JP2000229953A - Production of 5-halobutyl-1-cyclohexyl tetrazole - Google Patents
Production of 5-halobutyl-1-cyclohexyl tetrazoleInfo
- Publication number
- JP2000229953A JP2000229953A JP11108015A JP10801599A JP2000229953A JP 2000229953 A JP2000229953 A JP 2000229953A JP 11108015 A JP11108015 A JP 11108015A JP 10801599 A JP10801599 A JP 10801599A JP 2000229953 A JP2000229953 A JP 2000229953A
- Authority
- JP
- Japan
- Prior art keywords
- halobutyl
- general formula
- cyclohexyltetrasol
- represented
- producing
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【0001】[0001]
【発明の属する技術分野】本発明は、血栓治療剤である
シロスタゾル(Cilostazol)の合成中間体として有用で
ある5−ハロブチル−1−シクロヘキシルテトラゾルを
製造する方法に関する。The present invention relates to a method for producing 5-halobutyl-1-cyclohexyltetrazole, which is useful as an intermediate for synthesizing cilostazol, a therapeutic agent for thrombosis.
【0002】[0002]
【従来の技術】シロスタゾルは血栓治療剤として使われ
ており、その化学名は6−[4−(1−シクロヘキシル
−5−テトラゾリル)ブトキシ]−1,2,3,4−テト
ラヒドロ−2−オキソキノリンであり、その構造は下記
一般式(V)で表される。2. Description of the Related Art Cilostazol is used as a therapeutic agent for thrombosis, and its chemical name is 6- [4- (1-cyclohexyl-5-tetrazolyl) butoxy] -1,2,3,4-tetrahydro-2-oxo. It is quinoline, and its structure is represented by the following general formula (V).
【化5】 Embedded image
【0003】上記の一般式(V)で表されるシロスタゾ
ルは合成中間体である一般式(I)で表される5−ハロ
ブチル−1−シクロヘキシルテトラゾルを6−ヒドロキ
シ−2−オキソ−1,2,3,4−テトラヒドロキノリ
ンと反応させることにより製造される(Chem. Pharm. B
ull. 31,1151-1157 (1983))。The cilostazol represented by the above general formula (V) is obtained by converting 5-halobutyl-1-cyclohexyltetrazole represented by the general formula (I), which is a synthetic intermediate, into 6-hydroxy-2-oxo-1, It is produced by reacting with 2,3,4-tetrahydroquinoline (Chem. Pharm. B
ull. 31, 1151-1157 (1983)).
【0004】一般式(I)の化合物と構造が類似してい
る下記一般式(X)で表されるアルキル−1−シクロヘ
キシルテトラゾルを製造する方法が報告されている(Jo
urnalof Organic Chemistry,15, 1082-1087 (195
0))。この方法によれば、下記反応式に示すように、一
般式(VI)で表されるカルボン酸に塩化剤である塩化チ
オニルを反応させ、得られた一般式(VII)の酸塩化物
にシクロヘキシルアミンを反応させて一般式(IX)で表
されるN−シクロヘキシル−n−アルキルアミドを製造
し、再び塩化剤及びヒドラゾ酸を反応させ環化させるこ
とにより、一般式(X)の化合物が製造される。A method for producing an alkyl-1-cyclohexyltetrasol represented by the following general formula (X) having a structure similar to that of the compound of the general formula (I) has been reported (Jo).
urnalof Organic Chemistry, 15, 1082-1087 (195
0)). According to this method, as shown in the following reaction formula, a carboxylic acid represented by the general formula (VI) is reacted with thionyl chloride as a chlorinating agent, and the obtained acid chloride of the general formula (VII) is reacted with cyclohexyl. An N-cyclohexyl-n-alkylamide represented by the general formula (IX) is produced by reacting with an amine, and a chlorinating agent and hydrazoic acid are reacted again to produce a compound of the general formula (X). Is done.
【化6】 (式中、Rは炭素数1〜5のアルキル基またはベンジル
基である。)Embedded image (In the formula, R is an alkyl group having 1 to 5 carbon atoms or a benzyl group.)
【0005】しかし、上記の製造方法は工程が多く複雑
である。また、塩化剤として使われている塩化チオニル
は一般式(VI)の化合物との反応において、HC1及びSO2
ガスを激しく発生させる。さらに、最終段階で使用する
ヒドラゾ酸は毒性が非常に強く爆発性が高いため、工業
的規模での使用には問題がある。[0005] However, the above-mentioned manufacturing method has many steps and is complicated. Moreover, thionyl chloride is used as a chlorinating agent in the reaction with the compound of the general formula (VI), HC1 and SO 2
Generates violent gas. In addition, the hydrazoic acid used in the final stage is very toxic and highly explosive, which is problematic for use on an industrial scale.
