(7)
で示されるアミンと縮合させ、次式(8)
で示される化合物を得た後、次いでホルムアル
デヒドで還化して、前記式(2)で示される化合物
を得ることから成る。
３ ヨーロピアン・ジヤーナル・オブ・メデイカ
ル・ケミストリー・−キミカ・テラペウテイカ
（Eur.J.Med.Chem.−Chimca.Therapeutica）
９，483（1974）に記載されている方法は、次式
(1)
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、前記式(2)で示される化合物を得
ることから成る。
４ ジヤーナル・オブ・ケミカル・ソサイアテ
イ；ケミカル・コミユニケイシヨン（J.Chem.
Soc；Chem.Commun.）668，（1983）には、１
級アミド、エステル、エポキシドの水素化ホウ
素リチウム−メタノールによる還元が記載され
ている。
（発明が解決しようとする問題点）
１の方法での原料となるチエノ〔３，２−Ｃ〕
ピリジン(3)の公知の製造方法は、３−チオフエン
アルデヒドをイミノアセタール化し、次式(9)
を得た後、次に還元することから成る。
しかし、(9)からチエノ〔３，２−Ｃ〕ピリジン
(3)への収率は、ジヤーナル・オブ・ザ・アメリカ
ン・ケミカル・ソサイアテイ（J.Am.Chem.
Soc.）75，5122，（1953）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言い難い。
また、２の方法では、２−（２−チエニル）エ
チルトシレート(6)と２−クロロベンジルアミン(7)
との反応において、３級アミン等の副生成物が生
ずるため、精製分離に非常に煩雑な操作が必要で
ある。３級アミン等の副生成物を減少させるため
には、アミン(7)をトシレート(6)に対して２倍モル
以上用いなければならない。しかし、この場合に
おいても、３級アミン等の副生物の生成はさける
ことができない。また、次の還化反応では、２級
アミンから３級アミンへの変換であり、分離精製
が非常に困難である。
次に、３の方法においては、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
い上非常な危険性があり、また、副成物が生成す
るなど工業的実施プロセスとしては好ましくな
い。
さらに、４の方法においては、次式(10)
Ｒ−CONH2 (10)
（式中、Ｒはフエニルまたはｎ−ヘプチル基を
示す。）
で表わされる単純な炭化水素基を置換基にもつ１
級アミド化合物を、次式(11)
Ｒ−CH2−NH2 (11)
（式中、Ｒは前記と同じである。）
で表わされる１級アミン化合物に還元することに
成功しているが、３級アミドの還元については記
載がなく、また、置換基にチオフエン環のような
複雑なヘテロ環をもつアミド化合物の還元につい
ては行なわれていない。また、この方法において
は、高価で、かつ取り扱い上危険な水素化ホウ素
リチウムを還元剤として用いており、経済的かつ
工業的に満足のできるアミド化合物の還元方法と
は言い難い。
（問題点を解決するための手段および作用）
一般に、水素化ホウ素ナトリウムはアミドをア
ミンに還元することはできない。しかし、本発明
者らは、水素化ホウ素ナトリウムとハロゲン化リ
チウムを反応させた後、そのまま引き続き低級ア
ルコールの存在下、次式(1)
で示される５−（２−クロロベンゾイル）−４，
５，６，７−テトラヒドロチエノ〔３，２−Ｃ〕
ピリジンを還元することによる次式(2)
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
ジンの製造方法を見いだした。
以下、本発明の実施方法をさらに詳しく説明す
る。
１〜10倍モル望ましくは３〜５倍モルの水素化
ホウ素ナトリウムおよび１〜10倍モル望ましくは
３〜５倍モルのハロゲン化リチウムを、ジエチル
エーテル、THF、ダイグライムなどのエーテル
系溶媒望ましくはダイグライムに加え、20℃で還
流下３〜20時間望ましくは８〜10時間で反応を行
う。そのまま引き続き、その溶液にアミド(1)を加
え、100℃で還元温度望ましくは還流下で、１〜
30倍モル望ましくは10〜15倍モルの低級アルコー
ル望ましくはメタノールを、１〜５時間望ましく
は１〜３時間で徐々に滴下する。滴下終了後、
0.1〜３時間望ましくは0.5〜１時間そのままの温
度で攪拌する。
目的物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
ジンは塩基性物質であり、反応終了後、公知の精
製操作により、容易に単離することができる。
（発明の効果）
本発明により、取り扱い上危険な還元剤を使用
せずに、温和な還元剤である水素化ホウ素ナトリ
ウムとハロゲン化リチウムを反応させた後、さら
に、これを低級アルコールにより還元力を強化
し、５−（２−クロロベンゾイル）−４，５，６，
７−テトラヒドロチエノ〔３，２−Ｃ〕ピリジン
(1)を還元し、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(2)を製造することが可能となつた。
さらに、中性の原料から塩基性の目的化合物が
得られるため、分離精製が容易であり、工業的か
つ経済的プロセスであると言うことができる。
（実施例）
次に、本発明の実施例を挙げるが、この実施例
によつて本発明が限定されるものではない。
実施例 １
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
水素化ホウ素ナトリウム0.34ｇ（9mmol）と臭
化リチウム0.78ｇ（9mmol）をダイグライム５ml
に加え、100℃で10時間攪拌した。この溶液に５
−（２−クロロベンゾイル）−４，５，６，７−テ
トラヒドロチエノ〔３，２−Ｃ〕ピリジン0.83ｇ
（3mmol）のダイグライム７ml溶液を加え、還流
