KR100498004B1 - Novel process for the preparation of a quinoline carboxylic acid derivative having a 7-(4-aminomethyl-3-oxime)pyrrolidine substituent - Google Patents
Novel process for the preparation of a quinoline carboxylic acid derivative having a 7-(4-aminomethyl-3-oxime)pyrrolidine substituent Download PDFInfo
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Abstract
본 발명은 특정 계면활성제를 사용하여 기존의 방법에 비해 여과시간을 획기적으로 단축시킨, 7-(4-아미노메틸-3-옥심)피롤리딘 치환체를 갖는 퀴놀린 카르복실산 항생제, 예를들어 게미플록사신 또는 그의 염을 제조하는 신규 방법에 관한 것이다.The present invention relates to quinoline carboxylic acid antibiotics with 7- (4-aminomethyl-3-oxime) pyrrolidine substituents, for example gammies, which dramatically shorten the filtration time compared to conventional methods using certain surfactants. A novel process for preparing floxacin or salts thereof.
Description
본 발명은 하기 화학식 (1)의 화합물 또는 그의 염 및 하기 화학식 (2)의 화합물 또는 그의 염을 커플링(coupling)시켜 하기 화학식 (3)의 7-(4-아미노메틸-3-옥심)피롤리딘 치환체를 갖는 퀴놀린 카르복실산 유도체 또는 그의 염을 제조하는 신규 방법에 관한 것이다:The present invention provides a compound of formula (1) or a salt thereof and a compound of formula (2) or a salt thereof by coupling to 7- (4-aminomethyl-3-oxime) pi of formula (3) A novel process for preparing quinoline carboxylic acid derivatives or salts thereof having a lollidine substituent:
상기 식에서,Where
X 는 이탈기, 바람직하게는 할로겐이며,X is a leaving group, preferably halogen,
Q 는 C-H, C-F, C-Cl, C-OH, C-O-메틸 또는 N 이고,Q is C-H, C-F, C-Cl, C-OH, C-O-methyl or N,
R 은 수소, 메틸 또는 아미노이며,R is hydrogen, methyl or amino,
R1 은 사이클로프로필, 에틸 또는 하나이상의 불소원자로 치환된 페닐이고,R 1 is cyclopropyl, ethyl or phenyl substituted with one or more fluorine atoms,
R2 는 수소, C1-C4 의 직쇄 또는 측쇄 알킬, 아릴 또는 알릴이며,R 2 is hydrogen, C 1 -C 4 straight or branched alkyl, aryl or allyl,
R3 및 R4 는 각각 독립적으로 수소 또는 C1-C3 알킬이거나, 이들이 부착되어 있는 질소원자와 함께 환을 형성할 수 있다.R 3 and R 4 are each independently hydrogen or C 1 -C 3 alkyl, or together with the nitrogen atom to which they are attached may form a ring.
대한민국 특허출원 제94-13604호에 개시된 화학식 (3)의 화합물은 퀴놀론계 항생제이다. 화학식 (3)의 화합물로서 언급될 수 있는 특정 화합물로는 (R,S)-7-(3-아미노메틸-4-syn-메톡시이미노-피롤리딘-1-일)-1-사이클로프로필-6-플루오로-4-옥소-1,4-디하이드로-1,8-나프티리딘-3-카르복실산(게미플록사신; gemifloxacin)및 약제학적으로 허용되는 그의 염을 들 수 있다. 대한민국 특허공개 제98-80504호는 이 화합물의 바람직한 형태, 즉, (R,S)-7-(3-아미노메틸-4-syn-메톡시이미노-피롤리딘-1-일)-1-사이클로프로필-6-플루오로-4-옥소-1,4-디하이드로-1,8-나프티리딘-3-카르복실산 메탄설포네이트 및 그의 수화물, 특히 세스퀴 수화물을 개시하고 있다.The compound of formula (3) disclosed in Korean Patent Application No. 94-13604 is a quinolone antibiotic. Particular compounds that may be mentioned as compounds of formula (3) include (R, S) -7- (3-aminomethyl-4- syn -methoxyimino-pyrrolidin-1-yl) -1-cyclopropyl -6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (gemifloxacin) and pharmaceutically acceptable salts thereof. Korean Patent Publication No. 98-80504 discloses a preferred form of this compound, namely (R, S) -7- (3-aminomethyl-4- syn -methoxyimino-pyrrolidin-1-yl) -1- Cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid methanesulfonate and hydrates thereof, in particular sesquihydrates, are disclosed.
