KR100524453B1 - Process for the preparation of Levodropropizine - Google Patents
Process for the preparation of Levodropropizine Download PDFInfo
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- KR100524453B1 KR100524453B1 KR10-2003-0059165A KR20030059165A KR100524453B1 KR 100524453 B1 KR100524453 B1 KR 100524453B1 KR 20030059165 A KR20030059165 A KR 20030059165A KR 100524453 B1 KR100524453 B1 KR 100524453B1
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- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/12—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with only hydrogen atoms attached to the ring nitrogen atom
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Abstract
본발명은 하기 구조식 (A)로 표시되는 1-페닐피페라진과 하기 구조식 (B)의 (R)-글리시돌을 유기용매 중에서 구조식 (Ⅱ)의 리튬염 촉매 존재하 반응시켜 구조식 (Ⅰ)의 레보드로프로피진을 제조하는 방법에 관한 것이다.The present invention is prepared by reacting 1-phenylpiperazine represented by the following structural formula (A) with (R) -glycidol of the following structural formula (B) in the presence of a lithium salt catalyst of the structural formula (II). It relates to a method for producing leprotropypizin.
여기서, M 은 F, Cl, Br, I 또는 ClO4 이다.Where M is F, Cl, Br, I or ClO 4 .
Description
본 발명은 하기 구조식 (Ⅰ)의 레보드로프로피진(Levodropropizine)의 제조방법에 관한 것으로, 보다 상세하게는 레보드로프로피진을 리튬염 촉매를 사용하여 보다 빠른 반응 시간과 높은 수율로 제조하는 방법을 제공하고자 하는 것이다.The present invention relates to a process for preparing Levodropropizine of Structural Formula (I), and more particularly to a process for preparing Levodropropizine with a faster reaction time and higher yield using a lithium salt catalyst. It is to provide.
본 발명의 제조방법은, 특징적으로 반응촉매로 하기 구조식 (Ⅱ)의 리튬염을 사용하여 레보드로프로피진(Ⅰ)을 제조하는 신규 제조방법에 관한 것이다. The manufacturing method of this invention is related with the novel manufacturing method which manufactures a levothropropazine (I) using the lithium salt of following structural formula (II) as a reaction catalyst characteristically.
여기서, M 은 F, Cl, Br, I 또는 ClO4 이다.Where M is F, Cl, Br, I or ClO 4 .
레보드로프로피진(Ⅰ)은 레보-3-(4-페닐-1-피페라진일)-1,2-프로판디올로 명명되며, 한개의 비대칭 탄소원자를 가지고 있다. 라세미 혼합물형태의 드로프로피진(dropropizine)은 진해제로 사용되고 있으며(벨기에 특허 명세서 제601,394호 참조), 좌회전성 이성질체가 우회전성 이성질체 보다 훨씬 우수한 진해작용을 발현하고, 중추 신경계에 상당히 저하된 활성을 나타냄으로써 부작용을 감소시킨다(이탈리아 특허 명세서 제1,203,721호 참조). Levodropropizine (I) is named Levo-3- (4-phenyl-1-piperazinyl) -1,2-propanediol and has one asymmetric carbon atom. Dropropizine in the form of a racemic mixture is used as an antitussive (see Belgian Patent No. 601,394), and the left-rotating isomer expresses much better antitussive action than the right-rotating isomer and exhibits significantly lowered activity in the central nervous system. To reduce side effects (see Italian Patent Specification 1,203,721).
본 발명에서 제조하고자 하는 하기 구조식 (Ⅰ)의 화합물의 종래 제조방법으로는, 하기 구조식 (A)의 1-페닐피페라진과, 하기 구조식 (C)의 (-)-글리세롤-1-토실레이트를 용하여 제조하는 방법이 소개되어 있다(미국 특허명세서 제4,699,911호 참조).As a conventional method for preparing a compound of the following structural formula (I) to be prepared in the present invention, 1-phenylpiperazine of the following structural formula (A) and (-)-glycerol-1-tosylate of the following structural formula (C) Is prepared (see US Pat. No. 4,699,911).
