KR20010091379A - Novel process for the preparation of quinoline carboxylic acid derivatives having 7-(4-aminomethyl-3-oxime)pyrrolidine substituent - Google Patents

Novel process for the preparation of quinoline carboxylic acid derivatives having 7-(4-aminomethyl-3-oxime)pyrrolidine substituent Download PDF

Info

Publication number
KR20010091379A
KR20010091379A KR1020000013011A KR20000013011A KR20010091379A KR 20010091379 A KR20010091379 A KR 20010091379A KR 1020000013011 A KR1020000013011 A KR 1020000013011A KR 20000013011 A KR20000013011 A KR 20000013011A KR 20010091379 A KR20010091379 A KR 20010091379A
Authority
KR
South Korea
Prior art keywords
formula
compound
salt
surfactant
filtration
Prior art date
Application number
KR1020000013011A
Other languages
Korean (ko)
Inventor
김봉찬
김영대
최훈
김원섭
Original Assignee
성재갑
주식회사 엘지씨아이
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 성재갑, 주식회사 엘지씨아이 filed Critical 성재갑
Priority to KR1020000013011A priority Critical patent/KR20010091379A/en
Priority to KR10-2002-7011999A priority patent/KR100498004B1/en
Priority to PCT/KR2001/000399 priority patent/WO2001068649A1/en
Priority to AU41249/01A priority patent/AU4124901A/en
Publication of KR20010091379A publication Critical patent/KR20010091379A/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

PURPOSE: Provided is a quinolincarboxylic acid derivative having 7-(4-aminomethyl-3-oxim)pyrrolidine substituent of the formula(3) or its salts by coupling a compound of the formula(1) or its salt, or a compound of the formula(2) or its salts. Wherein, 7-(4-aminomethyl-3-oxim)pyrrolidine substituent of the formula(3) is an intermediate of Gemifloxacin, quinoline antibiotics. CONSTITUTION: The manufacturing method is characterized by reacting a compound of the formula(1) or its salts with a compound of the formula(2) or its salts in a solvent, in the presence of base and surfactant then followed by filtering. In the formulae, Q is C-H, C-F, C-Cl, C-OH, C-O-methyl or N; R is hydrogen, methyl or amino; R1 is cyclopropyl, ethyl or phenyl substituted with at least one fluorine atom; R2 is hydrogen, C1-C4 of linear or branched alkyl, aryl or alryl; and R3 and R4 are independently hydrogen or C1-C3 alkyl, or form a ring with a nitrogen atom attached thereto.

Description

7-(4-아미노메틸-3-옥심)피롤리딘 치환체를 갖는 퀴놀린 카르복실산 유도체의 신규 제조방법{Novel process for the preparation of quinoline carboxylic acid derivatives having 7-(4-aminomethyl-3-oxime)pyrrolidine substituent}New process for the preparation of quinoline carboxylic acid derivatives having 7- (4-aminomethyl-3-oxime) with 7- (4-aminomethyl-3-oxime) pyrrolidine substituent pyrrolidine substituent}

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

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,

R1은 사이클로프로필, 에틸 또는 하나이상의 불소원자로 치환된 페닐이고,R 1 is cyclopropyl, ethyl or phenyl substituted with one or more fluorine atoms,

R2는 수소, C1-C4의 직쇄 또는 측쇄 알킬, 아릴 또는 알릴이며,R 2 is hydrogen, C 1 -C 4 straight or branched alkyl, aryl or allyl,

R3및 R4는 각각 독립적으로 수소 또는 C1-C3알킬이거나, 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.

상기 화학식 (3)의 화합물은 새로운 퀴놀론 항생제로 개발되고 있는 원료의약물질(국내출원번호: 98-80504)의 핵심 중간체(국내출원번호: 96-874)로서 제품의 품질에 직접적인 영향을 미친다. 이에 지금까지는 상기 화학식 (3)의 화합물의 합성과정에서 반응용매로 사용한 아세토니트릴/물 혼합용매 대신에 물만을 사용함으로써 상기 화학식 (3)의 화합물의 품질을 상당히 개선시키고자 하였다. 그러나 반응용매를 바꿈으로써 상기 화학식 (3)의 화합물을 여과하는 시간이 매우 길어지게 되어 상업생산에 있어 제품의 안정성이나 생산 회전시간(Cycle Time)이 길어지는 등의 많은 문제점이 있었다.The compound of formula (3) is a key intermediate (domestic application number: 96-874) of a raw drug substance (domestic application number 98-80504), which is being developed as a new quinolone antibiotic, directly affects the quality of the product. Thus, until now, only water was used instead of the acetonitrile / water mixed solvent used as the reaction solvent in the synthesis of the compound of formula (3) to considerably improve the quality of the compound of formula (3). However, by changing the reaction solvent, the time for filtering the compound of formula (3) is very long, there are many problems such as the stability of the product in the commercial production or the production cycle time (Cycle Time).