【0006】また、一般式(I)の化合物と構造が類似
している一般式(XV)のテトラゾル誘導体の製造方法が
報告されている(Journal of Organic Chemistry,1
5,1082-1087 (1950))。A method for producing a tetrazole derivative of the general formula (XV) having a structure similar to that of the compound of the general formula (I) has been reported (Journal of Organic Chemistry, 1).
5,1082-1087 (1950)).
【0007】この方法においては、下記反応式に示すよ
うに、一般式(XI)で表されるアルキルニトリルにヒド
ラゾ酸を作用させて、反応中間体である一般式(XII)
のアザビニルアジドを環化させることによって一般式
(XIII)で表されるアルキルテトラゾルを製造し、これ
を一般式(XIV)のハロゲン化シクロヘキシルと反応さ
せ、一般式(XV)の化合物を製造している。In this method, as shown in the following reaction formula, hydrazoic acid is allowed to act on an alkyl nitrile represented by the general formula (XI) to give a reaction intermediate of the general formula (XII)
By cyclizing the azavinyl azide of formula (XIII) and reacting it with cyclohexyl halide of formula (XIV) to produce a compound of formula (XV) I have.
【化7】 (式中、R1は水素原子または炭素数1〜4のアルキル
基であり、Xはハロゲンである。)Embedded image (In the formula, R 1 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and X is a halogen.)
【0008】しかし、上記の製造方法においても毒性が
非常に強く爆発性が高いヒドラゾ酸を使用するため、工
業的規模での製造には問題がある。さらに、最終生産物
である一般式(XV)の化合物の収率が54%と非常に低
い。However, even in the above-mentioned production method, hydrazoic acid which is very toxic and highly explosive is used, so that there is a problem in production on an industrial scale. Furthermore, the yield of the compound of the general formula (XV), which is the final product, is as low as 54%.
【0009】[0009]
【0010】本発明の目的は、工業的に安全かつ簡便
で、収率のよい5−ハロブチル−1−シクロヘキシルテ
トラゾルの製造方法を提供することである。An object of the present invention is to provide a method for producing 5-halobutyl-1-cyclohexyltetrasol which is industrially safe, simple and high in yield.
【0011】本発明者らは上記の従来の製造上の問題点
を解決するために研究を重ねた結果、安全で簡単に5−
ハロブチル−1−シクロヘキシルテトラゾルを高収率で
製造できる方法を見い出し、本発明を完成した。すなわ
ち、本発明は一般式(II)で表されるN−シクロヘキシ
ル−5−ヒドロキシ−n−バレルアミドをハロゲン化剤
及びナトリウムアジドと反応させる工程を含む一般式
(I)で表される5−ハロブチル−1−シクロヘキシル
テトラゾルを製造する方法に関する。The present inventors have conducted various studies to solve the above-mentioned conventional problems in manufacturing, and as a result, have been able to safely and easily obtain 5-
The inventors have found a method for producing halobutyl-1-cyclohexyltetrasol in high yield, and have completed the present invention. That is, the present invention provides 5-halobutyl represented by the general formula (I) including a step of reacting N-cyclohexyl-5-hydroxy-n-valeramide represented by the general formula (II) with a halogenating agent and sodium azide. The present invention relates to a method for producing 1-cyclohexyltetrasol.
【化8】 (式中、Xは塩素原子、臭素原子またはヨウ素原子であ
る。)Embedded image (In the formula, X is a chlorine atom, a bromine atom or an iodine atom.)
【化9】 Embedded image
【0012】本発明の製造方法では、一般式(II)のN
−シクロヘキシル−5−ヒドロキシ−n−バレルアミド
をハロゲン化剤で活性化させた後、ヒドラゾ酸に比し毒
性及び爆発の危険性がほとんどなく取り扱いやすいナト
リウムアジドと反応させ、温和な条件で環化反応を行
い、目的の一般式(I)で表される化合物を高い収率で
簡単に製造することができる。In the production method of the present invention, the N of the general formula (II)
After activating cyclohexyl-5-hydroxy-n-valeramide with a halogenating agent, it is reacted with sodium azide, which is less toxic and less explosive than hydrazoic acid, and is easy to handle, and the cyclization reaction is performed under mild conditions. To easily produce the desired compound represented by the general formula (I) in a high yield.
