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KR20000055711A - A method of preparing 5-halobutyl-1-cyclohexyltetrazole - Google Patents

A method of preparing 5-halobutyl-1-cyclohexyltetrazole Download PDF

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KR20000055711A
KR20000055711A KR1019990004468A KR19990004468A KR20000055711A KR 20000055711 A KR20000055711 A KR 20000055711A KR 1019990004468 A KR1019990004468 A KR 1019990004468A KR 19990004468 A KR19990004468 A KR 19990004468A KR 20000055711 A KR20000055711 A KR 20000055711A
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이병석
유지상
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류덕희
경동제약 주식회사
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    • 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
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Abstract

PURPOSE: A method for preparing 5-halobutyl-1-cyclohexyltetrazole, is provided. The compound is useful as an intermediate in the preparation of Cilostazol, which is a therapeutic agent of thrombosis. The preparation method simply produces the 5-halobutyl-1-cyclohexyltetrazole with a high yield without the formation of by-product. CONSTITUTION: A preparation method of 5-halobutyl-1-cyclohexyltetrazole represented by formula (1) is characterized by comprising the steps of: activating N-cyclohexyl-5-hydroxy-n-valeramide represented by formula (2) with halogenating agent; and reacting with sodium azide having no toxicity and explosion risk to induce a cyclization. In formula (1) and (2), X is chloro, bromo or Iodo. N-cyclohexyl-5-hydroxy-n-valeramide of formula (2) is produced by reacting delta-valerolactone of formula (3) with cyclohexylamine of formula (4), and the halogenating agent is PCl5, PBr5, Pl5, PCl3, PBr3, Pl3, POCl3, POBr3, SOCl2 or SOBr2.

Description

5-할로부틸-1-시클로헥실테트라졸의 제조방법 {A method of preparing 5-halobutyl-1-cyclohexyltetrazole}Method for preparing 5-halobutyl-1-cyclohexyl tetrazole {A method of preparing 5-halobutyl-1-cyclohexyltetrazole}

본 발명은 혈전 치료제인 실로스타졸(Cilostazol) 제조시 중간체로 유용한 화학식 1의 5-할로부틸-1-시클로헥실테트라졸을 제조하는 방법에 관한 것이다.The present invention relates to a method for preparing 5-halobutyl-1-cyclohexyltetrazole of formula (I) useful as an intermediate in the preparation of cilostazol, a therapeutic agent for thrombosis.

상기 식에서 X는 클로로, 브로모, 또는 요오드이다.Wherein X is chloro, bromo, or iodine.

실로스타졸은 혈전치료제로 사용되는 의약품으로서, 그 화학명은 6-[4-(1-시클로헥실-5-테트라졸릴)부톡시]-1,2,3,4-테트라히드로-2-옥소퀴놀린이고, 구조식은 하기 화학식 5와 같다.Cilostazol is a drug used as a thrombolytic agent, and its chemical name is 6- [4- (1-cyclohexyl-5-tetrazolyl) butoxy] -1,2,3,4-tetrahydro-2-oxoquinoline And, the structural formula is the same as the formula (5).

상기 화학식 5의 실로스타졸은 중간체로서 화학식 1의 5-할로부틸-1-시클로헥실테트라졸과 6-히드록시-2-옥소-1,2,3,4-테트라히드로퀴놀린을 반응시켜 제조하고 있다[Chem. Pharm. Bull., Vol. 31, 1151~1157(1983)].The cilostazol of Formula 5 is prepared by reacting 5-halobutyl-1-cyclohexyl tetrazole of Formula 1 with 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline as an intermediate. [Chem. Pharm. Bull., Vol. 31, 1151-1157 (1983).

