KR100336400B1 - A Process for Preparing Cisapride - Google Patents
A Process for Preparing Cisapride Download PDFInfo
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- KR100336400B1 KR100336400B1 KR1020000016200A KR20000016200A KR100336400B1 KR 100336400 B1 KR100336400 B1 KR 100336400B1 KR 1020000016200 A KR1020000016200 A KR 1020000016200A KR 20000016200 A KR20000016200 A KR 20000016200A KR 100336400 B1 KR100336400 B1 KR 100336400B1
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- C—CHEMISTRY; METALLURGY
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
본 발명은 하기 식으로 표현되는 시스-4-아미노-5-클로로-N-[1-[3-(4-플루오로페녹시)프로필]-3-메톡시-4-피페리딘일]-2-메톡시벤즈아미드 (일반명 : 시사프라이드)의 새로운 제조방법에 대한 것이다.The present invention is cis-4-amino-5-chloro-N- [1- [3- (4-fluorophenoxy) propyl] -3-methoxy-4-piperidinyl] -2 represented by the following formula: To a new process for the preparation of methoxybenzamide (common name: cisapride).
본 발명은 구조식 1 화합물을 출발물질로 하여 4단계의 반응을 거쳐 목적 화합물을 높은 수율로 얻을 수 있으며, 모든 공정이 상온에서 수행될 수 있으므로 공업적인 적용이 수월하다.The present invention can be obtained in a high yield of the target compound through a four-step reaction using the compound of formula 1 as a starting material, it is easy to industrial applications because all processes can be carried out at room temperature.
Description
본 발명은 하기 식으로 표현되는 시스-4-아미노-5-클로로-N-[1-[3-(4-플루오로페녹시)프로필]-3-메톡시-4-피페리딘일]-2-메톡시벤즈아미드 (일반명 : 시사프라이드)의 새로운 제조방법에 대한 것이다.The present invention is cis-4-amino-5-chloro-N- [1- [3- (4-fluorophenoxy) propyl] -3-methoxy-4-piperidinyl] -2 represented by the following formula: To a new process for the preparation of methoxybenzamide (common name: cisapride).
시사프라이드는 위장관의 운동을 촉진시키는 약물로서 위식도 역류질환으로 인한 야간의 심와부작열감(nocturnal heartburn), 위배출 지연으로 인한 구토증, 당뇨병성자연적, 약물유도성 위아토니, 기능적 변비 등에 효과적인 약물이다. 국내 특허로는 공고번호 제86-1584호, 86-1603호에 기술되어 있다. 이들 공지의 특허에 기술된 목적 화합물의 대표적인 제조방법은 다음과 같이 두가지로 나눌 수 있다.Cisapride is a drug that promotes the movement of the gastrointestinal tract, and is effective for nighttime nocturnal heartburn due to gastroesophageal reflux disease, nausea due to delayed gastric emptying, diabetic natural, drug-induced gastrotoni, and functional constipation. Domestic patents are described in Publication Nos. 86-1584 and 86-1603. Representative methods for preparing the target compounds described in these known patents can be divided into two types.
첫번째, 구조식(II)의 화합물과 구조식(III)의 화합물을 치환 반응시켜 구조식(I)을 제조하는 방법First, a method of preparing the structural formula (I) by substitution reaction of the compound of the structural formula (II) with the compound of the structural formula (III)
두번째, 구조식(IV)의 화합물과 구조식(V)의 화합물을 축합반응시켜 구조식(I)을 제조하는 방법Second, a method of preparing Structural Formula (I) by condensation reaction of the compound of Structural Formula (IV) with a compound of Structural Formula (V)
상기 기술된 두가지 방법 모두 동일하게 N-알킬화 반응에 있어서 낮은 수율을 극복하지 못한 단점이 있다. 즉, 반응식(1)에 있어서 구조식(II)과 구조식(III) 사이의 낮은 반응성, 그리고 반응식(2)의 구조식(IV)의 화합물을 제조함에 있어서도 전술한 바와 동일한 낮은 반응성의 단점을 가지고 있다. 따라서, 위와 같은 문제점을 해결하는 합성방법이 절실하게 요구되어져 왔다.Both methods described above have the same disadvantage that they do not overcome low yields in N-alkylation reactions. That is, it has the disadvantages of low reactivity between Structural Formula (II) and Structural Formula (III) in Scheme (1), and the same low reactivity as described above in preparing the compound of Structural Formula (IV) of Scheme (2). Therefore, there is an urgent need for a synthesis method that solves the above problems.