그러나, 이 제조방법은 반응물질인 구조식 (C)화합물을 합성하기 위한 제조공정이 길고 어려우며, 화합물 (C)가 불안정하여 대량 생산 시 손실이 우려되었다. 또한 목적물질인 화합물 (Ⅰ)을 합성하는 시간이 길고 높은 온도를 요구하여 공업적으로 제조하기에 많은 문제점이 있었다.However, this manufacturing method has a long and difficult process for synthesizing the compound of formula (C), which is a reactant, and the compound (C) is unstable, causing loss in mass production. In addition, there is a problem in that it takes a long time to synthesize compound (I), which is a target substance, and requires high temperature for industrial production.
보다 더 진보된 방법으로, 하기 구조식 (A)의 1-페닐피페라진과 하기 구조식 (B)의 (R)-글리시돌을 사용하는 제조방법이 프랑스 특허 명세서 제2,634,765호에 소개되었다.In a more advanced method, a preparation method using 1-phenylpiperazine of the following structural formula (A) and (R) -glycidol of the following structural formula (B) is introduced in French Patent Specification 2,634,765.
하지만, 이와 같은 제조 방법은 반응 온도가 높아 대량 생산시 주의가 필요하고, 값비싼 중간체에 비해 낮은 수율로 인하여 생산비가 많이 드는 문제점이 있었다(수율 : 86.4%).However, such a manufacturing method has a problem that a high reaction temperature requires attention in mass production, and the production cost is high due to low yield compared to expensive intermediates (yield: 86.4%).
따라서, 본 발명은 상기의 문제점들을 보완하여 보다 더 온화한 반응조건에서 간단한 제조공정을 거쳐 고순도, 고수율로 목적물(Ⅰ)을 경제적, 공업적으로 제조할 수 있는 신규 방법을 제공하는데 그 목적이 있다. Accordingly, an object of the present invention is to provide a novel method that can economically and industrially produce the target (I) with high purity and high yield through a simple manufacturing process under milder reaction conditions to compensate for the above problems. .
본 발명의 레보드로프로피진(Levodropropizine)의 신규제조방법은, 하기 구조식 (A)로 표시되는 1-페닐피페라진과 하기 구조식 (B)의 (R)-글리시돌을 유기용매 중에서 반응촉매인 다양한 당량의 하기 구조식 (Ⅱ)의 리튬염 존재하 구조식(Ⅰ)의 레보드로프로피진을 고순도, 고수율로 제조하는 방법이다. The novel production method of levodropropizine of the present invention is a reaction catalyst of 1-phenylpiperazine represented by the following structural formula (A) and (R) -glycidol of the following structural formula (B) in an organic solvent. In the presence of various equivalents of the lithium salt of the following structural formula (II), levodropropizine of the structural formula (I) is produced in high purity and high yield.
이들의 제조방법을 도식화하면 다음과 같다.Schematic of these manufacturing methods are as follows.
여기서, M 은 F, Cl, Br, I 또는 ClO4 이다.Where M is F, Cl, Br, I or ClO 4 .
본 발명을 좀 더 상세히 설명하면 다음과 같다.The present invention is described in more detail as follows.
구조식 (B)의 (R)-글리시돌을 유기용매에 희석시킨 후 구조식 (Ⅱ)의 리튬염을 넣고 완전히 용해시킨 다음, 구조식 (A)의 1-페닐피페라진과 반응시켜 구조식 (Ⅰ)의 레보드로프로피진을 제조한다. 화합물 (Ⅰ)을 제조하는 공정에서 사용된 리튬염으로는 리튬플로라이드, 리튬클로라이드, 리튬브로마이드, 리튬아이오다이드, 리튬퍼클로레이트 등이 사용될 수 있으며, 반응조건이나 수율고려시 가장 바람직한 것으로는 리튬클로라이드와 리튬퍼클로레이트이다. 또한 유기용매로는 메틸렌클로라이드, 아세톤, 테트라히드로퓨란, 아세토니트릴 등이 사용될 수 있으나, 반응조건 고려시 특히 바람직한 것은 아세토니트릴을 사용하는 것이다. After diluting the (R) -glycidol of the structural formula (B) in an organic solvent and adding a lithium salt of the structural formula (II), completely dissolving it, and then reacting with the 1-phenylpiperazine of the structural formula (A), the structural formula (I) Manufacture of propilopipi of. Lithium salt used in the process of preparing compound (I) may be used lithium fluoride, lithium chloride, lithium bromide, lithium iodide, lithium perchlorate, etc., lithium chloride is most preferred when considering the reaction conditions or yield And lithium perchlorate. In addition, methylene chloride, acetone, tetrahydrofuran, acetonitrile, and the like may be used as the organic solvent, but in consideration of reaction conditions, acetonitrile is particularly preferable.