화학식 1의 화합물 제조와 관련한 선행기술로서 화학식 1의 화합물과 유사한 하기 화학식 10의 알킬-1-시클로헥실테트라졸을 제조하는 방법이 개시된 바 있다[Journal of Organic Chemistry, Vol. 15, 1082∼1087(1950)]. 즉, 이 방법은 하기 반응식 1에 나타낸 바와 같이 화학식 6의 카르복실산에 염화제인 염화티오닐을 사용하여 화학식 7의 산 염화물을 제조한 후 화학식 9의 N-시클로헥실-n-알킬아미드 (N-Cyclohexyl-n-alkylamide)를 제조하고 다시 염화제 및 트리아조수소산과 반응시켜 고리화 반응에 의해 화학식 10의 화합물을 수득하고 있다.As a prior art with respect to the preparation of the compound of formula (1) has been disclosed a method for preparing alkyl-1-cyclohexyl tetrazole of formula (10) similar to the compound of formula (1) [Journal of Organic Chemistry, Vol. 15, 1082-1087 (1950). In other words, this method is prepared by using an acid chloride of formula (7) using thionyl chloride as a chloride in the carboxylic acid of formula (6) as shown in Scheme 1 and then N-cyclohexyl-n-alkylamide (N -Cyclohexyl-n-alkylamide) was prepared and reacted with chloride and triazoic acid again to obtain a compound of formula 10 by cyclization.

상기 식에서 R은 C1∼C5의 저급 알킬기 및 벤질기이다.Wherein R is a lower alkyl group and a benzyl group of the C 1 ~C 5.

그러나 상기 선행기술에서 개시하고 있는 제조방법은 공정이 길고 복잡하며, 염화제로 사용되는 염화티오닐은 화학식 6의 화합물과 반응도중 HCl 및 SO2기체를 격렬하게 발생시킬 뿐만 아니라, 마지막 단계에서 사용하는 트리아조수소산은 독성이 매우 강하며, 폭발성이 높기 때문에 공업적 규모로 사용하기가 곤란한 문제점이 있다.However, the manufacturing method disclosed in the prior art has a long and complicated process, and thionyl chloride used as a chloride not only violently generates HCl and SO 2 gas during reaction with the compound of Formula 6, but also used in the last step. Triazoic acid is very toxic and has a problem of being difficult to use on an industrial scale because of its high explosiveness.

또한, 화학식 1의 화합물과 유사한 화학식 15의 테트라졸 유도체의 제조방법이 개시된 바 있다[Journal of Organic Chemistry, Vol. 15, 1082∼1087(1950)]. 이 제조방법은 하기 반응식 2에 나타낸 바와 같이 화학식 11의 알킬니트릴에 트리아조수소산을 사용하여 반응 중간체인 화학식 12의 아자비닐아지드를 경유하는 고리화 반응에 의해 화학식 13의 알킬 테트라졸을 제조하고 다시 화학식 14의 시클로헥실 할라이드 (Cyclohexyl halide)와 반응시켜 화학식 15의 화합물을 제조하고 있다.In addition, a method for preparing a tetrazole derivative of Formula 15 similar to the compound of Formula 1 has been disclosed [Journal of Organic Chemistry, Vol. 15, 1082-1087 (1950). This preparation method is an alkyl tetrazole of formula (13) by a cyclization reaction via azavinyl azide of formula (12) using a triaziohydroic acid in the alkyl nitrile of formula (11) as shown in Scheme 2 below The compound of Formula 15 is prepared by reacting with cyclohexyl halide of Formula 14 again.

상기 식에서 R1은 수소원자, 탄소수 1∼4의 저급알킬기이며, X는 할로겐이다.In the above formula, R 1 is a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, and X is a halogen.

그러나, 상기 선행기술에서 개시하고 있는 제조방법 또한 독성이 매우 강하며, 폭발성이 높은 트리아조수소산을 사용함으로써 공업적 규모로 사용하기가 곤란한 문제점이 있으며, 화학식 15의 화합물로 제조시 그 수율이 54%로 매우 저조하다는 단점이 있다.However, the production method disclosed in the prior art is also very toxic and difficult to use on an industrial scale by using a high explosive triazoic acid, the yield is 54 when the compound of formula 15 The disadvantage is that it is very low.

이에, 본 발명자들은 상기와 같은 종래의 제조방법상의 문제점을 해결하기 위하여 연구를 거듭한 결과, 안전하고 간단하게 5-할로부틸-1-시클로헥실테트라졸을 고수율로 제조할 수 있는 본 발명을 완성하게 되었다.Accordingly, the present inventors have repeatedly studied to solve the problems of the conventional manufacturing method as described above, as a result, the present invention can be produced safely and simply 5-halobutyl-1-cyclohexyl tetrazole in high yield It was completed.