따라서, 화학식 (3) 화합물의 유리 염기는 화학식 (3) 화합물의 염을 제조하는데 핵심 중간체라 할 수 있으며 최종 생성물의 품질에 직접적인 영향을 미친다. 화학식 (3)의 화합물을 제조함에 있어서, 반응용매로 아세토니트릴/물 혼합용매 대신에 물을 사용함으로써 생성된 화학식 (3)의 화합물의 순도를 개선시키고자 하는 시도가 있었다(참고: PCT/GB00/03366). 그러나 물을 포함하여 통상적으로 사용되는 용매는 여과시간이 길어 짧은 생산 회전시간(Cycle Time)이 요구되는 공업적 생산에 부적합하다는 문제를 안고 있다. Thus, the free base of the compound of formula (3) can be said to be a key intermediate for preparing salts of the compound of formula (3) and directly affect the quality of the final product. In preparing compounds of formula (3), attempts have been made to improve the purity of the compounds of formula (3) produced by using water instead of acetonitrile / water mixed solvents as reaction solvents (see PCT / GB00). / 03366). However, conventionally used solvents, including water, have a long filtration time, which is not suitable for industrial production requiring a short production cycle time (Cycle Time).
따라서 본 발명자들은 7-(4-아미노메틸-3-옥심)피롤리딘 치환체를 갖는 퀴놀린 카르복실산 유도체 및 그의 염을 제조함에 있어 상기와 같은 문제점을 해결하기 위하여 연구하던중, 반응액중에 계면활성제를 첨가한다는, 지금까지 시도된 바가 없는 방법을 도입하면 반응성에 아무런 영향없이 여과시간을 획기적으로 단축시킬 수 있음을 밝혀내고 본 발명을 완성하게 되었다.Accordingly, the present inventors have studied to solve the above problems in preparing a quinoline carboxylic acid derivative having a 7- (4-aminomethyl-3-oxime) pyrrolidine substituent and salts thereof, The present invention has been completed by discovering that adding an active agent, which has not been tried so far, can significantly reduce the filtration time without affecting the reactivity.
따라서, 본 발명의 목적은 화학식 (1)의 화합물 또는 그의 염을 용매중에서 염기 및 계면활성제의 존재하에 화학식 (2)의 화합물 또는 그의 염과 반응시킨 후 생성된 화학식 (3)의 화합물을 여과하고, 임의로 약제학적으로 허용되는 그의 염 및/또는 수화물을 형성함을 특징으로 하여 화학식 (3)의 화합물 또는 그의 염을 제조하는 방법을 제공하는 것이다. Accordingly, it is an object of the present invention to filter the resulting compound of formula (3) after reacting a compound of formula (1) or a salt thereof with a compound of formula (2) or a salt thereof in the presence of a base and a surfactant in a solvent and To optionally form a pharmaceutically acceptable salt and / or hydrate thereof, to provide a method of preparing a compound of formula (3) or a salt thereof.
상기 식에서,Where
X 는 이탈기, 바람직하게는 할로겐이며,X is a leaving group, preferably halogen,
Q 는 C-H, C-F, C-Cl, C-OH, C-O-메틸 또는 N 이고,Q is C-H, C-F, C-Cl, C-OH, C-O-methyl or N,
R 은 수소, 메틸 또는 아미노이며,R is hydrogen, methyl or amino,
R1 은 사이클로프로필, 에틸 또는 하나이상의 불소원자로 치환된 페닐이고,R 1 is cyclopropyl, ethyl or phenyl substituted with one or more fluorine atoms,
R2 는 수소, C1-C4 의 직쇄 또는 측쇄 알킬, 아릴 또는 알릴이며,R 2 is hydrogen, C 1 -C 4 straight or branched alkyl, aryl or allyl,
R3 및 R4 는 각각 독립적으로 수소 또는 C1-C3 알킬이거나, 이들이 부착되어 있는 질소원자와 함께 환을 형성할 수 있다.R 3 and R 4 are each independently hydrogen or C 1 -C 3 alkyl, or together with the nitrogen atom to which they are attached may form a ring.