본 발명에 있어서, 반응촉매인 구조식 (Ⅱ) 리튬염의 사용량은 구조식 (B) 화합물 1 몰당 1 당량 ~ 0.1 당량 사용이 가능하며, 반응온도는 0 ℃ ~ 70 ℃ 모두 가능하고, 반응시간은 조건에 따라서 다르나 3 시간 이내, 특히 5 분 ~ 2 시간 이내에 반응을 완결시킨다.In the present invention, the amount of the lithium salt of the structural formula (II) as the reaction catalyst may be used in the amount of 1 equivalent to 0.1 equivalent per mole of the structural formula (B), and the reaction temperature may be 0 ° C. to 70 ° C. Thus, the reaction is complete within 3 hours, in particular within 5 minutes to 2 hours.
본 발명을 수행함에 있어서, 리튬염을 0.1 당량 이하로 사용하였을 경우 반응시간이 길어지고, 반응에 필요한 온도가 높아짐으로 인해서 공업적으로 사용하기에 부적합하고, 1 당량 이상 사용시 반응시간과 수율에 변화가 없으므로 실용성이 없었다.In carrying out the present invention, when the lithium salt is used in an amount of 0.1 equivalent or less, the reaction time is longer, and the temperature required for the reaction is not suitable for industrial use, and when used in an amount of 1 equivalent or more, the reaction time and the yield are changed. There was no practical use.
또한, 온도를 0 ℃이하로 반응하였을 경우 리튬염을 1 당량 사용하였을때 반응시간과 수율에 별다른 변화가 없었지만, 0.1 당량 미만의 리튬염을 사용하면 반응시간이 길어지는 것을 확인하였다. 그리고, 온도가 올라감에 따라 리튬염의 사용량에 상관없이 반응시간은 짧아지는 것을 확인 하였지만, 리튬염을 사용시 발열반응이기 때문에 70 ℃까지는 별다른 외부 도움없이 온도를 올릴 수 있었으며, 그 이상 온도가 높아지면 임의적인 열을 가하여야 하기 때문에 실용적이지 못하였다.In addition, when the reaction temperature is 0 ℃ or less, when using 1 equivalent of lithium salt, there was no change in reaction time and yield, but using less than 0.1 equivalent of lithium salt was confirmed that the reaction time is longer. And, as the temperature increases, the reaction time is shortened regardless of the amount of lithium salt used. However, since the exothermic reaction when using the lithium salt, the temperature could be raised up to 70 ° C. without any external help. It was not practical because the tear had to be applied.
본 발명에 대한 실시예를 들어보면 다음과 같으며, 본 발명을 제한하는 것은 아니다.Examples for the present invention are as follows, but are not intended to limit the present invention.
실시예 1Example 1
리튬퍼클로레이트 1 당량을 사용한 레보드로프로피진의 제조.Preparation of Levodropropizine using 1 equivalent of lithium perchlorate.
(R)-글리시돌 32.3 g과 아세토니트릴 170 g을 반응기에 넣은 후 0 ℃를 유지하면서 리튬퍼클로레이트 51.6 g을 투입하고 1-페닐 피페라진 70.8 g을 천천히 적가 하였다. 적가가 완료되면 온도를 0 ℃로 유지하면서 5 분간 교반하였다. 반응이 완료되면 -10 ℃ ~ 0 ℃로 냉각하고, 2 시간동안 교반시킨 후 생성된 고체를 여과하고 차가운 아세토니트릴 30 g으로 세척하였다. 모아진 화합물을 건조하여 백색의 결정인 레보드로프로피진 100 g을 얻었다. After 32.3 g of (R) -glycidol and 170 g of acetonitrile were added to the reactor, 51.6 g of lithium perchlorate was added while maintaining 0 ° C, and 70.8 g of 1-phenyl piperazine was slowly added dropwise. When the addition was completed, the mixture was stirred for 5 minutes while maintaining the temperature at 0 ° C. After the reaction was completed, the mixture was cooled to −10 ° C. to 0 ° C., stirred for 2 hours, and the resulting solid was filtered and washed with 30 g of cold acetonitrile. The combined compounds were dried to obtain 100 g of levodropropazine as white crystals.