상기와 같이 기술된 문제점 즉, N-알킬화 반응의 낮은 수율을 해결하기 위하여 본 발명은 화합물(1)을 출발물질로 하여 4단계의 수식을 거쳐 목적 화합물(I)을 높은 수율로 합성하는 방법을 구축하였다.(반응식 3)In order to solve the problems described above, that is, the low yield of the N-alkylation reaction, the present invention provides a method for synthesizing the target compound (I) in high yield through a four-step modification using compound (1) as a starting material. (Scheme 3)
본 발명을 보다 구체적으로 설명하면 먼저, 50% 수산화나트륨 용액에 염화 트리에틸벤질암모늄을 가하고 교반시키면서 공지화합물인 구조식(1)과 1,3-디브로모 프로판을 가한 후 3시간동안 상온에서 격렬하게 교반하여 신규의 스피로 화합물인 구조식(2)를 얻을 수 있다. 이때, 사용되어진 염기로는 수산화 나트륨, 수산화 칼륨 등이 있다. 재결정 용매로는 벤젠, 톨루엔, 이소프로필 알코올, 에틸 아세테이트 등을 사용할 수 있으나 벤젠의 경우 가장 좋은 수율을 나타내었다. 신규의 반응중간체인 구조식(3)은 구조식(2)의 아민보호기를 제거하여 얻을 수 있다. 구체적 방법으로 브롬화 수소산과 초산을 이용하거나 에틸렌 글라이콜 또는 히드라진 수산화물에 수산화 칼륨을 가하여 얻을 수 있는데 상온에서 브롬화 수소산과 초산을 이용하였을 때 가장 좋은 수율을 나타내었다. 구조식(4)는 구조식(3)에 축합제를 가하고 4-아미노-5-클로로-2-메톡시벤조산과 반응시켜 구조식(4)를 얻을 수 있다. 본발명의 반응중간체인 구조식(4) 화합물 역시 본 발명에서 처음으로 합성된 신규물질이다. 기존의 특허에서 사용되어진 디시클로헥실카보디이미드, 에틸클로로 포메이트를 축합제로 사용할 경우 반응성을 향상시킬 수 없었으나 1-[3-(디메틸 아미노)프로필]-3-에틸카보디이미드(EDCI)와 1-히드록시 벤조트리아졸(HOBT)을 함께 축합제로 사용하여 반응성을 월등하게 향상시킬 수 있었다. 다음으로 목적화합물(I)은 구조식(4)에 4-플루오로페놀을 상온에서 알킬화 반응시켜 높은 수율로 얻을 수 있었다. 본 발명에서 반응중간체로 얻어지는 구조식(2), 구조식(3), 구조식(4)의 스피로 화합물은 모두 본 발명에서 처음으로 합성되는 신규 물질이며, 본 발명은 상기 반응공정에서 반응중간체인 상기 스피로 화합물들을 고체로 얻을 수 있어 정제과정이 간편하며, 반응식(2)와 (3)에서 설명한 바와 같이 종래의 기술은 피페리딘 구조의 아민에 4-(플루오로페녹시)프로필클로라이드를 이용한 N-알킬화 반응을 통하여 목적화합물을 합성하였으나 수율이 저조한 단점을 개선하지 못하였다. 본 발명은 이를 개선하고자 반응중간체로 상기 스피로 화합물을 합성한 후 4-플루오로 페놀을 이용한 알킬화 반응을 통하여 높은 수율로 목적 화합물을 합성할 수 있었다. 또한, 4-(플루오로페녹시)프로필클로라이드는 여러 단계의 반응을 통하여 합성하거나 특정 회사에서 구입해야 하는 단점이 있으나 본 발명에서 사용되어진 4-플루오로 페놀은 상업적으로 쉽게 구할 수 있는 유용한 시약이므로 경제적인 측면에서도 큰 장점이 있다.The present invention will be described in more detail. First, triethylbenzyl ammonium chloride is added to 50% sodium hydroxide solution, and the reaction mixture is stirred at room temperature for 3 hours after addition of the known compounds of formula (1) and 1,3-dibromopropane. By stirring to obtain a structural formula (2) which is a novel spiro compound. At this time, the base used may include sodium hydroxide, potassium hydroxide and the like. Benzene, toluene, isopropyl alcohol, ethyl acetate and the like can be used as the recrystallization solvent, but benzene showed the best yield. Structural formula (3), a novel reaction intermediate, can be obtained by removing the amine protecting group of structural formula (2). Specifically, it can be obtained by using hydrobromic acid and acetic acid, or by adding potassium hydroxide to ethylene glycol or hydrazine hydroxide, which shows the best yield when using hydrobromic acid and acetic acid at room temperature. Structural formula (4) can be obtained by adding a condensing agent to the structural formula (3) and reacting with 4-amino-5-chloro-2-methoxybenzoic acid to obtain the structural formula (4). The compound of formula (4), which is the reaction intermediate of the present invention, is also a novel substance synthesized for the first time in the present invention. Dicyclohexylcarbodiimide and ethylchloroformate used in the existing patents could not improve reactivity when used as a condensing