종래에는 화학식 (1)의 화합물을 용매인 물에 도입시키고 염기인 트리에틸아민을 적가하여 완전히 맑은 용액을 만든 후, 화학식 (2)의 화합물을 반응용액에 가하고 반응이 완료되면 여과를 수행하는 방법으로 화학식 (3)의 화합물을 제조하였다.Conventionally, a compound of formula (1) is introduced into water as a solvent, triethylamine as a base is added dropwise to make a completely clear solution, and then the compound of formula (2) is added to a reaction solution and filtration is performed when the reaction is completed. To prepare a compound of formula (3).
그러나, 본 발명에서는 하기 반응식 (1)에 도시한 바와 같이 화학식 (3)의 화합물을 제조하였다. However, in the present invention, the compound of formula (3) was prepared as shown in the following scheme (1).
본 발명에 따른 방법을 사용하면 기존의 방법에 비해 여과시간이 5 내지 20 배, 바람직하게는 15 내지 20 배 단축된다. 또한, 반응온도를 상승시켜 반응시간을 8 내지 10시간에서 2 내지 3시간으로 단축시켰으므로 경제적인 측면에서 매우 중요한 회전시간(Cycle Time)을 획기적으로 단축시킬 수 있었다.Using the method according to the invention reduces the filtration time 5 to 20 times, preferably 15 to 20 times, compared to the existing methods. In addition, the reaction time was shortened by increasing the reaction temperature from 8 to 10 hours to 2 to 3 hours, thereby significantly reducing the cycle time, which is very important in terms of economics.
화학식 (3)의 화합물의 약제학적으로 허용되는 염은 퀴놀론계 또는 피롤리딘계 화합물의 기술분야에서 일반적으로 공지되어 사용되고 있는 산들과의 염을 포함한다. 특히 메탄설폰산염을 언급할 수 있으며, 메탄설포네이트 및 그의 수화물은 대한민국 특허출원 제98-80504호에 기재된 바에 따라 유리 염기로부터 합성할 수 있다. Pharmaceutically acceptable salts of compounds of formula (3) include salts with acids that are generally known and used in the art of quinolone-based or pyrrolidine-based compounds. Mention may be made in particular of methanesulfonates, and methanesulfonates and their hydrates may be synthesized from free bases as described in Korean Patent Application No. 98-80504.
본 발명에 따른 방법에서 사용되는 화학식 (1) 및 (2)의 화합물의 염으로는 당업자에게 공지된 염을 사용한다. 화학식 (2)의 화합물의 염으로는 PCT/KR99/ 00099에 기재된 염산염, 트리플루오로아세트산염 및 황산염을 언급할 수 있고, PCT/GB00/03358에 기재된 메탄설폰산염을 특히 언급할 수 있다. As salts of the compounds of the formulas (1) and (2) used in the process according to the invention, salts known to those skilled in the art are used. As salts of the compounds of the formula (2), mention may be made of the hydrochlorides, trifluoroacetates and sulfates described in PCT / KR99 / 00099, and the methanesulfonic acid salts described in PCT / GB00 / 03358.
본 발명에 따른 방법에서 사용되는 계면활성제, 염기, 용매 등은 반응에 악영향을 미치지 않는 범위내에서 적절하게 선택될 수 있다. 계면활성제, 염기 및 용매의 양 및 종류 그리고 반응온도, 반응순서 등을 포함한 바람직한 반응조건은 다음과 같다.Surfactants, bases, solvents and the like used in the process according to the invention may be appropriately selected within a range not adversely affecting the reaction. Preferred reaction conditions including amounts and types of surfactants, bases and solvents, reaction temperatures and reaction sequences are as follows.
본 발명에서 사용하기에 바람직한 계면활성제로는 셀룰로스 에테르 (Cellulose Ether) 계통의 메톨로즈, 즉, 메틸셀룰로스 또는 하이드록시프로필 메틸셀룰로스, 구체적으로는 메틸셀룰로스, SM-25 (Shinetsu) 또는 하이드록시프로필 메틸셀룰로스 2910, 60SH-50 (Shinetsu)를 들 수 있다. 일반적으로 계면활성제의 양은 출발물질인 화학식 (1)의 화합물에 대해 0.5 내지 3.0 중량%로 사용되며, 이 범위를 벗어나는 경우에는 여과성이 좋지 않은 단점이 있다.Preferred surfactants for use in the present invention are metholose of the Cellulose Ether line, ie methylcellulose or hydroxypropyl methylcellulose, specifically methylcellulose, SM-25 (Shinetsu) or hydroxypropyl methyl. Cellulose 2910, 60SH-50 (Shinetsu). In general, the amount of the surfactant is used in an amount of 0.5 to 3.0% by weight based on the compound of the formula (1) as a starting material.