본 발명자들은 상기와 같은 문제점을 해결하기 위하여 연구하던중, 지금까지 시도된 바가 없는 계면활성제를 사용함으로써 여과시간을 획기적으로 단축시킬 수 있음을 밝혀내고 본 발명을 완성하게 되었다.The inventors of the present invention have been completed to solve the above problems, and found that by using a surfactant that has not been tried so far, the filtration time can be significantly shortened and the present invention has been completed.

본 발명의 목적은 하기 화학식 (1)의 화합물 또는 그의 염 및 화학식 (2)의 화합물 또는 그의 염으로부터 하기 화학식 (3)의 화합물 또는 그의 염을 제조하는 방법에 있어서 계면활성제를 사용함으로써 기존의 방법보다 반응시간을 단축하고 여과시간을 획기적으로 단축하는 새로운 방법을 제공하는 것이다:An object of the present invention is to provide a method for preparing a compound of formula (3) or a salt thereof from a compound of formula (1) or a salt thereof and a compound of formula (2) or a salt thereof. It provides a new way to shorten the reaction time and significantly reduce the filtration time:

[화학식 1][Formula 1]

[화학식 2][Formula 2]

[화학식 3][Formula 3]

상기 식에서,Where

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,

R1은 사이클로프로필, 에틸 또는 하나이상의 불소원자로 치환된 페닐이고,R 1 is cyclopropyl, ethyl or phenyl substituted with one or more fluorine atoms,

R2는 수소, C1-C4의 직쇄 또는 측쇄 알킬, 아릴 또는 알릴이며,R 2 is hydrogen, C 1 -C 4 straight or branched alkyl, aryl or allyl,

R3및 R4는 각각 독립적으로 수소 또는 C1-C3알킬이거나, 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.

이하, 본 발명을 상세히 설명하면 다음과 같다.Hereinafter, the present invention will be described in detail.

종래 방법은 화학식 (1)의 화합물을 용매인 물에 도입시키고 염기인 트리에틸아민을 적가하여 완전히 맑은 용액을 만든 후, 화학식 (2)의 화합물을 반응용액에 넣은 후 반응이 완료되면 여과를 수행하였다.In the conventional method, a compound of formula (1) is introduced into water as a solvent, triethylamine as a base is added dropwise to form a completely clear solution, and then the compound of formula (2) is added to a reaction solution and then filtered when the reaction is completed. It was.

본 발명에서는 하기 반응식 (1)과 같이, 계면활성제를 사용함으로써 여과시간을 종래방법에 비해 5 내지 20 배, 바람직하게는 15 내지 20 배 단축시키고, 또한 반응온도를 상승시켜 반응시간을 8 내지 10시간에서 2 내지 3시간으로 단축시킴으로써 상업생산에 경제적으로 매우 중요한 회전시간(Cycle Time)을 획기적으로 단축할 수 있는 방법을 제공한다. 본 발명에서 바람직한 계면활성제는 메톨로즈(하이드록시프로필 메틸셀룰로스 또는 메틸셀룰로스; USP)이다.In the present invention, as shown in the following reaction formula (1), by using the surfactant, the filtration time is shortened by 5 to 20 times, preferably 15 to 20 times, compared with the conventional method, and the reaction temperature is increased to increase the reaction time by 8 to 10 times. By shortening the time from 2 to 3 hours, it provides a way to drastically shorten the cycle time which is economically important for commercial production. Preferred surfactants in the present invention are metolose (hydroxypropyl methylcellulose or methylcellulose; USP).

본 반응에서의 계면활성제의 양 및 종류 그리고 반응온도, 반응순서 등을 포함한 반응조건은 다음과 같다.The reaction conditions, including the amount and type of surfactant in the reaction and the reaction temperature, reaction sequence, are as follows.

일반적으로 계면활성제의 양은 출발물질인 화학식 (1)의 화합물에 대해 0.5 내지 3.0 중량%로 사용될 수 있다. 계면활성제의 사용량이 상기 범위를 벗어나는 경우에는 여과성이 좋지 않은 단점이 있다.Generally, the amount of surfactant can be used at 0.5 to 3.0% by weight relative to the compound of formula (1) as starting material. When the amount of the surfactant is out of the above range, there is a disadvantage in that the filterability is not good.