【0013】本発明の製造方法で使用できるハロゲン化
剤としては、PCl5、PBr5、PI5、PCl 3、PBr3、PI3、POCl
3、POBr3、SOCl2 またはSOBr2 が好ましく挙げられる。
特にPCl5、PBr5またはPI5が好ましい。PI5はPI3/I2から
直接製造し使用することができる。Halogenation usable in the production method of the present invention
As the agent, PClFive, PBrFive, PIFive, PCl Three, PBrThree, PIThree, POCl
Three, POBrThree, SOClTwo Or SOBrTwo Are preferred.
Especially PClFive, PBrFiveOr PIFiveIs preferred. PIFiveIs PIThree/ ITwoFrom
Can be directly manufactured and used.
【0014】本発明の製造方法は、下記反応式で表され
る。The production method of the present invention is represented by the following reaction formula.
【化10】 (式中、Xは塩素原子、臭素原子またはヨウ素原子であ
る。)Embedded image (In the formula, X is a chlorine atom, a bromine atom or an iodine atom.)
【0015】本発明の製造方法において好ましく使用さ
れる溶媒としては、クロロホルム、塩化メチレン及びア
セトニトリルなどが挙げられる。また、本発明の製造方
法において、一般式(II)の化合物とハロゲン化剤及び
ナトリウムアジドとの反応は、一般式(II)の化合物に
対して、ハロゲン化剤を1〜5モル、好ましくは1.2〜2モ
ル、ナトリウムアジドを1〜5モル、好ましくは1.2〜2モ
ルを使用し、5〜100℃、好ましくは20〜50℃で、2〜80
時間、好ましくは24〜48時間行われる。Solvents preferably used in the production method of the present invention include chloroform, methylene chloride and acetonitrile. Further, in the production method of the present invention, the reaction of the compound of the general formula (II) with the halogenating agent and sodium azide is performed by adding the halogenating agent to the compound of the general formula (II) in an amount of 1 to 5 mol, preferably 1.2 to 2 moles, 1 to 5 moles of sodium azide, preferably 1.2 to 2 moles, 5 to 100 ° C, preferably 20 to 50 ° C, 2 to 80
It is carried out for an hour, preferably 24-48 hours.
【0016】反応生成物である一般式(I)の化合物
は、公知の方法、例えば、イソパノールと水の混合液か
らの再結晶、溶出液として酢酸エチルを用いるカラムク
ロマトグラフィー等により精製することができる。The compound of the formula (I), which is a reaction product, can be purified by a known method, for example, recrystallization from a mixed solution of isopanol and water, column chromatography using ethyl acetate as an eluent, and the like. it can.
【0017】出発物質である一般式(II)の化合物は一
般式(III)で表されるδ-バレロラクトンを一般式(I
V)で表されるシクロヘキシルアミンと反応させること
により簡単に高収率(97%)で得ることができる。The starting compound of the general formula (II) is a compound represented by the general formula (III)
It can be easily obtained in high yield (97%) by reacting with cyclohexylamine represented by V).
【化11】 この反応は溶媒中で撹拌しながら20〜150℃の温度で2〜
12時間行うことができる。また、無溶媒でδ-バレロラ
クトンに対してシクロヘキシルアミンを1〜5モル、好ま
しくは1.2から2モル使用し、120〜150℃で、2〜4時間反
応させることもできる。Embedded image The reaction is carried out in a solvent at a temperature of
Can be done for 12 hours. The reaction can also be carried out at 120 to 150 ° C. for 2 to 4 hours without using a solvent, using 1 to 5 mol, preferably 1.2 to 2 mol, of cyclohexylamine with respect to δ-valerolactone.
【0018】得られた一般式(II)の化合物は、公知の
方法、例えば、酢酸エチルからの再結晶等により精製す
ることができる。The obtained compound of the general formula (II) can be purified by a known method, for example, recrystallization from ethyl acetate.
【0019】本発明の方法に従って製造された一般式
(I)の5−ハロブチル−1−シクロヘキシルテトラゾ
ルは、血栓治療剤として有用な薬剤であるシロスタゾル
の製造時の中間体として有用である。The 5-halobutyl-1-cyclohexyltetrazole of the general formula (I) produced according to the method of the present invention is useful as an intermediate in the production of cilostazol, a drug useful as a therapeutic agent for thrombosis.