염기로는 트리에틸아민, 피리딘 등의 유기 염기, 바람직하게는 트리에틸아민을 바람직하게는 화학식 (1)의 화합물을 기준으로 하여 2 내지 5 당량배의 양으로 사용한다. As the base, an organic base such as triethylamine or pyridine, preferably triethylamine, is preferably used in an amount of 2 to 5 equivalents based on the compound of the formula (1).
용매로는 아세토니트릴, 물, 알콜류, 디메틸포름아미드 및 디메틸설폭사이드 중에서 선택된 1 종 이상의 용매를 바람직하게 사용하나, 생성물의 순도를 고려하여 특히 바람직하게는 물을 사용한다. As the solvent, one or more solvents selected from acetonitrile, water, alcohols, dimethylformamide and dimethyl sulfoxide is preferably used, but water is particularly preferably used in consideration of the purity of the product.
반응온도는 0℃ 내지 40℃ 가 바람직하며, 반응온도에 따라 적절한 계면활성제를 선택함으로써 좋은 결과를 얻을 수 있다. 예를 들어, 상온반응의 경우 메틸셀룰로스, SM-25를 사용하여 가장 좋은 결과를 얻을 수 있었으며 (대략 10배의 여과시간 단축), 40℃ 반응의 경우 하이드록시프로필 메틸셀룰로스 2910, 60SH-50을 사용하여 가장 좋은 결과를 얻을 수 있었다 (약 15 내지 20배의 여과시간 단축).The reaction temperature is preferably 0 ° C to 40 ° C, and good results can be obtained by selecting an appropriate surfactant according to the reaction temperature. For example, in the case of room temperature reaction, the best results were obtained by using methyl cellulose and SM-25 (approximately 10 times less filtration time), and in the case of 40 ° C, hydroxypropyl methylcellulose 2910 and 60SH-50 Best results were obtained (shortening about 15-20 times of filtration time).
상기와 같은 조건하에 본 발명에 따른 방법은 다음과 같은 실시태양중의 하나에 따라 수행될 수 있다.Under the above conditions, the method according to the present invention can be carried out according to one of the following embodiments.
a) 화학식 (1)의 화합물 또는 그의 염을 용매중에 도입하고, 염기를 첨가(완전히 맑은 용액을 만들기 위함)한 다음, 계면활성제를 첨가하고, 경우에 따라 반응온도를 높이며, 화학식 (2)의 화합물 또는 그의 염을 가하여 반응이 완료되면 여과를 수행한다.a) a compound of formula (1) or a salt thereof is introduced into a solvent, a base is added (to make a completely clear solution), then a surfactant is added, optionally a reaction temperature is raised, and Filtration is carried out when the reaction is complete by adding the compound or a salt thereof.
b) 화학식 (1)의 화합물 또는 그의 염과 계면활성제를 함께 용매에 가하고, 염기를 가하고(바람직하게는 적가, 경우에 따라 염기를 대략 2시간에 걸쳐 천천히 첨가), 경우에 따라 반응온도를 높이며, 화학식 (2)의 화합물 또는 그의 염을 가하여 반응이 완료되면 필요에 따라 상온에서 2 내지 3시간 정도 반응용액을 숙성시켜 여과를 수행한다.b) adding a compound of formula (1) or a salt thereof and a surfactant together to a solvent, adding a base (preferably dropwise, optionally adding the base slowly over approximately 2 hours), optionally increasing the reaction temperature When the reaction is completed by adding the compound of Formula (2) or a salt thereof, filtration is performed by aging the reaction solution at room temperature for 2 to 3 hours as needed.
본 명세서에서 언급된 특허 및 특허출원을 포함한 모든 간행물들은 이들 각각의 간행물이 참고문헌으로서 구체적이고 개별적으로 표시되며 내용이 충분히 설명된 것으로 간주된다. All publications, including patents and patent applications mentioned herein, are deemed to be specific and individually indicated by reference to each of these publications and the content is fully described.
이하, 본 발명을 하기 실시예에 의거하여 보다 구체적으로 설명한다. 그러나 이들 실시예는 본 발명을 설명하기 위한 것일 뿐, 어떤 의미로도 본 발명의 범위를 한정하는 것은 아니다. Hereinafter, the present invention will be described in more detail based on the following examples. However, these examples are only for illustrating the present invention, and do not limit the scope of the present invention in any sense.
