KR0137810B1 - The process for preparing ripamycin derivatives - Google Patents
The process for preparing ripamycin derivativesInfo
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- KR0137810B1 KR0137810B1 KR1019940039201A KR19940039201A KR0137810B1 KR 0137810 B1 KR0137810 B1 KR 0137810B1 KR 1019940039201 A KR1019940039201 A KR 1019940039201A KR 19940039201 A KR19940039201 A KR 19940039201A KR 0137810 B1 KR0137810 B1 KR 0137810B1
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- rifamycin
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- deoxo
- imino
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/08—Bridged systems
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Abstract
본 발명은 리파마이신 유도체의 제조방법에 관한 것으로, 더욱 상세하게는 하기 구조식 (Ⅱ)로 표시되는 3-브로모 리파마이신 S를 기체상의 암모니아와 반응시키는 것을 특징으로 하는 구조식(Ⅰ)로 표시되는 3-아미노-4-데옥소-4-이미노 리파마이신 S(3-amino-4-deoxo-4-imino rifamycin S)의 제조방법 및 이를 이용한 리파부틴(Rifabutin)의 제조방법에 관한 것이다.The present invention relates to a method for preparing a lipamycin derivative, and more particularly, 3-bromo rifamycin S represented by the following structural formula (II) is reacted with gaseous ammonia, which is represented by the structural formula (I) The present invention relates to a method for preparing 3-amino-4-deoxo-4-imino rifamycin S (3-amino-4-deoxo-4-imino rifamycin S) and to a method for preparing rifabubutin using the same.
Description
본 발명은 리파마이신 유도체의 제조방법에 관한 것으로, 더욱 상세하게는 하기 구조식(Ⅱ)로 표시되는 3-브로모 리파마이신 S를 기체상의 암모니아와 반응시키는 것을 특징으로 하는 구조식(Ⅰ)로 표시되는 3-아미노-4-데옥소-4-이미노 리파마이신 S(3-amino-4-deoxo-4-imino rifamycin S)의 제조방법 및 이를 이용한 리파부틴(Rifabutin)의 제조방법에 관한 것이다.The present invention relates to a method for preparing a lipamycin derivative, and more particularly, 3-bromo rifamycin S represented by the following structural formula (II) is reacted with gaseous ammonia, which is represented by the structural formula (I) The present invention relates to a method for preparing 3-amino-4-deoxo-4-imino rifamycin S (3-amino-4-deoxo-4-imino rifamycin S) and to a method for preparing rifabubutin using the same.
구조식(Ⅰ)로 표시되는 3-아미노4-데옥소-4-이미노 리파마이신 S는 그 자체로도 항균력을 갖을 뿐 아니라 리파부틴을 제조하기 위한 중간체로도 사용할 수 있는 리파마이신 유도체로서, 하기 구조식 (Ⅲ)로 표시되는 리파마이신 S로부터 제조하는 방법이 종래에 알려져 있다.3-amino4-deoxo-4-imino rifamycin S represented by Structural Formula (I) is a lipamycin derivative that can be used as an intermediate for preparing rifabutin as well as having antibacterial activity by itself. A method for producing from rifamycin S represented by the formula (III) is known in the art.
즉, 구조식 (Ⅲ)의 리파마이신 S로부터 구조식 (Ⅰ)의 3-아미노4-데옥소-4-이미노 리파마이신 S를 제조하기 위한 종래의 방법으로는 미국특허 4,007,169호 및 미국특허 4,017,481호가 공지되어 있다.That is, US Pat. Nos. 4,007,169 and 4,017,481 are known as conventional methods for preparing 3-amino4-deoxo-4-imino-rifamycin S of formula (I) from rifamycin S of formula (III). It is.