【0020】[0020]
【実施例】以下、本発明を実施例によりさらに詳しく説
明するが、本発明はこれらの実施例に限定されるもので
はない。EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.
【0021】[実施例1] N−シクロヘキシル−5−
ヒドロキシ−n−バレルアミド(II)の製造 窒素気流下でマグネティックスターラーを入れたフラス
コ内にδ-バレロラクトン100.12g(1mol)及びシクロヘ
キシルアミン148.77g(1.5mol)を加え、室温から徐々に
温度を上昇させ、150℃で2時間撹拌しながら反応させ
た。生成したオイルを室温まで放冷した後、酢酸エチル
(500ml)を加え、撹拌しながら1時間加熱還流した。温
度を徐々に下げ、5℃で濾過した。濾取した生成物を酢
酸エチルで洗浄し、真空乾燥させ、N−シクロヘキシル
−5−ヒドロキシ−n−バレルアミド193.31g(収率97
%)を得た。 融点: 63℃〜65℃(実測:64℃〜65℃)。 IR:νmax(cm-1) 3415 (N-H strech), 3304 (O-H stre
ch), 1642 (C=O strech), 1538, 1448, 1412, 1382, 13
42, 1252, 1056, 1004, 710。1 H NMR:δ1.04〜1.88 (14H, m, シクロヘキシル環のメ
チレンプロトン, -OCH2 CH 2CH2 CH2-), 2.19 (2H, t, -CH
2 CO-), 3.64 (2H, t, -OCH2 -), 3.73〜3.77 (1H,m, シ
クロヘキシル環のメチンプロトン), 5.45 (1H, s, =N
H)。Example 1 N-cyclohexyl-5
Production of hydroxy-n-valeramide (II) 100.12 g (1 mol) of δ-valerolactone and 148.77 g (1.5 mol) of cyclohexylamine were added to a flask containing a magnetic stirrer under a nitrogen stream, and the temperature was gradually raised from room temperature. The mixture was reacted at 150 ° C. with stirring for 2 hours. After allowing the generated oil to cool to room temperature, ethyl acetate
(500 ml), and the mixture was heated under reflux for 1 hour with stirring. The temperature was gradually reduced and filtered at 5 ° C. The product collected by filtration was washed with ethyl acetate, dried in vacuo and 193.31 g of N-cyclohexyl-5-hydroxy-n-valeramide (97% yield).
%). Melting point: 63-65 ° C (actual measurement: 64-65 ° C). IR: νmax (cm -1 ) 3415 (NH strech), 3304 (OH stre
ch), 1642 (C = O strech), 1538, 1448, 1412, 1382, 13
42, 1252, 1056, 1004, 710. 1 H NMR: δ 1.04 to 1.88 (14H, m, methylene proton of cyclohexyl ring, -OCH 2 CH 2 CH 2 CH 2- ), 2.19 (2H, t, -CH
2 CO-), 3.64 (2H, t, -O CH 2- ), 3.73 to 3.77 (1H, m, methine proton of cyclohexyl ring), 5.45 (1H, s, = N
H ).
【0022】[実施例2] 5−クロロブチル−1−シ
クロヘキシルテトラゾル(I)の製造 窒素気流下でマグネティックスターラーを入れたフラス
コ内に塩化メチレン2000ml及びN−シクロヘキシル−5
−ヒドロキシ−n−バレルアミド199.29g(1mol)を加え
た。室温で五塩化リン312.36g(1.5mol)を上記混合物に
徐々に滴下した後、24時間激しく撹拌した。上記反応液
にナトリウムアジド97.52g(1.5mol)を加え室温で24時間
撹拌し、8時間加熱還流させた。この反応液に水2000ml
を加え、残った酸を完全に除去した後、有機層を分離
し、水2000mlで洗浄した。この有機層を希水酸化ナトリ
ウム溶液で中和した。有機層を再度分離し,硫酸マグネ
シウムを用いて乾燥させた。減圧蒸留により溶媒を除去
した後、真空乾燥させ、5−クロロブチル−1−シクロ
ヘキシルテトラゾル223.33g(収率92%)を得た。 IR:νmax(cm-1) 2938, 2862, 1512, 1450, 1276, 1096,
894, 756, 648。1 H NMR:δ1.09〜2.17 (14H, m, シクロヘキシル環のメ
チレンプロトン, ClCH2 CH 2CH2 CH2-), 2.87 (2H, t, Cl
(CH2)3 CH2 -), 3.60 (2H, t, ClCH2 -), 4.12 (1H, m, シ
クロヘキシル環のメチンプロトン)。Example 2 Preparation of 5-chlorobutyl-1-cyclohexyltetrazol (I) 2000 ml of methylene chloride and N-cyclohexyl-5 were placed in a flask containing a magnetic stirrer under a nitrogen stream.