비교예 1: 종래 방법에 따른 예Comparative Example 1: Example according to the conventional method
(R,S)-7-(3-아미노메틸-4-syn-메톡시이미노-피롤리딘-1-일)-1-사이클로프로필-6-플루오로-4-옥소-1,4-디하이드로-1,8-나프티리딘-3-카르복실산의 제조(R, S) -7- (3-Aminomethyl-4-syn-methoxyimino-pyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-di Preparation of Hydro-1,8-naphthyridine-3-carboxylic Acid
500㎖ 반응기에 하기 화학식 (1a)의 화합물(30.0g, 106.14mmol):In a 500 ml reactor (30.0 g, 106.14 mmol) of the formula (1a):
및 물(300㎖, 10㎖/g)을 넣고 상온(24∼26℃)에서 교반하였다. 트리에틸아민 3.4당량(36.51g, 360.81mmol)을 상온에서 넣고(이때 온도가 ∼30℃ 까지 올라감), 10분 동안 교반하여 맑은 용액을 만든 후, 온도를 16∼20℃로 낮추었다. 하기 화학식 (2a)의 화합물(37.46g, 111.68mmol):And water (300ml, 10ml / g) was added and stirred at room temperature (24 ~ 26 ℃). 3.4 equivalents (36.51 g, 360.81 mmol) of triethylamine were added at room temperature (the temperature was raised to ˜30 ° C.), stirred for 10 minutes to form a clear solution, and the temperature was lowered to 16 to 20 ° C. Compound (37.46 g, 111.68 mmol) of the formula (2a)
을 16∼20℃에서 넣은 후 상온에서 교반하였다. 교반 후 15.5시간이 지난 후 반응이 완결되었다 (HPLC 분석 결과 화학식 (1a)의 화합물이 2%이하로 나타나 반응이 완결되었다고 간주함). 반응이 완결된 혼합물을 글래스필터를 사용하여 여과하고, 물(150㎖) 및 에탄올(150㎖)로 차례로 세척한 후 질소가스로 건조시켜 표제화합물을 고체로 37.32g(잔류용매 10.7%, 수율 81%) 수득하였다. 이때 여과시간은 처음 여과는 52 분, 두 번째 여과는 43 분, 세번째 여과는 42 분이 걸렸다. It was put at 16-20 ℃ and stirred at room temperature. The reaction was complete after 15.5 hours after stirring (HPLC analysis indicated that the compound of formula (1a) was less than 2% and the reaction was considered complete). The reaction mixture was filtered using a glass filter, washed successively with water (150 mL) and ethanol (150 mL), and dried over nitrogen gas to give 37.32 g of the title compound as a solid (10.7% residual solvent, yield 81). %) Was obtained. The filtration time took 52 minutes for the first filtration, 43 minutes for the second, and 42 minutes for the third.
실시예 1: 상온반응에서 계면활성제를 염기보다 나중에 넣은 예Example 1 Example of Adding Surfactant After Base in Room Temperature Reaction
(R,S)-7-(3-아미노메틸-4-syn-메톡시이미노-피롤리딘-1-일)-1-사이클로프로필-6-플루오로-4-옥소-1,4-디하이드로-1,8-나프티리딘-3-카르복실산의 제조(R, S) -7- (3-Aminomethyl-4-syn-methoxyimino-pyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-di Preparation of Hydro-1,8-naphthyridine-3-carboxylic Acid
500㎖ 반응기에 비교예 1에서 사용한 화학식 (1a)의 화합물(30.0g, 106.14mmol)과 물(300㎖, 10㎖/g)을 넣고 상온(24∼26℃)에서 교반하였다. 트리에틸아민 3.4당량(36.51g, 360.81mmol)을 상온에서 넣고(이때 온도가 ∼30℃ 까지 올라감), 10분 동안 교반하여 맑은 용액을 만든 후, 계면활성제인 메틸셀룰로스, SM-25 300mg(1.0중량%/화학식 (1a)의 화합물)을 넣고 10분 동안 교반하였다. 비교예 1에서 사용한 화학식 (2a)의 화합물(37.46g, 111.68mmol)을 상온에서 넣은 후 교반하였다. 교반 후 16.5시간이 지난 후 반응이 완결되었다 (HPLC 분석 결과 화학식 (1a)의 화합물이 2% 이하로 나타나 반응이 완결되었다고 간주함). 반응이 완결된 혼합물을 글래스필터를 사용하여 여과하고, 물(150㎖) 및 에탄올(150㎖)로 차례로 세척한 후 질소가스로 건조시켜 표제화합물을 고체로 34.31g(잔류용매 6.5%, 수율 78%) 수득하였다. 이때 여과시간은 처음 여과가 5 분, 두 번째 여과 5 분, 세번째 여과가 5 분 걸림으로써 총 여과시간이 비교예 1에 비해 9배 가량 빨라졌다. Compound (30.0 g, 106.14 mmol) and water (300 mL, 10 mL / g) used in Comparative Example 1 were added to a 500 mL reactor and stirred at room temperature (24 to 26 ° C.). 