미국특허 4,007,169호에 따르면, 구조식 (Ⅲ)의 리파마이신 S에 소듐아지드(NaN3)를 반응시켜 3-아지도 리파마이신 S를 제조한 다음, 이를 환원하여 3-아미노 리파마이신 S를 제조한 후 암모니아 가스를 반응시켜 구조식 (Ⅰ)의 3-아미노-4-데옥소-4-이미노 리파마이신 S를 제조하였다. 그러나 미국특허 4,007,169호에 따른 제조방법은 소듐아지드를 사용함으로써 다량생산을 위한 제조공정에 있어서 폭발성이 매우 높다는 점이 문제점으로 지적되고있다.According to US Pat. No. 4,007,169, 3-azido rifamycin S was prepared by reacting sodium azide (NaN 3 ) with rifamycin S of formula (III), followed by reduction to prepare 3-amino rifamycin S. After reacting ammonia gas to prepare 3-amino-4-deoxo-4-imino rifamycin S of formula (I). However, the manufacturing method according to US Pat. No. 4,007,169 has been pointed out as a problem that the explosiveness is very high in the manufacturing process for mass production by using sodium azide.
미국특허 4,007,169호 제조방법의 폭발성 문제를 해결하기 위하여 미국특허 4,017,481호에서는 구조식(Ⅲ)의 리파마이신 S에 브롬을 반응시켜 구조식(Ⅱ)의 3-브로모 리파마이신 S를 제조한 다음, 니트로기를 도입하여 3-니트로 리파마이신 S를 제조한 다음, 이를 환원하여 3-아미노 리파마이신 S를 제조한 후 암모니아 가스를 반응시켜 구조식(Ⅰ)의 3-아미노-4-데옥소-4-이미노 리파마이신 S를 제조하였다. 그러나 미국특허 4,017,481호의 제조방법에 있어서 종래의 소듐아지드를 사용하지 않고 니트로기를 도입하여 제조할지라도 니트로기를 환원시 발생하는 폭발성의 문제점은 여전히 남아있게 된다.In order to solve the explosive problem of the manufacturing method of U.S. Patent 4,007,169, U.S. Patent 4,017,481 reacts bromine to rifamycin S of formula (III) to prepare 3-bromo rifamycin S of formula (II), and then nitro group. Introduce 3-nitro rifamycin S, reduce it to prepare 3-amino rifamycin S, and then react with ammonia gas to react 3-amino-4-deoxo-4-imino lipase of formula (I). Mycin S was prepared. However, in the manufacturing method of US Pat. No. 4,017,481, even if the nitro group is prepared without using the conventional sodium azide, the explosive problem occurring upon reduction of the nitro group remains.
특히, 미국특허 4,007,169호 및 미국특허 4,017,481호의 제조방법은 모두 구조식 (Ⅰ)의 3-아미노-4-데옥소-4-니트로 리파마이신 S을 제조하기 위하여 여러 단계의 공정을 거쳐야 하기 때문에 제조가 매우 복잡하다는 문제점이 있다.In particular, the preparation methods of US Pat. No. 4,007,169 and US Pat. No. 4,017,481 are both very difficult to prepare because they have to undergo several steps to prepare 3-amino-4-deoxo-4-nitro rifamycin S of formula (I). There is a problem of complexity.
이에, 본 발명자들은 구조식 (Ⅰ)의 3-아미노-4-데옥소-4-이미노 리파마이신 S를 간단한 공정으로 폭발성의 문제가 전혀 없이 제조하기 위한 연구를 거듭한 결과, 구조식 (Ⅱ)의 3-브로모 리파마이신 S에 기체상의 암모니아를 반응시켰을 때, 3위치가 아미노기로 치환됨과 동시에 4위치가 이미노기로 치환된다는 것을 발견하여 본 발명을 완성하게 되었다.Accordingly, the inventors of the present invention have repeatedly studied to prepare 3-amino-4-deoxo-4-imino-rifamycin S of formula (I) without any problem of explosiveness in a simple process. When gaseous ammonia was reacted with 3-bromo rifamycin S, it was found that the 3 position was substituted with an amino group and the 4 position was substituted with an imino group, thereby completing the present invention.