199.29 g (1 mol) of -hydroxy-n-valeramide were added. At room temperature, 312.36 g (1.5 mol) of phosphorus pentachloride was gradually added dropwise to the above mixture, followed by vigorous stirring for 24 hours. 97.52 g (1.5 mol) of sodium azide was added to the above reaction solution, and the mixture was stirred at room temperature for 24 hours and heated under reflux for 8 hours. 2000 ml of water
After the remaining acid was completely removed, the organic layer was separated and washed with 2000 ml of water. This organic layer was neutralized with dilute sodium hydroxide solution. The organic layer was separated again and dried using magnesium sulfate. After removing the solvent by distillation under reduced pressure, the residue was dried under vacuum to obtain 223.33 g of 5-chlorobutyl-1-cyclohexyltetrasol (yield: 92%). IR: νmax (cm -1 ) 2938, 2862, 1512, 1450, 1276, 1096,
894, 756, 648. 1 H NMR: δ 1.09 to 2.17 (14H, m, methylene proton of cyclohexyl ring, ClCH 2 CH 2 CH 2 CH 2- ), 2.87 (2H, t, Cl
(CH 2 ) 3 CH 2- ), 3.60 (2H, t, Cl CH 2- ), 4.12 (1H, m, methine proton of cyclohexyl ring).
【0023】[実施例3] 5−ブロモブチル−1−シ
クロヘキシルテトラゾル(I)の製造 窒素気流下でマグネティックスターラーを入れたフラス
コ内に塩化メチレン2000ml及びN−シクロヘキシル−5
−ヒドロキシ−n−バレルアミド199.29g(1mol)を加え
た。室温で五臭化リン645.78g(1.5mol)を上記混合物に
徐々に滴下した後、24時間激しく撹拌した。上記反応液
にナトリウムアジド97.52g(1.5mol)を加え室温で24時間
撹拌し、8時間加熱還流させた。この反応液に水2000ml
を加え、残った酸を完全に除去した後、有機層を分離
し、有機層を水2000mlで洗浄した。この有機層を希水酸
化ナトリウム溶液で中和した。再び有機層を分離し、硫
酸マグネシウムを用いて乾燥させた。減圧蒸留により溶
媒を除去した後、真空乾燥させ、5−ブロモブチル−1
−シクロヘキシルテトラゾル220.90g(収率91%)を得
た。 IR:νmax(cm-1) 2935, 2853, 1501, 1432, 1266, 1087,
885, 732, 645。1 H NMR:δ1.10〜2.21 (14H, m, シクロヘキシル環のメ
チレンプロトン, BrCH2 CH 2CH2 CH2-), 2.78 (2H, t, Br
(CH2)3 CH2 -), 3.54 (2H, t, BrClCH2 -), 4.01 (1H,m,
シクロヘキシル環のメチンプロトン)。Example 3 Preparation of 5-bromobutyl-1-cyclohexyltetrazol (I) 2000 ml of methylene chloride and N-cyclohexyl-5 were placed in a flask containing a magnetic stirrer under a nitrogen stream.
199.29 g (1 mol) of -hydroxy-n-valeramide were added. After 645.78 g (1.5 mol) of phosphorus pentabromide was slowly added dropwise to the above mixture at room temperature, the mixture was vigorously stirred for 24 hours. 97.52 g (1.5 mol) of sodium azide was added to the above reaction solution, and the mixture was stirred at room temperature for 24 hours and heated under reflux for 8 hours. 2000 ml of water
After the remaining acid was completely removed, the organic layer was separated, and the organic layer was washed with 2000 ml of water. This organic layer was neutralized with dilute sodium hydroxide solution. The organic layer was separated again and dried using magnesium sulfate. After the solvent was removed by distillation under reduced pressure, the residue was dried under vacuum, and 5-bromobutyl-1 was removed.