따라서, 본 발명은 화학식 1의 5-할로부틸-1-시클로헥실테트라졸의 제조방법을 제공하는 것을 목적으로 한다.Accordingly, an object of the present invention is to provide a method for preparing 5-halobutyl-1-cyclohexyl tetrazole of formula (1).

본 발명은 화학식 2의 N-시클로헥실-5-히드록시-n-발레르아미드를 할로겐화제 및 나트륨아지드와 반응시키는 공정을 포함하는 화학식 1의 5-할로부틸-1-시클로헥실테트라졸을 제조하는 방법에 관한 것이다.The present invention provides a 5-halobutyl-1-cyclohexyl tetrazole of formula (I) comprising the step of reacting N-cyclohexyl-5-hydroxy-n-valeramide of formula (2) with a halogenating agent and sodium azide It is about how to.

본 발명에 따른 제조방법은 화학식 2의 N-시클로헥실-5-히드록시-n-발레르아미드(N-Cyclohexyl-5-hydroxy-n-valeramide)를 할로겐화제로 활성화시킨 후 독성 및 폭발 위험성이 없는 나트륨아지드와 반응시켜 고리화 반응을 수행하기 때문에 온화한 조건하에서 목적하는 화학식 1의 화합물을 높은 수율로 쉽게 제조할 수 있다.The preparation method according to the present invention is a sodium having no toxicity and risk of explosion after activating N-Cyclohexyl-5-hydroxy-n-valeramide of Formula 2 with a halogenating agent. Since the cyclization reaction is carried out by reacting with an azide, it is possible to easily prepare the desired compound of formula 1 in high yield under mild conditions.

본 발명에 따른 제조방법에서 사용가능한 할로겐화제로는 PCl5, PBr5, PI5, PCl3, PBr3, PI3, POCl3, POBr3, SOCl2또는 SOBr2이 바람직하며, 특히 PCl5, PBr5또는 PI5이 더욱 바람직하다. PI5는 PI3/I2로부터 직접 제조하여 사용할 수 있다.Halogenating agent usable in the production method according to the present invention, PCl 5, PBr 5, PI 5 , PCl 3, PBr 3, PI 3, POCl 3, POBr 3, SOCl 2 or SOBr 2 are preferred, especially PCl 5, PBr 5 or PI 5 is more preferred. PI 5 can be prepared and used directly from PI 3 / I 2 .

본 발명에 따른 제조방법에 바람직하게 사용될 수 있는 반응용매로는 클로로포름, 메틸렌 클로라이드 및 아세토니트릴 등이 있다. 또한, 본 발명에 따른 제조방법은 5∼100℃의 온도에서 2∼80시간 동안 수행하는 것이 바람직하다.Reaction solvents that can be preferably used in the preparation method according to the present invention include chloroform, methylene chloride, acetonitrile and the like. In addition, the production method according to the invention is preferably carried out for 2 to 80 hours at a temperature of 5 ~ 100 ℃.

상기 본 발명에 따른 제조방법을 반응식으로 나타내면 반응식 3과 같다.Representation of the production method according to the present invention as shown in Scheme 3.

상기 식에서 X는 클로로, 브로모, 또는 요오드이다.Wherein X is chloro, bromo, or iodine.

출발물질로 사용되는 화학식 2의 화합물은 화학식 3의 δ-발레로락톤(δ-Valerolactone)을 화학식 4의 시클로헥실아민과 반응시켜 간단하게 고수율(97%)로 얻을 수 있다.The compound of Formula 2 used as a starting material can be obtained in high yield (97%) simply by reacting δ-Valerolactone of Formula 3 with cyclohexylamine of Formula 4.

상기 반응식 4의 반응은 교반하면서 20∼150℃의 온도에서 2~12 시간 동안 수행하는 것이 바람직하다.The reaction of Scheme 4 is preferably performed for 2 to 12 hours at a temperature of 20 ~ 150 ℃ while stirring.