즉, 본 발명은 구조식 (Ⅱ)의 3-브로모 리파마이신 S를 기체상의 암모니아와 반응시켜 구조식 (Ⅰ)의 3-아미노-4-데옥소-4-이미노 리파마이신 S를 단일공정으로 제조하는 방법을 제공하는 것을 목적으로 한다.That is, the present invention prepares 3-amino-4-deoxo-4-imino-rifamycin S of formula (I) by reacting 3-bromo rifamycin S of formula (II) with gaseous ammonia in a single process. It aims to provide a way to.
또한, 본 발명은 그러한 제조방법을 이용하여 리파부틴을 제조하는 방법을 제공하는 것을 포함한다.The present invention also includes providing a method for preparing lipabutin using such a method of preparation.
이하, 본 발명을 상세히 설명하면 다음과 같다.Hereinafter, the present invention will be described in detail.
본 발명은 구조식 (Ⅱ)로 표시되는 3-브로모 리파마이신 S를 기체상의 암모니아와 반응시키는 것을 특징으로 하는 구조식(Ⅰ)로 표시되는 3-아미노-4-데옥소-4-이미노 리파마이신 S(3-amino-4-deoxo-4-imino rifamycin S)의 제조방법에 관한 것이다.The present invention provides 3-amino-4-deoxo-4-imino rifamycin represented by structural formula (I), wherein 3-bromo rifamycin S represented by structural formula (II) is reacted with gaseous ammonia. It relates to a method for preparing S (3-amino-4-deoxo-4-imino rifamycin S).
또한, 본 발명은 구조식 (Ⅱ)로 표시되는 3-브로모 리파마이신 S를 기체상의 암모니아와 반응시켜 구조식(Ⅰ)로 표시되는 3-아미노-4-데옥소-4-이미노 리파마이신 S(3-amino-4-deoxo-4-imino rifamycin S)의 제조한 다음, N-이소부틸 피페리돈을 반응시키는 것을 특징으로 하는 구조식(Ⅳ)의 리파부틴의 제조방법에 관한 것이다.In addition, the present invention is the reaction of 3-bromo rifamycin S represented by the formula (II) with gaseous ammonia, 3-amino-4-deoxo-4-imino rifamycin S ( To prepare a 3-amino-4-deoxo-4-imino rifamycin S), and then to react with N-isobutyl piperidone relates to a method for preparing rifabutin of formula (IV).
이하, 본 발명을 더욱 상세히 설명하면 다음과 같다.Hereinafter, the present invention will be described in more detail.
구조식(Ⅱ)의 3-브로모 리파마이신 S는 독일특허 공개 제 2,548,148호에 따라 쉽게 제조할 수 있다. 본 발명에 따라 3-브로모 리파마이신 S를 기체상 암모니아와 반응시키기 전에, 3-브로모 리파마이신 S를 적당한 유기용매에 용해시킨다. 본 발명에 사용가능한 유기용매로는 디옥산, 테트라 히드로푸란, 벤젠 등이 바람직하며, 그 양은 3-브로모 리파마이신 S를 충분히 용해시킬 수 있는 것이 바람직하다.3-Bromo rifamycin S of formula II can be readily prepared according to German Patent Publication No. 2,548,148. Prior to reacting 3-bromo rifamycin S with gaseous ammonia according to the invention, 3-bromo rifamycin S is dissolved in a suitable organic solvent. As the organic solvent usable in the present invention, dioxane, tetra hydrofuran, benzene and the like are preferable, and the amount thereof is preferably capable of sufficiently dissolving 3-bromo rifamycin S.
3-브로모 리파마이신 S 용액을 기체상 암모니아와 반응시키면 3위치가 아미노기로 치환됨과 동시에 4위치가 이미노기로 치환된다. 여기서, 기체상 암모니아와의 반응온도는 0 내지 30℃의 온도가 바람직하다.Reacting the 3-bromo rifamycin S solution with gaseous ammonia replaces the 3 position with an amino group and the 4 position with an imino group. Here, the reaction temperature with gaseous ammonia is preferably 0 to 30 ° C.