220.90 g (91% yield) of cyclohexyltetrasol were obtained. IR: νmax (cm -1 ) 2935, 2853, 1501, 1432, 1266, 1087,
885, 732, 645. 1 H NMR: δ 1.10 to 2.21 (14H, m, methylene proton of cyclohexyl ring, BrCH 2 CH 2 CH 2 CH 2- ), 2.78 (2H, t, Br
(CH 2 ) 3 CH 2- ), 3.54 (2H, t, BrCl CH 2- ), 4.01 (1H, m,
Methine proton on the cyclohexyl ring).
【0024】[実施例4] 5−ヨードブチル−1−シ
クロヘキシルテトラゾル(I)の製造 窒素気流下でマグネティックスターラーを入れたフラス
コ内に塩化メチレン2000ml及びN−シクロヘキシル−5
−ヒドロキシ−n−バレルアミド199.29g(1mol)を加え
た。この混合物に室温で五ヨウ化リン998.25g(1.5mol)
を徐々に滴下した後、24時間激しく撹拌した。上記反応
液にナトリウムアジド97.52g(1.5mol)を加え室温で24時
間撹拌し、8時間加熱還流させた。この反応液に水2000m
lを加え、残った酸を完全に除去した後、有機層を分離
し、有機層を水2000mlで洗浄した。この有機層を希水酸
化ナトリウム溶液で中和した。再び有機層を分離し、硫
酸マグネシムを用いて乾燥させ、減圧蒸留により溶媒を
除去した後、真空乾燥させ、5−ヨードブチル−1−シ
クロヘキシルテトラゾル221.02g(収率91%)を得た。 IR:νmax(cm-1) 2933, 2857, 1511, 1417, 1259, 1067,
896, 753, 667。1 H NMR:δ1.08〜2.17 (14H, m, シクロヘキシル環のメ
チレンプロトン, ICH2 CH2CH2 CH2-), 2.81 (2H, t, I(CH
2)3 CH2 -), 3.65 (2H, t, ICH2 -), 4.12 (1H, m,シクロ
ヘキシル環のメチンプロトン)。Example 4 Production of 5-iodobutyl-1-cyclohexyltetrazol (I) 2000 ml of methylene chloride and N-cyclohexyl-5 were placed in a flask containing a magnetic stirrer under a nitrogen stream.
199.29 g (1 mol) of -hydroxy-n-valeramide were added. To this mixture at room temperature phosphorus pentaiodide 998.25 g (1.5 mol)
Was slowly added dropwise, followed by vigorous stirring for 24 hours. 97.52 g (1.5 mol) of sodium azide was added to the above reaction solution, and the mixture was stirred at room temperature for 24 hours and heated under reflux for 8 hours. 2000m of water
After l was added to completely remove the remaining acid, the organic layer was separated, and the organic layer was washed with 2000 ml of water. This organic layer was neutralized with dilute sodium hydroxide solution. The organic layer was separated again, dried using magnesium sulfate, the solvent was removed by distillation under reduced pressure, and then dried under vacuum to obtain 221.02 g (yield 91%) of 5-iodobutyl-1-cyclohexyltetrasol. IR: νmax (cm -1 ) 2933, 2857, 1511, 1417, 1259, 1067,
896, 753, 667. 1 H NMR: δ1.08~2.17 (14H, m, methylene protons of cyclohexyl ring, ICH 2 CH 2 CH 2 CH 2 -), 2.81 (2H, t, I (CH
2 ) 3 CH 2- ), 3.65 (2H, t, I CH 2- ), 4.12 (1H, m, methine proton of cyclohexyl ring).
【0025】[0025]
【発明の効果】本発明によれば、5−ハロブチル−1−
シクロヘキシルテトラゾルを簡単に、収率よく製造する
ことができる。また、危険な副産物を生じることがない
ので、工業的な生産に容易に応用することができる。本
発明によって得られる5−ハロブチル−1−シクロヘキ
シルテトラゾルは血栓治療剤であるシロスタゾルの合成
中間体として有用である。According to the present invention, 5-halobutyl-1-
Cyclohexyltetrasol can be easily produced with high yield. In addition, since no dangerous by-products are generated, it can be easily applied to industrial production. The 5-halobutyl-1-cyclohexyltetrazol obtained according to the present invention is useful as a synthetic intermediate for cilostazol, a therapeutic agent for thrombosis.