수율 : 97 %Yield: 97%
융점 : 98-100 ℃Melting Point: 98-100 ℃
[α]D = -30.936 o (C = 3, 1N - HCl)[α] D = -30.936 o (C = 3, 1N-HCl)
실시예 2Example 2
리튬퍼클로레이트 0.1 당량을 사용한 레보드로프로피진의 제조 Preparation of Levodropropazine Using 0.1 Equivalent of Lithium Perchlorate
(R)-글리시돌 32.3 g과 아세토니트릴 170 g을 반응기에 넣은 후 리튬퍼클로레이트 5.2 g을 투입하고 1-페닐 피페라진 70.8 g을 천천히 적가하였다. 적가가 완료되면 상승된 온도(약 45 ℃)를 유지하면서 2 시간 교반하였다. 반응이 완료되면 -10 ℃ ~ 0 ℃로 냉각하고, 2 시간동안 교반시킨 후 생성된 고체를 여과하고 차가운 아세토니트릴 30 g으로 세척하였다. 모아진 화합물을 건조하여 백색의 결정인 레보드로프로피진 100 g을 얻었다.After 32.3 g of (R) -glycidol and 170 g of acetonitrile were added to the reactor, 5.2 g of lithium perchlorate was added and 70.8 g of 1-phenyl piperazine was slowly added dropwise. When the addition was completed, the mixture was stirred for 2 hours while maintaining the elevated temperature (about 45 ° C). After the reaction was completed, the mixture was cooled to −10 ° C. to 0 ° C., stirred for 2 hours, and the resulting solid was filtered and washed with 30 g of cold acetonitrile. The combined compounds were dried to obtain 100 g of levodropropazine as white crystals.
수율 : 97 %Yield: 97%
융점 : 98-100 ℃Melting Point: 98-100 ℃
[α]D = -30.769 o (C = 3, 1N-HCl)[α] D = -30.769 o (C = 3, 1N-HCl)
실시예 3-15Example 3-15
실시예 1에 따르데, 하기의 조건으로 실시하여, 그 결과를 표에 기재하였다.According to Example 1, but under the following conditions, the results are shown in the table.
표 table
본 발명의 효과는, 목적 화합물 (Ⅰ)의 레보드로프로피진을 제조함에 있어서, 유기용매 중에서 반응촉매로 화합물 (Ⅱ)의 리튬염과 같은 루이스 첨가제 존재하 반응시킴으로써, 기존 반응의 문제점으로 제기되었던 높은 반응온도로 인한 대량생산의 위험성과 낮은 수율 및 제조공정의 복잡성으로 인한 문제점 등을 해결하여 공정의 단순화, 고순도 및 고수율 (기존방법 : 86.4 %, 신규방법 : 97 %)과 짧은 생산 시간(5 분 ~ 2 시간이내)으로 목적물을 경제적으로 생산할 수 있다는 특장점이 있는바, 본 발명은 산업적으로 매우 유용한 발명임을 알 수 있다. The effect of the present invention has been raised as a problem of the conventional reaction by reacting in the presence of a Lewis additive such as a lithium salt of compound (II) with a reaction catalyst in an organic solvent in the preparation of the levodropropazine of the target compound (I). Simplification of process, high purity and high yield (existing method: 86.4%, new method: 97%) and short production time by solving the problems of mass production due to high reaction temperature, problems of low yield and complexity of manufacturing process It can be seen that the present invention is an industrially useful invention because it has an advantage of economically producing a target product within 5 minutes to 2 hours).
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| KR10-2003-0059165A KR100524453B1 (en) | 2003-08-26 | 2003-08-26 | Process for the preparation of Levodropropizine |
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| KR10-2003-0059165A KR100524453B1 (en) | 2003-08-26 | 2003-08-26 | Process for the preparation of Levodropropizine |
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