agent, but 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide (EDCI) And 1-hydroxy benzotriazole (HOBT) can be used together as a condensing agent to improve reactivity significantly. Next, the target compound (I) was obtained in high yield by alkylation of 4-fluorophenol to Structural Formula (4) at room temperature. The spiro compounds of Structural Formula (2), Structural Formula (3) and Structural Formula (4) obtained as reaction intermediates in the present invention are all novel substances synthesized for the first time in the present invention, and the present invention is the spiro compound which is a reaction intermediate in the reaction process. Can be obtained as a solid, so the purification process is simple. As described in Schemes (2) and (3), the conventional technique is N-alkylation using 4- (fluorophenoxy) propyl chloride in an amine of piperidine structure. Although the target compound was synthesized through the reaction, the yield was not improved. The present invention was able to synthesize the target compound in a high yield through the alkylation reaction using 4-fluoro phenol after synthesis of the spiro compound as a reaction intermediate to improve this. In addition, 4- (fluorophenoxy) propyl chloride has the disadvantage of having to be synthesized through a multi-step reaction or purchased from a specific company, but 4-fluoro phenol used in the present invention is a useful reagent that is readily available commercially. There is a big advantage in terms of economy.
본 발명의 목적화합물(I)은 필요에 따라 공지의 방법으로 생리학적으로 허용되는 수화물 및 산부가염으로 전환할 수 있다. 다음의 실시예는 본 발명을 설명하는 것이지 본 발명의 범위를 제한하는 것은 아니다.The desired compound (I) of the present invention can be converted into physiologically acceptable hydrates and acid addition salts by known methods as necessary. The following examples illustrate the invention but do not limit the scope thereof.
실시예 1 : 시스-6-메톡시-7-메톡시카보닐아미노-4-아조니아-스피로[3.5]노난의 제조Example 1 Preparation of cis-6-methoxy-7-methoxycarbonylamino-4-azonia-spiro [3.5] nonane
50% 수산화나트륨 용액 300ml에 염화 트리에틸벤질암모늄 60.5g (0.26mol)을 가하고 격렬하게 교반시키면서 시스-4-(N-메톡시카보닐아미노)-3-메톡시-1-피페리딘 (1) 50.0g(0.26mol)과 1,3-디브로모 프로판 78.7g(0.39mol)을 가한 후 3시간동안 상온에서 격렬하게 교반하였다. 반응이 완결되면 반응액을 냉각한 상태에서 진한 염산을 사용하여 pH 2-3으로 맞추고 디에틸 에테르(300ml)로 3회 추출하였다. 유기층을 합하여 무수 MgSO4로 건조하고 활성탄을 이용하여 탈색시킨 후 여과 및 감압농축하였다. 잔류물을 벤젠으로 처리하여 백색 결정상의 표제 화합물 38.7g(수율 65%)을 수득하였다.60.5 g (0.26 mol) of triethylbenzylammonium chloride was added to 300 ml of a 50% sodium hydroxide solution, followed by vigorous stirring, and cis-4- (N-methoxycarbonylamino) -3-methoxy-1-piperidine (1 50.0 g (0.26 mol) and 78.7 g (0.39 mol) of 1,3-dibromo propane were added thereto, followed by vigorous stirring at room temperature for 3 hours. When the reaction was completed, the reaction solution was cooled to pH 2-3 using concentrated hydrochloric acid and extracted three times with diethyl ether (300 ml). The combined organic layers were dried over anhydrous MgSO 4 , decolorized with activated carbon, filtered and concentrated under reduced pressure. The residue was treated with benzene to give 38.7 g (65% yield) of the title compound as white crystals.