───────────────────────────────────────────────────── フロントページの続き (71)出願人 599053001 535−3, Daeyang−ri, Y angkam−myun, Hwasun g−gun,Kyonggi−do 445 −930, Korea (72)発明者 ヨー ジ サン 大韓民国 ソウル セオチョグ バンバエ 3 ドン 530−34 Fターム(参考) 4C063 AA01 BB08 CC47 DD14 EE01 ──────────────────────────────────────────────────続 き Continuation of the front page (71) Applicant 599053001 535-3, Daeyang-ri, Yangkam-myun, Hwasun g-gun, Kyonggi-do 445-930, Korea (72) Inventor Yoji San Korea South Korea Seoul Theochog Bambaye 3 Don 530-34 F term (reference) 4C063 AA01 BB08 CC47 DD14 EE01
Claims (8)
ヘキシル−5−ヒドロキシ−n−バレルアミドを溶媒中
でハロゲン化剤及びナトリウムアジドと反応させる工程
を含む一般式(I)で表される5−ハロブチル−1−シ
クロヘキシルテトラゾルの製造方法。 【化1】 (式中、Xは塩素原子、臭素原子またはヨウ素原子であ
る。) 【化2】 1. A compound represented by the general formula (I) including a step of reacting N-cyclohexyl-5-hydroxy-n-valeramide represented by the following general formula (II) with a halogenating agent and sodium azide in a solvent. A method for producing 5-halobutyl-1-cyclohexyltetrasol. Embedded image (In the formula, X is a chlorine atom, a bromine atom or an iodine atom.)
シル−5−ヒドロキシ−n−バレルアミドが一般式(II
I)で表されるδ-バレロラクトンと一般式(IV)で表さ
れるシクロヘキシルアミンを反応させて得られる、請求
項1に記載の5−ハロブチル−1−シクロヘキシルテト
ラゾルの製造方法。 【化3】 【化4】 2. N-cyclohexyl-5-hydroxy-n-valeramide represented by the general formula (II) is represented by the general formula (II)
The method for producing a 5-halobutyl-1-cyclohexyltetrasol according to claim 1, which is obtained by reacting δ-valerolactone represented by I) with cyclohexylamine represented by the general formula (IV). Embedded image Embedded image
3 ,PBr3、PI3、POCl3、POBr3、SOCl2 及びSOBr2 からな
る群より選ばれる、請求項1に記載の5−ハロブチル−
1−シクロヘキシルテトラゾルの製造方法。3. The method according to claim 1, wherein the halogenating agent is PCl 5 , PBr 5 , PI 5 , PCl
3, PBr 3, PI 3, POCl 3, POBr 3, selected from the group consisting of SOCl 2, and SOBr 2, according to claim 1 5- halobutyl -
A method for producing 1-cyclohexyltetrasol.
アセトニトリルから選択される1種の単一溶媒または2
種以上の混合溶媒である、請求項1に記載の5−ハロブ
チル−1−シクロヘキシルテトラゾルの製造方法。4. A single solvent or a solvent wherein the solvent is selected from chloroform, methylene chloride and acetonitrile.
The method for producing 5-halobutyl-1-cyclohexyltetrasol according to claim 1, which is a mixed solvent of at least one kind.
請求項1に記載の5−ハロブチル−1−シクロヘキシル
テトラゾルの製造方法。5. The reaction is performed at 5-100 ° C. for 2-80 hours,
A method for producing 5-halobutyl-1-cyclohexyltetrasol according to claim 1.
トンと一般式(IV)で表されるシクロヘキシルアミンと
の反応が20〜150℃で行われる、請求項2に記載の5−
ハロブチル−1−シクロヘキシルテトラゾルの製造方
法。6. The method according to claim 2, wherein the reaction between δ-valerolactone represented by the general formula (III) and cyclohexylamine represented by the general formula (IV) is carried out at 20 to 150 ° C.
A method for producing halobutyl-1-cyclohexyltetrasol.
により5−ハロブチル−1−シクロヘキシルテトラゾル
を製造する工程及び得られた5−ハロブチル−1−シク
ロヘキシルテトラゾルを6−ヒドロキシ−2−オキソ−
1,2,3,4−テトラヒドロキノリンと反応させる工
程を含む、シロスタゾルの製造方法。7. A process for producing 5-halobutyl-1-cyclohexyltetrasol by the method according to claim 1, and converting the resulting 5-halobutyl-1-cyclohexyltetrasol to 6-hydroxy-2. -Oxo-
A method for producing cilostazol, comprising a step of reacting with 1,2,3,4-tetrahydroquinoline.