3.4 equivalents (36.51 g, 360.81 mmol) of triethylamine were added at room temperature (the temperature was raised to ˜30 ° C.) and stirred for 10 minutes to form a clear solution, followed by surfactant 300 mg (1.0 mg) of methylcellulose, SM-25. Wt% / compound of formula (1a)) was added and stirred for 10 minutes. Compound (37.46 g, 111.68 mmol) of the formula (2a) used in Comparative Example 1 was added at room temperature, followed by stirring. The reaction was complete after 16.5 hours after stirring (HPLC analysis indicated that the compound of formula (1a) was less than 2% and the reaction was considered complete). The reaction mixture was filtered using a glass filter, washed successively with water (150 mL) and ethanol (150 mL), and dried over nitrogen gas to give 34.31 g of the title compound as a solid (6.5% residual solvent, yield 78). %) Was obtained. In this case, the filtration time was 5 minutes for the first filtration, 5 minutes for the second filtration, and 5 minutes for the third filtration, so that the total filtration time was about 9 times faster than in Comparative Example 1.
실시예 2: 상온반응에서 계면활성제를 염기보다 먼저 넣은 예Example 2: Example of adding surfactant before base in room temperature reaction
(R,S)-7-(3-아미노메틸-4-syn-메톡시이미노-피롤리딘-1-일)-1-사이클로프로필-6-플루오로-4-옥소-1,4-디하이드로-1,8-나프티리딘-3-카르복실산의 제조(R, S) -7- (3-Aminomethyl-4-syn-methoxyimino-pyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-di Preparation of Hydro-1,8-naphthyridine-3-carboxylic Acid
500㎖ 반응기에 비교예 1에서 사용한 화학식 (1a)의 화합물(30.0g, 106.14mmol)과 계면활성제인 하이드록시프로필 메틸셀룰로스 2910, 60SH-50 300mg (1.0중량%/ 화학식 (1a)의 화합물), 물 (300㎖, 10㎖/g)을 넣고 상온 (24∼26℃)에서 교반하였다. 트리에틸아민 3.4당량(36.51g, 360.81mmol)을 상온에서 넣어(이때 온도가 ∼30℃ 까지 올라감), 10분 동안 교반하여 맑은 용액을 만들었다. 비교예 1에서 사용한 화학식 (2a)의 화합물(37.46g, 111.68mmol)을 상온에서 가하고 교반하였다. 이후, 반응시간이 15시간인 것을 제외하고는 실시예 1과 동일한 방법으로 실험을 수행하여 표제화합물을 고체로 32.25g(잔류용매 7.49%, 수율 72%) 수득하였다. 이때 여과시간은 처음 여과가 6 분, 두 번째 여과 5 분, 세번째 여과가 6분 걸림으로써 총 여과시간이 비교예 1에 비해 8배 가량 빨라지는 결과를 얻었다. Compound (1a) (30.0 g, 106.14 mmol) used in Comparative Example 1 in a 500 ml reactor and hydroxypropyl methylcellulose 2910, 60SH-50 300 mg (1.0% by weight / compound of formula (1a)) as surfactants, Water (300 mL, 10 mL / g) was added thereto and stirred at room temperature (24-26 ° C.). 3.4 equivalents (36.51 g, 360.81 mmol) of triethylamine were added at room temperature (the temperature was raised to ˜30 ° C.) and stirred for 10 minutes to form a clear solution. The compound of formula (2a) (37.46 g, 111.68 mmol) used in Comparative Example 1 was added at room temperature and stirred. Thereafter, the reaction was carried out in the same manner as in Example 1, except that the reaction time was 15 hours, to obtain 32.25 g of the title compound as a solid (7.49% residual solvent, 72% yield). In this case, the filtration time of the first filtration was 6 minutes, the second filtration 5 minutes, the third filtration took 6 minutes, the total filtration time was 8 times faster than Comparative Example 1.