1H NMR(ppm) 1.95(m, 2H), 2.17(m, 2H), 3.24(m, 9H), 3.37(d, 2H), 3.67(s, 3H), 1 H NMR (ppm) 1.95 (m, 2H), 2.17 (m, 2H), 3.24 (m, 9H), 3.37 (d, 2H), 3.67 (s, 3H),
3.90(m, 1H), 4.08(m, 1H)3.90 (m, 1 H), 4.08 (m, 1 H)
융점: 110℃~118℃Melting Point: 110 ℃ ~ 118 ℃
실시예 2 : 시스-7-아미노-6-메톡시-4-아조니아-스피로[3.5]노난의 제조Example 2 Preparation of cis-7-amino-6-methoxy-4-azonia-spiro [3.5] nonane
실시예 1에서 수득한 화합물 38g(0.16mol)과 브롬화 수소산 38.8g(0.48mol)을 초산 200ml에 가하고 25℃에서 24시간동안 교반하였다. 반응이 완결되면 반응액을 냉각시키고 1N 수산화나트륨 수용액 300ml을 가하여 교반하여 pH 10-11으로 맞추고 디클로로 메탄(200ml)으로 3회 추출하였다. 유기층을 합하여 무수 MgSO4로 건조, 여과 및 감압농축하여 표제화합물 21.9g(80%)을 수득하였다. 수득한 화합물은 더 이상의 정제과정없이 다음 반응에 이용하였다.38 g (0.16 mol) of the compound obtained in Example 1 and 38.8 g (0.48 mol) of hydrobromic acid were added to 200 ml of acetic acid and stirred at 25 ° C. for 24 hours. When the reaction was completed, the reaction solution was cooled, 300 ml of 1N aqueous sodium hydroxide solution was added thereto, stirred, adjusted to pH 10-11, and extracted three times with dichloromethane (200 ml). The organic layers were combined, dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure to obtain 21.9 g (80%) of the title compound. The obtained compound was used in the next reaction without further purification.
1H NMR(ppm) 1.95(m, 2H), 2.17(m, 2H), 2.93(m, 1H), 3.24(m, 9H), 3.37(d, 2H), 1 H NMR (ppm) 1.95 (m, 2H), 2.17 (m, 2H), 2.93 (m, 1H), 3.24 (m, 9H), 3.37 (d, 2H),
3.69(m, 1H)3.69 (m, 1 H)
실시예3 : 시스-7-(4-아미노-5-클로로-2-메틸벤조일아미노)-6-메톡시-4-아조니아-스피로[3.5]노난의 제조Example 3: Preparation of cis-7- (4-amino-5-chloro-2-methylbenzoylamino) -6-methoxy-4-azonia-spiro [3.5] nonane
실시예 2에서 수득한 화합물 21g (0.12mol) 및 4-아미노-5-클로로-2-메톡시벤조산 30.2g (0.15mol), 1-[3-(디메틸 아미노)프로필]-3-에틸카보디이미드(EDCI) 57.5g (0.3mol)와 1-히드록시 벤조트리아졸(HOBT) 40.5 (0.3mol)을 디클로로 메탄250ml에 용해시키고 상온에서 17시간동안 교반시킨 후 여과하고 증류수 100ml로 세척한 후 무수 MgSO4로 건조, 여과 및 감압농축하여 표제화합물 30.4g (75%)을 수득하였다.21 g (0.12 mol) of the compound obtained in Example 2 and 30.2 g (0.15 mol) of 4-amino-5-chloro-2-methoxybenzoic acid, 1- [3- (dimethyl amino) propyl] -3-ethylcarbodii 57.5 g (0.3 mol) of medi (EDCI) and 40.5 (0.3 mol) of 1-hydroxy benzotriazole (HOBT) were dissolved in 250 ml of dichloromethane, stirred at room temperature for 17 hours, filtered, washed with 100 ml of distilled water, and dried. Drying with MgSO 4 , filtration and concentration under reduced pressure gave 30.4 g (75%) of the title compound.