下メタノール1.4mlを１時間で徐々に滴下した。
滴下後、さらに１時間還流攪拌した。反応終了
後、水40ml、次に濃塩酸１mlを加え、反応液をPH
２以下とした後、エーテル30mlで３回分液し、中
性物質を除去した。次いで、その水層を1N−
NaOH15mlでPH９以上とした後、エーテル30ml
で３回抽出し、そのエーテル層を乾燥後、溶媒を
減圧留去し、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0.57ｇ（70％）を得た。
NMR（CDCl3）； δ2.90（4H，Ｓ）
3.60（2H，Ｓ）
3.85（2H，Ｓ）
6.90（2H，dd）
7.30（4H，ｍ）
元素分析値C14H14ClNSとして
計算値Ｃ ；63.76％
Ｈ；5.31％
Ｎ；5.31％
Cl；13.47％
Ｓ；12.14％
実測値Ｃ ；63.51％
Ｈ；5.49％
Ｎ；5.30％
Cl；13.21％
Ｓ；12.41％
実施例 ２
水素化ホウ素ナトリウム0.34ｇ（9mmol）と塩
化リチウム0.38ｇ（9mmol）をダイグライム５ml
に加え、還流下10時間攪拌した。この溶液に５−
（２−クロロベンゾイル）−４，５，６，７−テト
ラヒドロチエノ〔３，２−Ｃ〕ピリジン0.83ｇ
（3mmol）のダイグライム７ml溶液を加え、加熱
還流下メタノール1.4mlを１時間で徐々に滴下し
た後、さらに１時間還流攪拌した。反応終了後、
実施例１と同様の操作を行ない、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0.55ｇ（収率68％）
を得た。 Detailed Description of the Invention (Industrial Field of Application) The present invention provides 5-(2-chlorobenzyl)-4,
5,6,7-tetrahydrothieno[3,2-C]
This invention relates to a new method for producing pyridine (common name: ticlopidine). An object of the present invention is to industrially produce ticlopidine and its salts having inhibitory effects on platelet aggregation and platelet adhesion in a high yield. (Prior art) 5-(2-chlorobenzyl)-4,5,6,7-
There are the following three methods for producing tetrahydrothieno[3,2-C]pyridine (2). 1 The method described in Japanese Patent Publication No. 52-31357 is
The following formula (3) The thieno[3,2-C]pyridine represented by the following formula (4) (In the formula, Hal represents a halogen atom.) By condensing with a halogen compound represented by the following formula (5) (In the formula, Hal has the same meaning as above.) The method consists of obtaining a pyridinium salt represented by the following formula, and then hydrogenating the pyridinium salt to obtain a compound represented by (2) above. 2 The method described in JP-A-51-101996 and JP-A-54-1994 is based on the following formula (6) (In the formula, R represents a substituted alkyl, aryl or aralkyl group.) A compound represented by the following formula (7) Condensation with the amine shown by the following formula (8) After obtaining the compound represented by formula (2), the compound is then reduced with formaldehyde to obtain the compound represented by formula (2). 3 European Journal of Medical Chemistry - Chimca Therapeutica (Eur.J.Med.Chem. - Chimca.Therapeutica)
9, 483 (1974), the following formula
(1) The method consists of reducing the compound represented by the formula (2) with lithium aluminum hydride to obtain the compound represented by the formula (2). 4 Journal of Chemical Society (J.Chem.