상기와 같이 3-브로모 리파마이신 S에 기체상의 암모니아를 반응시켜 제조한 3-아미노-4-데옥소-4-이미노 리파마이신 S는 공지의 방법(예를 들면, 미국특허 제 4,017,481호)에 따라 정제할 수 있다. 즉, 디클로르메탄을 가하여 묽은 아세트산 및 물로 세척한 다음, 유기층 탈수시키고 2-메톡시에탄올 등으로 재결정하면 3-아미노-4-데옥소-4-이미노 리파마이신 S를 쉽게 정제할 수 있다.As described above, 3-amino-4-deoxo-4-imino-rifamycin S prepared by reacting 3-bromo rifamycin S with gaseous ammonia is known in the art (for example, US Pat. No. 4,017,481). It can be purified according to. That is, 3-amino-4-deoxo-4-imino rifamycin S can be easily purified by adding dichloromethane, washing with dilute acetic acid and water, then dehydrating the organic layer and recrystallization with 2-methoxyethanol.
상기와 같이 제조한 3-아미노-4-데옥소-4-이미노 리파마이신 S를 공지의 방법(특허공고 82-546)에 따라 N-이소부틸 피페리돈과 반응시키면 구조식(Ⅳ)의 리파부틴을 쉽게 제조할 수 있다.When 3-amino-4-deoxo-4-imino-rifamycin S prepared as described above is reacted with N-isobutyl piperidone according to a known method (Patent Publication 82-546), lipabutin of formula (IV) It can be manufactured easily.
즉, 3-아미노-4-데옥소-4-이미노 리파마이신 S를 유기용매인 THF에서 아연과 초산암모늄을 사용하여 이를 N-이소부틸 피페리돈과 상온에서 24시간 반응시키면, 리파부틴을 쉽게 제조할 수 있다.That is, if 3-amino-4-deoxo-4-imino rifamycin S is reacted with N-isobutyl piperidone at room temperature for 24 hours using zinc and ammonium acetate in THF, an organic solvent, lipabutin is easily reacted. It can manufacture.
본 발명을 실시예를 통하여 더욱 구체적으로 설명하면 다음과 같다. 그러나 이것이 본 발명의 범위를 제한하는 것은 아니다.The present invention will be described in more detail with reference to the following Examples. However, this does not limit the scope of the present invention.
실시예 1Example 1
45g의 3-브로모 리파마이신 S를 450ml의 디옥산에 녹인 다음, 암모니아 가스를 투입하여 상온에서 30시간 교반하였다. 600ml의 디클로르메탄을 반응용액에 가하고 묽은 아세트산으로 세척한 후 다시 물로 세척한 다음, 유기층을 황산나트륨상에서 탈수시키고 감압하에 용매를 제거한 후, 2-메톡시에탄올로 재결정하여 3-아미노-4-데옥소-4-이미노 리파마이신 S 24g (수율 58%)을 제조하였다. 이렇게 제조한 3-아미노-4-데옥소-4-이미노 리파마이신 S는 장미빛 분말로서 물에 불용성이고 대부분의 유기용매에 잘 녹는다.45 g of 3-bromo rifamycin S was dissolved in 450 ml of dioxane, and then ammonia gas was added and stirred at room temperature for 30 hours. 600 ml of dichloromethane was added to the reaction solution, washed with dilute acetic acid and then again with water, and then the organic layer was dehydrated over sodium sulfate, the solvent was removed under reduced pressure, and then recrystallized with 2-methoxyethanol to give 3-amino-4-de. 24 g of oxo-4-imino rifamycin S (yield 58%) were prepared. The 3-amino-4-deoxo-4-imino-rifamycin S thus prepared is a rosy powder, insoluble in water and soluble in most organic solvents.