또한, 계면활성제는 셀룰로스 에테르(Cellulose Ether) 계통의 계면활성제인 메톨로즈를 사용함으로써 가장 좋은 결과를 얻을 수 있다. 특히, 상온반응의 경우 메톨로즈중의 하나인 메틸셀룰로스, SM-25 를 사용할 때 가장 좋은 결과를 얻었으며(대략 10배의 여과시간 단축), 40℃ 반응의 경우 메틸로즈중의 하나인 하이드록시프로필 메틸셀룰로스 2910, 60SH-50 을 사용했을 때 가장 좋은 결과를 얻을 수 있었다(15 내지 20배의 여과시간 단축).In addition, the surfactant can be obtained the best results by using the Metolose, a surfactant of the cellulose ether (Cellulose Ether) system. In particular, the room temperature reaction showed the best results when using methylcellulose, SM-25, which is one of metolose (approximately 10 times less filtration time), and hydroxy, which is one of methylose, at 40 ° C. The best results were obtained when propyl methylcellulose 2910, 60SH-50 was used (15-20 times less filtration time).

반응온도는 0℃ 내지 40℃ 가 가능하며, 반응온도에 따라 적절한 계면활성제를 선택하여 첨가한다. 예를 들어, 상기와 같이 상온반응의 경우에는 메틸셀룰로스, SM-25를 사용하고, 40℃ 반응의 경우에는 하이드록시프로필 메틸셀룰로스 2910, 60SH-50를 사용한다.The reaction temperature may be 0 ° C to 40 ° C, and an appropriate surfactant is selected and added according to the reaction temperature. For example, in the case of the room temperature reaction as described above, methyl cellulose, SM-25 is used, and in the case of the 40 ℃ reaction hydroxypropyl methyl cellulose 2910, 60SH-50 is used.

본 발명에 따른 방법은 다음과 같다.The method according to the invention is as follows.

첫째, 화학식 (1)의 화합물 또는 그의 염을 용매중에 도입하고 염기를 적가하여 완전히 맑은 용액을 만든다. 그후, 계면활성제를 첨가한 후, 경우에 따라 반응온도를 높이고, 화학식 (2)의 화합물 또는 그의 염을 넣어 반응이 완료되면 여과를 수행한다.First, a compound of formula (1) or a salt thereof is introduced into a solvent and a base is added dropwise to form a completely clear solution. Thereafter, after the addition of the surfactant, the reaction temperature is optionally increased, and the reaction is completed by adding the compound of formula (2) or a salt thereof and completing the reaction.

둘째, 화학식 (1)의 화합물 또는 그의 염과 계면활성제를 함께 용매에 넣은 후 염기를 넣고, 경우에 따라 반응온도를 높인다. 이때, 경우에 따라 염기는 대략 2 시간에 걸쳐 첨천히 첨가할 수 있다. 그후, 화학식 (2)의 화합물 또는 그의 염을 넣은 후, 필요에 따라 상온에서 2 내지 3시간 정도 반응용액을 숙성시킨다. 반응이 완료되면 여과를 수행한다.Second, the compound of formula (1) or a salt thereof and a surfactant are put together in a solvent, and then a base is added, and if necessary, the reaction temperature is increased. At this time, base may optionally be added over approximately 2 hours. Thereafter, the compound of formula (2) or a salt thereof is added thereto, and then the reaction solution is aged at room temperature for 2 to 3 hours as necessary. Filtration is carried out when the reaction is complete.

본 발명에 따른 방법에서 용매로는 물이 사용되며, 염기로는 트리에틸아민이 사용된다.In the process according to the invention water is used as solvent and triethylamine is used as base.

본 발명에 따른 화합물의 염은 퀴놀론계 화합물 기술분야에서 공지되어 사용되고 있는 기타 다른 산들과의 염, 바람직하게는 염산염, 트리플루오로아세트산염,황산염, 메탄설폰산염 등의 염을 포함하며, 그중에서 바람직한 염은 메탄설폰산염이다.Salts of the compounds according to the invention include salts with other acids known and used in the quinolone compound art, preferably salts such as hydrochloride, trifluoroacetic acid salts, sulfates, methanesulfonates, etc. Preferred salts are methanesulfonic acid salts.

이하 본 발명을 실시예에 의거하여 구체적으로 설명하지만 이들 실시예가 본 발명의 기술적 범위를 한정하는 것은 아니다.Hereinafter, the present invention will be described in detail with reference to Examples, but these Examples do not limit the technical scope of the present invention.