실시예 3: 40℃ 반응에서 계면활성제를 염기보다 먼저 넣은 예Example 3: Example of adding surfactant before base in 40 ° C reaction
(R,S)-7-(3-아미노메틸-4-syn-메톡시이미노-피롤리딘-1-일)-1-사이클로프로필-6-플루오로-4-옥소-1,4-디하이드로-1,8-나프티리딘-3-카르복실산의 제조(R, S) -7- (3-Aminomethyl-4-syn-methoxyimino-pyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-di Preparation of Hydro-1,8-naphthyridine-3-carboxylic Acid
500㎖ 반응기에 비교예 1에서 사용한 화학식 (1a)의 화합물(30.0g, 106.14 mmol)과 계면활성제인 하이드록시프로필 메틸셀룰로스 2910, 60SH-50 300mg(1.0중량%/화학식 (1a)의 화합물), 물 (300㎖, 10㎖/g)을 넣고 상온 (24∼26℃)에서 교반하였다. 트리에틸아민 3.4당량(36.51g, 360.81mmol)을 상온에서 넣고(이때 온도가 ∼30℃ 까지 올라감), 10분 동안 교반하여 맑은 용액을 만들어 주었다. 이 반응 용액을 40℃로 가열한 후 비교예 1에서 사용한 화학식 (2a)의 화합물(37.46g, 111.68mmol)을 40℃에서 가하고 교반하여 3.5시간동안 반응시켰다. 이 반응액을 40분에 걸쳐 상온으로 온도를 내린 다음 실시예 1과 동일한 방법으로 여과, 세척 및 건조시켜 표제화합물을 고체로 34.16g(잔류용매 7.4%, 수율 77%) 수득하였다. 이때 여과시간은 처음 여과가 3 분, 두 번째 여과 2 분, 세번째 여과가 3분 걸림으로써 총 여과시간이 비교예 1에 비해 17배 가량 빨라지는 결과를 얻었다. Compound (1a) (30.0 g, 106.14 mmol) used in Comparative Example 1 in a 500 ml reactor and hydroxypropyl methylcellulose 2910, 60SH-50 300 mg (1.0 wt% / compound (1a)), which is a surfactant, Water (300 mL, 10 mL / g) was added thereto and stirred at room temperature (24-26 ° C.). 3.4 equivalents (36.51 g, 360.81 mmol) of triethylamine were added at room temperature (the temperature was raised to ˜30 ° C.) and stirred for 10 minutes to form a clear solution. The reaction solution was heated to 40 ° C., and then the compound of formula (2a) used in Comparative Example 1 (37.46 g, 111.68 mmol) was added at 40 ° C. and stirred for reaction for 3.5 hours. The reaction solution was cooled to room temperature over 40 minutes, and then filtered, washed and dried in the same manner as in Example 1 to obtain 34.16 g of the title compound as a solid (7.4% residual solvent, 77% yield). In this case, the filtration time was 3 minutes for the first filtration, 2 minutes for the second filtration, and 3 minutes for the third filtration. Thus, the total filtration time was 17 times faster than that of Comparative Example 1.
실시예 4: 40℃ 반응에서 염기를 가능한 한 천천히 넣은 예Example 4 Example of adding base as slowly as possible in 40 ° C reaction
(R,S)-7-(3-아미노메틸-4-syn-메톡시이미노-피롤리딘-1-일)-1-사이클로프로필-6-플루오로-4-옥소-1,4-디하이드로-1,8-나프티리딘-3-카르복실산의 제조(R, S) -7- (3-Aminomethyl-4-syn-methoxyimino-pyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-di Preparation of Hydro-1,8-naphthyridine-3-carboxylic Acid
실시예 3과 동일한 방법으로 실험을 수행하되 염기인 트리에틸아민을 2시간에 걸쳐 천천히 가하고 2.5시간 반응시켜 표제화합물을 고체로 34.52g(잔류용매 6.4%, 수율 78%) 수득하였다. 이때 여과시간은 처음 여과가 3 분, 두 번째 여과 3 분, 세번째 여과가 3분 걸림으로써 총 여과시간이 비교예 1에 비해 15배 가량 빨라지는 결과를 얻었다. The experiment was carried out in the same manner as in Example 3 except that the base triethylamine was slowly added over 2 hours and reacted for 2.5 hours to obtain 34.52 g (6.4% residual solvent, 78%) of the title compound as a solid. In this case, the filtration time was 3 minutes for the first filtration, 3 minutes for the second filtration, and 3 minutes for the third filtration. Thus, the total filtration time was 15 times faster than that of Comparative Example 1.