본 발명의 공정에 따라 제조된 화학식 1의 5-할로부틸-1-시클로헥실테트라졸은 혈전치료제로 유용한 약제인 화학식 실로스타졸의 제조시 중간체로 사용될 수 있다.5-halobutyl-1-cyclohexyl tetrazole of formula (1) prepared according to the process of the present invention can be used as an intermediate in the preparation of the formula cilostazol, a drug useful as a thrombolytic agent.

이하 본 발명을 실시예를 통하여 더욱 상세히 설명한다. 그러나 본 발명이 이에 제한되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples. However, the present invention is not limited thereto.

실시예 1 : N-시클로헥실-5-히드록시-n-발레르아미드(2)의 제조Example 1 Preparation of N-cyclohexyl-5-hydroxy-n-valeramide (2)

질소 기류하에서 자기 교반기가 장착된 플라스크 내에 δ-발레로락톤 100.12g(1mol), 시클로헥실아민 148.77g(1.5mol)을 넣은 다음 실온에서 서서히 온도를 상승시켜 150℃에서 2시간 동안 교반하여 반응시켰다. 이들 생성된 오일상을 실온까지 서서히 냉각시킨 후 에틸 아세테이트(500ml)을 가하고 교반하면서 1시간 동안 가열환류시키고 온도를 서서히 내려서 5℃에서 여과 및 에틸 아세테이트로 세척하였다. 여과된 생성물을 진공건조시켜 N-시클로헥실-5-히드록시-n-발레르아미드 193.31g(97%)를 얻었다.In a flask equipped with a magnetic stirrer under nitrogen stream, 100.12 g (1 mol) of δ-valerolactone and 148.77 g (1.5 mol) of cyclohexylamine were added, and the temperature was gradually increased at room temperature, followed by stirring at 150 ° C. for 2 hours. . The resulting oil phases were slowly cooled to room temperature, then ethyl acetate (500 ml) was added and heated to reflux with stirring for 1 hour, the temperature was slowly lowered, filtered at 5 ° C. and washed with ethyl acetate. The filtered product was dried in vacuo to give 193.31 g (97%) of N-cyclohexyl-5-hydroxy-n-valeramide.

융점: 63°내지 65°(실측: 64°내지 65°)Melting Point: 63 ° to 65 ° (Actual: 64 ° to 65 °)

IR: νmax(cm-1) 3415 (N-H strech), 3304 (O-H strech), 1642 (C=O strech), 1538, 1448, 1412, 1382, 1342, 1252, 1056, 1004, 710IR: ν max (cm -1 ) 3415 (NH strech), 3304 (OH strech), 1642 (C = O strech), 1538, 1448, 1412, 1382, 1342, 1252, 1056, 1004, 710

H1NMR: δ 1.04∼1.88 (14H, m, methylene protons of cyclohexyl ring, -OCH2CH2CH2CH2-)H 1 NMR: δ 1.04 to 1.88 (14H, m, methylene protons of cyclohexyl ring, -OCH 2 CH 2 CH 2 CH 2- )

2.19 (2H, t, -CH2CO-)2.19 (2H, t, -CH 2 CO-)

3.64 (2H, t, -OCH2-)3.64 (2H, t, -OCH 2- )

3.73∼3.77 (1H, m, methine proton of cyclohexyl ring)3.73-3.77 (1H, m, methine proton of cyclohexyl ring)

5.45 (1H, s, =NH)5.45 (1H, s, = NH)

실시예 2: 5-클로로부틸-1-시클로헥실테트라졸(1)의 제조Example 2: Preparation of 5-chlorobutyl-1-cyclohexyl tetrazole (1)