n−バレルアミドの5−ハロブチル−1−シクロヘキシ
ルテトラゾル合成原料としての使用。8. N-cyclohexyl-5-hydroxy-
Use of n-valeramide as a raw material for synthesizing 5-halobutyl-1-cyclohexyltetrazole.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1999-4468 | 1999-02-09 | ||
KR1019990004468A KR100281593B1 (en) | 1999-02-09 | 1999-02-09 | A method of preparing 5-halobutyl-1-cyclohexyltetrazole |
Publications (1)
Publication Number | Publication Date |
---|---|
JP2000229953A true JP2000229953A (en) | 2000-08-22 |
Family
ID=19573884
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP11108015A Pending JP2000229953A (en) | 1999-02-09 | 1999-04-15 | Production of 5-halobutyl-1-cyclohexyl tetrazole |
Country Status (2)
Country | Link |
---|---|
JP (1) | JP2000229953A (en) |
KR (1) | KR100281593B1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7026486B2 (en) | 2002-09-10 | 2006-04-11 | Otsuka Pharmaceutical Co., Ltd. | Process for production cilostazol |
US7399864B2 (en) | 2001-05-02 | 2008-07-15 | Otsuka Pharmaceutical Co., Ltd. | Process for producing carbostyril derivatives |
US7825251B2 (en) | 2001-05-02 | 2010-11-02 | Otsuka Pharmaceutical Co., Ltd. | Process for producing carbostyril derivatives |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR100935893B1 (en) * | 2007-09-11 | 2010-01-07 | 국방과학연구소 | Process for production of 1,1'-dimethyl-5,5'-bitetrazole |
-
1999
- 1999-02-09 KR KR1019990004468A patent/KR100281593B1/en not_active IP Right Cessation
- 1999-04-15 JP JP11108015A patent/JP2000229953A/en active Pending
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7399864B2 (en) | 2001-05-02 | 2008-07-15 | Otsuka Pharmaceutical Co., Ltd. | Process for producing carbostyril derivatives |
US7825251B2 (en) | 2001-05-02 | 2010-11-02 | Otsuka Pharmaceutical Co., Ltd. | Process for producing carbostyril derivatives |
US7026486B2 (en) | 2002-09-10 | 2006-04-11 | Otsuka Pharmaceutical Co., Ltd. | Process for production cilostazol |
Also Published As
Publication number | Publication date |
---|---|
KR100281593B1 (en) | 2001-02-15 |
KR20000055711A (en) | 2000-09-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
DE69723846T2 (en) | Process for the preparation of sildenafil | |
HU214216B (en) | Process for producing substituted n-aryl-1,2,4-triazolopyrimidine-2-sulfonamide derivatives | |
JP4559385B2 (en) | Process for producing pranlukast or a hydrate thereof, and synthetic intermediates thereof | |
JP3839813B2 (en) | Compounds useful for the preparation of camptothecin derivatives | |
JP2000229953A (en) | Production of 5-halobutyl-1-cyclohexyl tetrazole | |
JP2825517B2 (en) | Method for producing herbicidal O-carboxyali-loumidazolinones | |
JP6781030B2 (en) | L-carnosine derivative or salt thereof, and method for producing L-carnosine or salt thereof | |
JPS61176578A (en) | Piperazine derivative | |
JP2549931B2 (en) | Pyrimidobenzimidazole derivative | |
JPH02289563A (en) | Improved process for producing ortho-carboxypyridyl- and ortho-carboxyquinolylimidazolinones | |
KR960010351B1 (en) | Process for the preparation of benzoxazine derivative | |
AU627609B2 (en) | New quinoline derivatives and process for the preparation thereof | |
WO1991001315A1 (en) | New quinoline derivatives and process for the preparation thereof | |
JPS6152826B2 (en) | ||
JPS5916878A (en) | Production of 2,4-dihydroxy-3-acetylquinoline | |
PL166748B1 (en) | Method of obtaining derivatives of 1-alkyl-2-quinolone | |
JP3256325B2 (en) | Method for producing quinolone carboxylic acid derivative | |
JPS61260064A (en) | Dihydropyridine derivative | |
KR930009817B1 (en) | Process for preparation of pyridine derivatives | |
JP3332171B2 (en) | Method for producing thieno [3,2-b] pyridine derivative | |
JPH0234943B2 (en) | ||
JPH0128013B2 (en) | ||
JPH0649685B2 (en) | 1-benzylpyridinium salt derivative and method for producing the same | |
JPH0812658A (en) | Production of sydnones | |
JP2001002645A (en) | Production of 2,6-diamino-3,5-difluoropyridine |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
RD04 | Notification of resignation of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7424 Effective date: 20050420 |