Soc; Chem.Commun.) 668, (1983), 1
The reduction of grade amides, esters, and epoxides with lithium borohydride-methanol is described. (Problem to be solved by the invention) Thieno[3,2-C] as a raw material in method 1
A known method for producing pyridine (3) is to convert 3-thiophenaldehyde into iminoacetal and form the following formula (9): It consists of obtaining and then reducing. However, from (9) to thieno[3,2-C]pyridine
The yield to (3) was determined by the Journal of the American Chemical Society (J.Am.Chem.
According to Soc.) 75 , 5122, (1953), only 10%;
It cannot be called an economical and industrial implementation process. In addition, in method 2, 2-(2-thienyl)ethyl tosylate (6) and 2-chlorobenzylamine (7)
Because by-products such as tertiary amines are produced in the reaction with tertiary amines, very complicated operations are required for purification and separation. In order to reduce by-products such as tertiary amines, amine (7) must be used in an amount of at least twice the amount of tosylate (6). However, even in this case, the production of by-products such as tertiary amines cannot be avoided. Furthermore, the next reflux reaction involves converting a secondary amine into a tertiary amine, which is very difficult to separate and purify. Next, in method 3, lithium aluminum hydride is used as a reducing agent, which is very dangerous in handling and also produces by-products, which is not suitable for industrial implementation. Furthermore, in method 4, 1 having a simple hydrocarbon group as a substituent represented by the following formula (10) R-CONH 2 (10) (wherein R represents a phenyl or n-heptyl group)
We have succeeded in reducing a primary amine compound to a primary amine compound represented by the following formula (11) R-CH 2 -NH 2 (11) (wherein R is the same as above). , there is no description of the reduction of tertiary amides, and no reduction of amide compounds having complex heterocycles such as thiophene rings as substituents. Furthermore, this method uses lithium borohydride, which is expensive and dangerous to handle, as a reducing agent, and cannot be said to be an economically and industrially satisfactory method for reducing amide compounds. (Means and Actions for Solving the Problems) Generally, sodium borohydride cannot reduce amides to amines. However, after reacting sodium borohydride with lithium halide, the present inventors continued to react with the following formula (1) in the presence of a lower alcohol. 5-(2-chlorobenzoyl)-4,
5,6,7-tetrahydrothieno[3,2-C]
The following formula (2) by reducing pyridine 5-(2-chlorobenzyl)-4,5,
We have discovered a method for producing 6,7-tetrahydrothieno[3,2-C]pyridine. Hereinafter, the method of implementing the present invention will be explained in more detail. 1 to 10 times the mole, preferably 3 to 5 times the mole of sodium borohydride and 1 to 10 times the mole, preferably 3 to 5 times the mole of lithium halide, in an ether solvent such as diethyl ether, THF, diglyme, etc., preferably diglyme. In addition, the reaction is carried out at 20° C. under reflux for 3 to 20 hours, preferably 8 to 10 hours. Continuously, amide (1) is added to the solution, and the reduction temperature is preferably 1 to 100°C under reflux.