질소 기류하에서 자기 교반기가 장착된 플라스크 내에 메틸렌 클로라이드 2000㎖, N-시클로헥실-5-히드록시-n-발레르아미드 199.29g(1mol)을 가하고 실온에서 오염화인 312.36g(1.5mol)을 서서히 적하한 다음 24시간 격렬하게 교반시켰다. 상기 반응액에 다시 나트륨아지드 97.52g(1.5mol)를 가하여 상온에서 24시간 교반하고 8시간 가열환류시켰다. 상기 반응액에 물 2000㎖를 가하여 잔존하는 산을 완전히 제거시킨 후 유기층을 분리하고 다시 유기층을 물 2000㎖로 세척한 후 분리된 유기층을 묽은 수산화나트륨 용액으로 중화시켰다. 이 유기층을 분리하여 망초로 건조하고 감압증류하여 용매를 제거한 후 진공건조하여 5-클로로부틸-1-시클로헥실테트라졸 223.33g(92%)를 수득하였다.2000 ml of methylene chloride and 199.29 g (1 mol) of N-cyclohexyl-5-hydroxy-n-valeramide were added to a flask equipped with a magnetic stirrer under nitrogen stream, and 312.36 g (1.5 mol) of contaminant phosphorus was slowly added dropwise at room temperature. Stir vigorously for the next 24 hours. Sodium azide 97.52 g (1.5 mol) was further added to the reaction solution, stirred at room temperature for 24 hours, and heated to reflux for 8 hours. 2000 ml of water was added to the reaction solution to completely remove the remaining acid. The organic layer was separated, the organic layer was washed with 2000 ml of water, and the separated organic layer was neutralized with dilute sodium hydroxide solution. The organic layer was separated, dried over forget-me-not, distilled under reduced pressure to remove the solvent, and dried in vacuo to yield 223.33 g (92%) of 5-chlorobutyl-1-cyclohexyl tetrazole.

IR: νmax(cm-1) 2938, 2862, 1512, 1450, 1276, 1096, 894, 756, 648IR: ν max (cm -1 ) 2938, 2862, 1512, 1450, 1276, 1096, 894, 756, 648

H1NMR: δ 1.09∼2.17 (14H, m, methylene protons of cyclohexyl ring,H 1 NMR: δ 1.09 to 2.17 (14H, m, methylene protons of cyclohexyl ring,

ClCH2CH2CH2CH2-)ClCH 2 CH 2 CH 2 CH 2- )

2.87 (2H, t, Cl(CH2)3CH2-)2.87 (2H, t, Cl (CH 2 ) 3 CH 2- )

3.60 (2H, t, ClCH2-)3.60 (2H, t, ClCH 2- )

4.12 (1H, m, methine proton of cyclohexyl ring)4.12 (1H, m, methine proton of cyclohexyl ring)

실시예 3 : 5-브로모부틸-1-시클로헥실테트라졸(1)의 제조Example 3: Preparation of 5-bromobutyl-1-cyclohexyl tetrazole (1)

질소 기류하에서 자기 교반기가 장착된 플라스크 내에 메틸렌 클로라이드 2000㎖, N-시클로헥실-5-히드록시-n-발레르아미드 199.29g(1mol)를 가하고 실온에서 오브롬화인 645.78g(1.5mol)를 서서히 적하한 다음 24시간 격렬하게 교반시켰다. 상기 반응액에 다시 나트륨아지드 97.52g(1.5mol)를 가하여 상온에서 24시간 교반하고 8시간 가열환류시켰다. 상기 반응액에 물 2000㎖를 가하여 잔존하는 산을 완전히 제거시킨 후 유기층을 분리하고 다시 유기층을 물 2000㎖로 세척한 후 분리된 유기층을 묽은 수산화나트륨 용액으로 중화시켰다. 이 유기층을 분리하여 망초로 건조하고 감압증류하여 용매를 제거한 후 진공건조하여 5-브로모부틸-1-시클로헥실테트라졸 220.90g(91%)를 수득하였다.2000 ml of methylene chloride and 199.29 g (1 mol) of N-cyclohexyl-5-hydroxy-n-valeramide were added to a flask equipped with a magnetic stirrer under nitrogen stream, and 645.78 g (1.5 mol) of oromide was slowly added dropwise at room temperature. Then vigorously stirred for 24 hours. Sodium azide 97.52 g (1.5 mol) was further added to the reaction solution, stirred at room temperature for 24 hours, and heated to reflux for 8 hours. 2000 ml of water was added to the reaction solution to completely remove the remaining acid. The organic layer was separated, the organic layer was washed with 2000 ml of water, and the separated organic layer was neutralized with dilute sodium hydroxide solution. The organic layer was separated, dried over manganese, distilled under reduced pressure to remove the solvent, and dried in vacuo to yield 220.90 g (91%) of 5-bromobutyl-1-cyclohexyl tetrazole.