1H NMR(ppm) 1.99(m, 2H), 2.17(m, 2H), 2.35(s, 3H), 3.24(m, 9H), 3.37(d, 2H), 1 H NMR (ppm) 1.99 (m, 2H), 2.17 (m, 2H), 2.35 (s, 3H), 3.24 (m, 9H), 3.37 (d, 2H),
3.90(m, 1H), 4.08(m, 1H), 6.38(s, 1H), 7.59(d, 1H)3.90 (m, 1H), 4.08 (m, 1H), 6.38 (s, 1H), 7.59 (d, 1H)
융점: 125℃~136℃Melting Point: 125 ℃ ~ 136 ℃
실시예4 : 시스-4-아미노-5-클로로-N-[1-[3-(4-플루오로페녹시)프로필]-3-메톡시-4-피페리딘일]-2-메톡시벤즈아미드. 모노하이드레이트의 제조Example 4: cis-4-amino-5-chloro-N- [1- [3- (4-fluorophenoxy) propyl] -3-methoxy-4-piperidinyl] -2-methoxybenz amides. Preparation of Monohydrate
실시예 3에서 수득한 화합물 20g(0.06mol)에 4-플루오로 페놀 13.4g(0.12mol)을 가하고 상온에서 15시간동안 교반시켰다. 반응이 완결되면 클로로포름 200ml를 가하여 희석시키고 묽은 염산(20ml)으로 3회 세척한 후 1N 수산화나트륨 수용액 100ml로 세척한다. 무수 MgSO4로 건조, 여과 및 감압농축하여 얻어진 잔사물을 이소프로필알콜로 재결정하여 표제화합물 18.8g(70%)을 수득하였다.To 20 g (0.06 mol) of the compound obtained in Example 3, 13.4 g (0.12 mol) of 4-fluorophenol was added and stirred at room temperature for 15 hours. After the reaction was completed, 200 ml of chloroform was added, diluted, washed three times with dilute hydrochloric acid (20 ml), and then washed with 100 ml of 1N aqueous sodium hydroxide solution. The residue obtained by drying over anhydrous MgSO 4 , filtered and concentrated under reduced pressure was recrystallized with isopropyl alcohol to give 18.8 g (70%) of the title compound.
1H NMR(ppm) 1.75-1.9(m, 2H), 1.9-2.1(m, 2H), 2.2-2.4(m, 2H), 2.6(m, 2H), 1 H NMR (ppm) 1.75-1.9 (m, 2H), 1.9-2.1 (m, 2H), 2.2-2.4 (m, 2H), 2.6 (m, 2H),
2.8-2.9(m, 1H), 3.0-3.1(m, 1H), 3.4-3.5(m, 4H), 3.9(m, 3H),2.8-2.9 (m, 1H), 3.0-3.1 (m, 1H), 3.4-3.5 (m, 4H), 3.9 (m, 3H),
4.0-4.1(m, 2H), 4.2-4.3(m, 1H), 4.4(s, 2H), 6.3(s, 1H),4.0-4.1 (m, 2H), 4.2-4.3 (m, 1H), 4.4 (s, 2H), 6.3 (s, 1H),
6.7-7.0(m, 4H), 8.2(d, 1H)6.7-7.0 (m, 4H), 8.2 (d, 1H)
이상 설명하고 실시예를 통하여 알 수 있는 바와 같이, 본 발명은 구조식(1)의 화합물을 출발물질로 하여 4단계의 반응을 거쳐 목적화합물을 높은 수율로 얻을 수 있다. 특히, 1-[3-(디메틸 아미노)프로필]-3-에틸카보디이미드(EDCI)와 1-히드록시 벤조트리아졸(HOBT)을 함께 축합제로 사용하여 축합반응을 월등하게 향상시킬 수 있었으며, 본 발명의 모든 공정이 상온에서 수행이 가능하게 됨으로써 공업적인 적용도 수월하게 되었다.As described above and it can be seen through the examples, the present invention can be obtained in a high yield by the reaction of the compound of formula (1) as a starting material through a four-step reaction. In particular, the condensation reaction was significantly improved by using 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide (EDCI) and 1-hydroxy benzotriazole (HOBT) together as condensing agents. All the processes of the present invention can be carried out at room temperature, thereby facilitating industrial application.
Claims (4)
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| WO1998016511A1 (en) * | 1996-10-15 | 1998-04-23 | Janssen Pharmaceutica N.V. | Synthesis of cisapride |
| KR20000074593A (en) * | 1999-05-24 | 2000-12-15 | 류덕희 | A process for preparing cisapride |
| KR20010084830A (en) * | 2000-02-29 | 2001-09-06 | 류덕희 | A Method of Preparing Cisapride and Intermediates Thereof |
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| WO1998016511A1 (en) * | 1996-10-15 | 1998-04-23 | Janssen Pharmaceutica N.V. | Synthesis of cisapride |
| KR20000074593A (en) * | 1999-05-24 | 2000-12-15 | 류덕희 | A process for preparing cisapride |
| KR20010084830A (en) * | 2000-02-29 | 2001-09-06 | 류덕희 | A Method of Preparing Cisapride and Intermediates Thereof |
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