IR (KBr) 3400, 1672, 1341, 1142, 1069IR (KBr) 3400, 1672, 1341, 1142, 1069
NMR δ : 0.02(d), 0.64(d), 0.90(d), 1.04(d), 1.84(d), 2.05(s), 2.35(s), 3.11(s), 5.05(dd), 5.23(d), 5.78-6.87(m), 8.71(s), 14.13(s), 15.15(s)NMR δ: 0.02 (d), 0.64 (d), 0.90 (d), 1.04 (d), 1.84 (d), 2.05 (s), 2.35 (s), 3.11 (s), 5.05 (dd), 5.23 ( d), 5.78-6.87 (m), 8.71 (s), 14.13 (s), 15.15 (s)
실시예 2Example 2
15g의 3-브로모 리파마이신 S를 150ml의 테트라히드로푸란에 녹인 다음, 암모니아가스를 투입하여 상온에서 34시간 교반하였다. 200ml의 디클로르메탄을 반응용액에 가하고 묽은 아세트산으로 세척한 후 다시 물로 세척한 다음, 유기층을 황산나트륨상에서 탈수시키고 감압하에 용매를 제거한 후, 2-메톡시에탄올로 재결정하여 3-아미노-4-데옥소-4-이미노 리파마이신 S 7.5g(수율 54.4%)을 제조하였다. 이렇게 제조한 3-아미노-4-데옥소-4-이미노 리파마이신 S는 실시예 1의 생성물과 화학적, 물리적 성질이 동일하였다.15 g of 3-bromo rifamycin S was dissolved in 150 ml of tetrahydrofuran, ammonia gas was added thereto, and the mixture was stirred at room temperature for 34 hours. 200 ml of dichloromethane was added to the reaction solution, washed with dilute acetic acid and then again with water, and then the organic layer was dehydrated over sodium sulfate, the solvent was removed under reduced pressure, and then recrystallized with 2-methoxyethanol to 3-amino-4-de. 7.5 g oxo-4-imino rifamycin S (yield 54.4%) were prepared. Thus prepared 3-amino-4-deoxo-4-imino rifamycin S had the same chemical and physical properties as the product of Example 1.
실시예 3Example 3
5g의 3-브로모 리파마이신 S를 50ml의 벤젠에 녹인 다음, 암모니아 가스를 투입하여 상온에서 40시간 교반하였다. 70ml의 디클로르메탄을 반응용액에 가하고 묽은 아세트산으로 세척한 후 다시 물로 세척한 다음, 유기층을 무수황산나트륨으로 탈수시키고 감압하에 용매를 제거한 후, 2-메톡시에탄올로 재결정하여 목적 화합물 0.5g(수율 11%)을 제조하였다. 이렇게 제조한 3-아미노-4-데옥소-4-이미노 리파마이신 S는 실시예 1의 생성물과 화학적, 물리적 성질이 동일하였다.5 g of 3-bromo rifamycin S was dissolved in 50 ml of benzene, and ammonia gas was added thereto and stirred at room temperature for 40 hours. 70 ml of dichloromethane was added to the reaction solution, washed with dilute acetic acid and washed again with water, and then the organic layer was dehydrated with anhydrous sodium sulfate, the solvent was removed under reduced pressure, and then recrystallized with 2-methoxyethanol to yield 0.5 g of a target compound (yield). 11%) was prepared. Thus prepared 3-amino-4-deoxo-4-imino rifamycin S had the same chemical and physical properties as the product of Example 1.
실시예 4Example 4
5g의 3-브로모 리파마이신 S를 50ml의 테트라히드로푸란에 녹인 다음, 암모니아 가스를 투입하여 35℃에서 20시간 교반하였다. 70ml의 디클로르메탄을 반응용액에 가하고 묽은 아세트산으로 세척한 후 다시 물로 세척한 다음, 유기층을 무수황산나트륨으로 탈수시키고 감압하에 용매를 제거한 후, 2-메톡시에탄올로 재결정하여 목적 화합물 2.2g(수율 48.4%)을 제조하였다. 이렇게 제조한 3-아미노-4-데옥소-4-이미노 리파마이신 S는 실시예 1의 생성물과 화학적, 물리적 성질이 동일하였다.5 g of 3-bromo rifamycin S was dissolved in 50 ml of tetrahydrofuran, ammonia gas was added thereto, and the mixture was stirred at 35 ° C. for 20 hours. 70 ml of dichloromethane was added to the reaction solution, washed with dilute acetic acid and washed again with water. The organic layer was dehydrated with anhydrous sodium sulfate, the solvent was removed under reduced pressure, and recrystallized with 2-methoxyethanol to yield 2.2 g of a target compound (yield). 48.4%) was prepared. Thus prepared 3-amino-4-deoxo-4-imino rifamycin S had the same chemical and physical properties as the product of Example 1.