IR: νmax(cm-1) 2935, 2853, 1501, 1432, 1266, 1087, 885, 732, 645IR: ν max (cm -1 ) 2935, 2853, 1501, 1432, 1266, 1087, 885, 732, 645

H1NMR: δ 1.10∼2.21 (14H, m, methylene protons of cyclohexyl ring,H 1 NMR: δ 1.10 to 2.21 (14H, m, methylene protons of cyclohexyl ring,

BrCH2CH2CH2CH2-)BrCH 2 CH 2 CH 2 CH 2- )

2.78 (2H, t, Br(CH2)3CH2-)2.78 (2H, t, Br (CH 2 ) 3 CH 2- )

3.54 (2H, t, BrClCH2-)3.54 (2H, t, BrClCH 2- )

4.01 (1H, m, methine proton of cyclohexyl ring)4.01 (1H, m, methine proton of cyclohexyl ring)

실시예 4 : 5-요오도부틸-1-시클로헥실테트라졸(1)의 제조Example 4: Preparation of 5-iodobutyl-1-cyclohexyl tetrazole (1)

질소 기류하에서 자기 교반기가 장착된 플라스크 내에 메틸렌 클로라이드 2000㎖, N-시클로헥실-5-히드록시-n-발레르아미드 199.29g(1mol)을 가하고 실온에서 오요오도화인 998.25g(1.5mol)을 서서히 적가한 다음 24시간 격렬하게 교반시켰다. 상기 반응액에 다시 나트륨아지드 97.52g(1.5mol)를 가하여 상온에서 24시간 교반하고 8시간 가열환류시켰다. 상기 반응액에 물 2000㎖를 가하여 잔존하는 산을 완전히 제거시킨 후 유기층을 분리하고 다시 유기층을 물 2000㎖로 세척한 후 분리된 유기층을 묽은 수산화나트륨 용액으로 중화시켰다. 이 유기층을 분리하여 망초로 건조하고 감압증류하여 용매를 제거한 후 진공건조하여 5-요오도부틸-1-시클로헥실테트라졸 221.02g(91%)를 수득하였다.2000 ml of methylene chloride and 199.29 g (1 mol) of N-cyclohexyl-5-hydroxy-n-valeramide were added to a flask equipped with a magnetic stirrer under nitrogen stream and 998.25 g (1.5 mol) of iodoinated at room temperature was added slowly. It was added dropwise and stirred vigorously for 24 hours. Sodium azide 97.52 g (1.5 mol) was further added to the reaction solution, stirred at room temperature for 24 hours, and heated to reflux for 8 hours. 2000 ml of water was added to the reaction solution to completely remove the remaining acid. The organic layer was separated, the organic layer was washed with 2000 ml of water, and the separated organic layer was neutralized with dilute sodium hydroxide solution. The organic layer was separated, dried over forget-me-not, distilled under reduced pressure to remove the solvent, and dried in vacuo to yield 221.02 g (91%) of 5-iodobutyl-1-cyclohexyl tetrazole.

IR: νmax(cm-1) 2933, 2857, 1511, 1417, 1259, 1067, 896, 753, 667IR: ν max (cm -1 ) 2933, 2857, 1511, 1417, 1259, 1067, 896, 753, 667

H1NMR: δ 1.08∼2.17 (14H, m, methylene protons of cyclohexyl ring,H 1 NMR: δ 1.08 to 2.17 (14H, m, methylene protons of cyclohexyl ring,

ICH2CH2CH2CH2-)ICH 2 CH 2 CH 2 CH 2- )

2.81 (2H, t, I(CH2)3CH2-)2.81 (2H, t, I (CH 2 ) 3 CH 2- )

3.65 (2H, t, ICH2-)3.65 (2H, t, ICH 2- )