실시예 5: 40℃ 반응에서 계면활성제를 염기보다 먼저 넣고 상온에서 반응완료후 반응용액을 2∼3시간 숙성시킨 예 Example 5 Example in which a surfactant was added before a base in a 40 ° C. reaction and the reaction solution was aged at room temperature for 2 to 3 hours
(R,S)-7-(3-아미노메틸-4-syn-메톡시이미노-피롤리딘-1-일)-1-사이클로프로필-6-플루오로-4-옥소-1,4-디하이드로-1,8-나프티리딘-3-카르복실산의 제조(R, S) -7- (3-Aminomethyl-4-syn-methoxyimino-pyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-di Preparation of Hydro-1,8-naphthyridine-3-carboxylic Acid
실시예 3과 동일한 방법으로 실험을 수행하되 2.5시간 반응시키고 반응이 끝난 용액을 상온에서 2∼3시간 숙성시켜 표제화합물을 고체로 33.23g(잔류용매 6.5%, 수율 75%) 수득하였다. 이때 여과시간은 처음 여과가 3 분, 두 번째 여과 2 분, 세번째 여과가 2분 걸림으로써 총 여과시간이 비교예 1에 비해 20배 가량 빨라지는 결과를 얻었다. The experiment was carried out in the same manner as in Example 3, but the reaction was carried out for 2.5 hours and the finished solution was aged at room temperature for 2 to 3 hours to obtain 33.23 g of the title compound as a solid (6.5% residual solvent, 75% yield). At this time, the filtration time was 3 minutes for the first filtration, 2 minutes for the second filtration, and 2 minutes for the third filtration, so that the total filtration time was about 20 times faster than Comparative Example 1.
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| GB9920917D0 (en) | 1999-09-03 | 1999-11-10 | Sb Pharmco Inc | Novel process |
| GB9920919D0 (en) | 1999-09-03 | 1999-11-10 | Sb Pharmco Inc | Novel compound |
| KR100517638B1 (en) | 2002-04-08 | 2005-09-28 | 주식회사 엘지생명과학 | New process for preparing acid salts of Gemifloxacin |
| KR100653334B1 (en) | 2003-03-07 | 2006-12-04 | 주식회사 엘지생명과학 | New process for preparing 4-aminomethyl-3-alkoxyiminopyrrolidine methanesulphonate |
| JP6800834B2 (en) * | 2016-12-20 | 2020-12-16 | アース製薬株式会社 | Methods for increasing plant chlorophyll, methods for inhibiting pest colonization, and compositions applicable to these methods. |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0688772B1 (en) * | 1994-06-16 | 1999-05-06 | LG Chemical Limited | Quinoline carboxylic acid derivatives having 7-(4-amino-methyl-3-oxime) pyrrolidine substituents and processes for their preparation |
| MA24500A1 (en) * | 1997-03-21 | 1998-10-01 | Lg Life Sciences Ltd | CARBOXYLIC ACID SALT DERIVATIVE FROM NAPHTHYRIDINE. |
| KR100222081B1 (en) * | 1997-07-16 | 1999-10-01 | 성재갑 | Quinoline carboxylic acid derivatives having a substituent of 7-[3-aminomethyl-4-(z)-substituted oxime] pyrrolidine |
| GB9820405D0 (en) * | 1998-09-18 | 1998-11-11 | Smithkline Beecham Plc | Process |
-
2000
- 2000-03-15 KR KR1020000013011A patent/KR20010091379A/en active Search and Examination
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2001
- 2001-03-14 KR KR10-2002-7011999A patent/KR100498004B1/en not_active IP Right Cessation
- 2001-03-14 WO PCT/KR2001/000399 patent/WO2001068649A1/en active IP Right Grant
- 2001-03-14 AU AU41249/01A patent/AU4124901A/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| KR20010091379A (en) | 2001-10-23 |
| KR20030017475A (en) | 2003-03-03 |
| AU4124901A (en) | 2001-09-24 |
| WO2001068649A1 (en) | 2001-09-20 |
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