실시예 5Example 5
실시예 1에서 제조한 3-아미노-4-데옥소-4-아미노리파마이신 S 20g을 THF-100ml에 용해시킨 다음, Zn 1.5g, 암모니움 아세테이트 1.5g, N-이소부틸-4-피페리돈 14g을 각각 투입하여 상온에서 24시간 교반하였다. 이를 여과하고 1250ml의 에틸에테르로 희석시킨 후 증류수 1500ml로 세척하였다. 에틸에테르를 250ml로 농축후 묽은 아세트산 (증류수 : 아세트산 = 2000 : 40)으로 추출한 다음, 디클로르메탄 2000ml로 재추출한 후 농축한후, 생성된 잔유물을 시클로헥산으로 재결정하여 목적화합물 10.54g(수율 44.2%)을 제조하였다.20 g of 3-amino-4-deoxo-4-aminolipamycin S prepared in Example 1 was dissolved in THF-100 ml, followed by 1.5 g of Zn, 1.5 g of ammonium acetate, and N-isobutyl-4-piperidone Each 14g was added and stirred at room temperature for 24 hours. It was filtered, diluted with 1250 ml of ethyl ether and washed with 1500 ml of distilled water. Concentrate ethyl ether to 250 ml, extract with dilute acetic acid (distilled water: acetic acid = 2000: 40), re-extract with dichloromethane 2000 ml, concentrate, and recrystallize the resulting residue with cyclohexane to give 10.54 g of the target compound (yield 44.2). %) Was prepared.
Claims (2)
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| KR1019940039201A KR0137810B1 (en) | 1994-12-30 | 1994-12-30 | The process for preparing ripamycin derivatives |
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| KR1019940039201A KR0137810B1 (en) | 1994-12-30 | 1994-12-30 | The process for preparing ripamycin derivatives |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103408571A (en) * | 2013-08-23 | 2013-11-27 | 成都樵枫科技发展有限公司 | Crystal form I of rifabutin, and preparation method and application thereof |
| US9566270B2 (en) | 2008-02-26 | 2017-02-14 | Salix Pharmaceuticals, Ltd | Methods for treating irritable bowel syndrome (IBS) |
| US11779571B2 (en) | 2008-02-26 | 2023-10-10 | Salix Pharmaceuticals, Inc. | Methods for treating irritable bowel syndrome (IBS) |
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1994
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9566270B2 (en) | 2008-02-26 | 2017-02-14 | Salix Pharmaceuticals, Ltd | Methods for treating irritable bowel syndrome (IBS) |
| US9931325B2 (en) | 2008-02-26 | 2018-04-03 | Salix Pharmaceuticals, Ltd. | Methods for treating irritable bowel syndrome (IBS) |
| US10456384B2 (en) | 2008-02-26 | 2019-10-29 | Salix Pharmaceuticals, Inc. | Methods for treating irritable bowel syndrome (IBS) |
| US10765667B2 (en) | 2008-02-26 | 2020-09-08 | Salix Pharmaceuticals, Inc. | Methods for treating irritable bowel syndrome (IBS) |
| US11779571B2 (en) | 2008-02-26 | 2023-10-10 | Salix Pharmaceuticals, Inc. | Methods for treating irritable bowel syndrome (IBS) |
| CN103408571A (en) * | 2013-08-23 | 2013-11-27 | 成都樵枫科技发展有限公司 | Crystal form I of rifabutin, and preparation method and application thereof |
| CN103408571B (en) * | 2013-08-23 | 2015-11-18 | 成都樵枫科技发展有限公司 | Crystal formation I of Mycobutin and its production and use |
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| KR960022533A (en) | 1996-07-18 |
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