4.12 (1H, m, methine proton of cyclohexyl ring)4.12 (1H, m, methine proton of cyclohexyl ring)

상술한 바와 같이 본 발명은 제조공정이 간단하면서도 부산물 형성이 거의 없고, 수율도 높은 5-할로부틸-1-시클로헥실테트라졸을 제조하는 우수한 방법을 제공한다. 이 5-할로부틸-1-시클로헥실테트라졸은 혈전치료제로 유용한 실로스타졸의 제조시 유용한 중간체로 사용될 수 있다.As described above, the present invention provides an excellent method for preparing 5-halobutyl-1-cyclohexyl tetrazole having a simple manufacturing process and little by-product formation and high yield. This 5-halobutyl-1-cyclohexyl tetrazole can be used as a useful intermediate in the preparation of cilostazol, which is useful as a thrombolytic agent.

Claims (6)

화학식 2의 N-시클로헥실-5-히드록시-n-발레르아미드를 할로겐화제 및 나트륨아지드와 반응시키는 공정을 포함하는 화학식 1의 5-할로부틸-1-시클로헥실테트라졸의 제조방법.A process for preparing 5-halobutyl-1-cyclohexyl tetrazole of formula (I) comprising the step of reacting N-cyclohexyl-5-hydroxy-n-valeramide of formula (2) with a halogenating agent and sodium azide. 상기 식에서 X는 클로로, 브로모, 또는 요오드이다.Wherein X is chloro, bromo, or iodine. 제1항에 있어서, 화학식 2의 N-시클로헥실-5-히드록시-n-발레르아미드는 화학식 3의 δ-발레로락톤과 화학식 4의 시클로헥실아민을 반응시켜 제조되는 것을 특징으로 하는 화학식 1의 5-할로부틸-1-시클로헥실테트라졸의 제조방법.The N-cyclohexyl-5-hydroxy-n-valeramide of claim 2 is prepared by reacting δ-valerolactone of Formula 3 with cyclohexylamine of Formula 4. Method for producing 5-halobutyl-1-cyclohexyl tetrazole. 제1항에 있어서, 할로겐화제가 PCl5, PBr5, PI5, PCl3, PBr3, PI3, POCl3, POBr3, SOCl2또는 SOBr2인 것을 특징으로 하는 화학식 1의 5-할로부틸-1-시클로헥실테트라졸의 제조방법.The method of claim 1 wherein the halogenating agent of the 5-halo PCl 5, PBr 5, PI 5 , PCl 3, PBr 3, PI 3, POCl 3, POBr 3, SOCl formula (1), characterized in that 2 or SOBr 2-butyl- Method for preparing 1-cyclohexyl tetrazole. 제1항에 있어서, 반응용매가 클로로포름, 메틸렌 클로라이드 및 아세토니트릴로부터 선택된 1 종의 단일용매 또는 2종 이상의 혼합용매인 것을 특징으로 하는 화학식 1의 5-할로부틸-1-시클로헥실테트라졸의 제조방법.The preparation of 5-halobutyl-1-cyclohexyl tetrazole of formula (1) according to claim 1, wherein the reaction solvent is a single solvent or two or more mixed solvents selected from chloroform, methylene chloride and acetonitrile. Way. 제1항에 있어서, 반응이 5∼100℃에서 2∼80 시간 동안 수행되는 것을 특징으로 하는 화학식 1의 5-할로부틸-1-시클로헥실테트라졸의 제조방법.The method for preparing 5-halobutyl-1-cyclohexyl tetrazole of formula 1 according to claim 1, wherein the reaction is performed at 5 to 100 ° C. for 2 to 80 hours. 제2항에 있어서, 반응이 20∼150℃의 온도에서 수행되는 것을 특징으로 하는 화학식 1의 5-할로부틸-1-시클로헥실테트라졸의 제조방법.The process for preparing 5-halobutyl-1-cyclohexyltetrazole of claim 1, wherein the reaction is performed at a temperature of 20 to 150 ° C.
KR1019990004468A 1999-02-09 1999-02-09 A method of preparing 5-halobutyl-1-cyclohexyltetrazole Expired - Fee Related KR100281593B1 (en)

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