A lower alcohol, preferably methanol, in an amount of 30 times the mole, preferably 10 to 15 times the mole, is gradually added dropwise over a period of 1 to 5 hours, preferably 1 to 3 hours. After finishing dropping,
Stir at the same temperature for 0.1 to 3 hours, preferably 0.5 to 1 hour. Target product 5-(2-chlorobenzyl)-4,5,
6,7-tetrahydrothieno[3,2-C]pyridine is a basic substance, and after the reaction is completed, it can be easily isolated by known purification procedures. (Effects of the Invention) According to the present invention, after reacting sodium borohydride, which is a mild reducing agent, with lithium halide without using a reducing agent that is dangerous to handle, this is further reacted with a lower alcohol for reducing power. 5-(2-chlorobenzoyl)-4,5,6,
7-tetrahydrothieno[3,2-C]pyridine
(1) is reduced, 5-(2-chlorobenzyl)-4,
5,6,7-tetrahydrothieno[3,2-C]
It became possible to produce pyridine (2). Furthermore, since a basic target compound is obtained from a neutral raw material, separation and purification is easy, and it can be said that it is an industrial and economical process. (Example) Next, examples of the present invention will be described, but the present invention is not limited to these examples. Example 1 5-(2-chlorobenzyl)-4,5,6,7-
Tetrahydrothieno[3,2-C]pyridine Add 0.34 g (9 mmol) of sodium borohydride and 0.78 g (9 mmol) of lithium bromide to 5 ml of diglyme.
and stirred at 100°C for 10 hours. 5 in this solution
-(2-chlorobenzoyl)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine 0.83g
(3 mmol) of diglyme (7 ml) was added thereto, and 1.4 ml of methanol was gradually added dropwise over 1 hour under reflux.
After the addition, the mixture was further stirred under reflux for 1 hour. After the reaction is complete, add 40ml of water and then 1ml of concentrated hydrochloric acid to adjust the pH of the reaction solution.
After reducing the concentration to 2 or less, the solution was separated three times with 30 ml of ether to remove neutral substances. Then, the aqueous layer was heated to 1N−
After adjusting the pH to 9 or higher with 15 ml of NaOH, 30 ml of ether
After drying the ether layer, the solvent was distilled off under reduced pressure to obtain 5-(2-chlorobenzyl)-4,
5,6,7-tetrahydrothieno[3,2-C]
0.57 g (70%) of pyridine was obtained. NMR (CDCl 3 ); δ2.90 (4H, S) 3.60 (2H, S) 3.85 (2H, S) 6.90 (2H, dd) 7.30 (4H, m) Elemental analysis value C As 14 H 14 ClNS Calculated value C ; 63.76% H; 5.31% N; 5.31% Cl; 13.47% S; 12.14% Actual value C; 63.51% H; 5.49% N; 5.30% Cl; 13.21% S; 12.41% Example 2 Sodium borohydride 0.34 g (9 mmol) and 0.38 g (9 mmol) of lithium chloride in 5 ml of diglyme.
and stirred under reflux for 10 hours. Add 5-
(2-chlorobenzoyl)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine 0.83g
(3 mmol) of diglyme was added, 1.4 ml of methanol was gradually added dropwise over 1 hour while heating under reflux, and the mixture was further stirred under reflux for 1 hour. After the reaction is complete,
The same operation as in Example 1 was carried out to obtain 0.55 g of 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine (yield 68%).
I got it.
Claims (1)
ムを反応させた後、引き続き低級アルコールの存
在下、次式(1) で示される５−（２−クロロベンゾイル）−４，
５，６，７−テトラヒドロチエノ〔３，２−Ｃ〕
ピリジンを還元することを特徴とする次式(2) 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。[Claims] 1. After reacting sodium borohydride and lithium halide, in the presence of a lower alcohol, the following formula (1) 5-(2-chlorobenzoyl)-4,
5,6,7-tetrahydrothieno[3,2-C]
The following formula (2) is characterized by reducing pyridine. 5-(2-chlorobenzyl)-4,5,
A method for producing 6,7-tetrahydrothieno[3,2-C]pyridine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP9532087A JPS63264589A (en) | 1987-04-20 | 1987-04-20 | Production of ticlopidine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP9532087A JPS63264589A (en) | 1987-04-20 | 1987-04-20 | Production of ticlopidine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS63264589A JPS63264589A (en) | 1988-11-01 |
| JPH059435B2 true JPH059435B2 (en) | 1993-02-04 |
Family
ID=14134450
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP9532087A Granted JPS63264589A (en) | 1987-04-20 | 1987-04-20 | Production of ticlopidine |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS63264589A (en) |
-
1987
- 1987-04-20 JP JP9532087A patent/JPS63264589A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS63264589A (en) | 1988-11-01 |
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