비교예 1: 종래 방법으로 제조한 예Comparative Example 1: Example prepared by conventional method

7-(4-아미노메틸-3-메톡시이미노피롤리딘-1-일)-1-사이클로프로필-6-플루오로-4-옥소-1,4-디하이드로[1,8]나프티리딘-3-카르복실산의 제조7- (4-aminomethyl-3-methoxyiminopyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro [1,8] naphthyridine- Preparation of 3-carboxylic Acid

500㎖ 반응기에 하기 화학식 (1a)In a 500 ml reactor, the formula (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 넣어(이때 온도가 ∼30℃ 까지 올라감), 10분 동안 교반하여 맑은용액을 만든 후, 온도를 16∼20℃로 낮추었다. 하기 화학식 (2a)Compound (30.0 g, 106.14 mmol) and water (300 mL, 10 mL / g) were added thereto, and the mixture was 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.), stirred for 10 minutes to form a clear solution, and the temperature was lowered to 16 to 20 ° C. Formula (2a)

의 화합물(37.46g, 111.68mmol)을 16∼20℃에서 넣은 후 상온에서 교반하였다. 교반 후 15.5시간이 지난 후 반응이 완결 되었다(HPLC 분석 결과 화학식 (1)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, 마지막 여과는 42 분이 걸렸다.Compound (37.46g, 111.68mmol) was added to 16-20 ℃ and stirred at room temperature. After 15.5 hours after stirring, the reaction was completed (HPLC analysis showed that the compound of formula (1) 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 last.

실시예 1: 상온반응에서 계면활성제를 염기보다 나중에 넣은 예Example 1 Example of Adding Surfactant After Base in Room Temperature Reaction

7-(4-아미노메틸-3-메톡시이미노피롤리딘-1-일)-1-사이클로프로필-6-플루오로-4-옥소-1,4-디하이드로[1,8]나프티리딘-3-카르복실산의 제조7- (4-aminomethyl-3-methoxyiminopyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro [1,8] naphthyridine- Preparation of 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 넣어(이때 온도가 ∼30℃ 까지 올라감), 10분 동안 교반하여 맑은용액을 만든 후, 계면활성제인 메틸셀룰로스 SM-25 300mg(1.0wt.%/화학식 1a)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 완결 되었다(HPLC 분석 결과 화학식 (1)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, 마지막 여과가 5 분 걸림으로써 비교예 1에 비해 9배 가량 빨라진다.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), stirred for 10 minutes to form a clear solution, and then 300 mg (1.0wt) of methylcellulose SM-25 as a surfactant. .% / 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. After 16.5 hours after stirring, the reaction was completed (HPLC analysis showed that the compound of formula (1) 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. At this time, the filtration time is about 9 times faster than Comparative Example 1 because the first filtration 5 minutes, the second filtration 5 minutes, the last filtration takes 5 minutes.

실시예 2: 상온반응에서 계면활성제를 염기보다 먼저 넣은 예Example 2: Example of adding surfactant before base in room temperature reaction

7-(4-아미노메틸-3-메톡시이미노피롤리딘-1-일)-1-사이클로프로필-6-플루오로-4-옥소-1,4-디하이드로[1,8]나프티리딘-3-카르복실산의 제조7- (4-aminomethyl-3-methoxyiminopyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro [1,8] naphthyridine- Preparation of 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%/ QN09), 물 (300㎖, 10㎖/g)을 넣고 상온 (24∼26℃)에서 교반하였다. 이후 실시예 1과 동일한 방법으로 실험을 수행하여 표제화합물을 고체로 32.25g(수율 83%) 수득하였다. 이때 여과시간은 처음 여과가 6 분, 두 번째 여과 5 분, 마지막 여과가 6분 걸림으로써 비교예 1에 비해 8배 가량 빨라지는 결과를 얻었다.In a 500 mL reactor, the compound of the formula (1a) used in Comparative Example 1 (30.0 g, 106.14 mmol) and hydroxypropyl methylcellulose 2910, 60SH-50 300 mg (1.0 wt% / QN09) as a surfactant, water (300 mL, 10 ml / g) was added and stirred at room temperature (24-26 ° C.). Thereafter, the experiment was carried out in the same manner as in Example 1, to obtain 32.25 g (yield 83%) of the title compound as a solid. In this case, the filtration time of the first filtration was 6 minutes, the second filtration 5 minutes, the last filtration took 6 minutes by 8 times faster than Comparative Example 1 was obtained.

실시예 3: 40℃ 반응에서 계면활성제를 염기보다 먼저 넣은 예Example 3: Example of adding surfactant before base in 40 ° C reaction

7-(4-아미노메틸-3-메톡시이미노피롤리딘-1-일)-1-사이클로프로필-6-플루오로-4-옥소-1,4-디하이드로[1,8]나프티리딘-3-카르복실산의 제조7- (4-aminomethyl-3-methoxyiminopyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro [1,8] naphthyridine- Preparation of 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), 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 맑은용액을 만들어 주었다. 이 반응 용액을 40℃로 가열한 후 비교예 1에서 사용한 화학식 (2a)의 화합물(37.46g, 111.68mmol)을 40℃에서 넣고 교반하였다. 이 반응용액을 40분동안 상온으로 온도를 내린 이후 실시예 1과 동일한 방법으로 실험을 수행하여 표제화합물을 고체로 34.16g(잔류용매 7.4%, 수율 72%) 수득하였다. 이때 여과시간은 처음 여과가 3 분, 두 번째 여과 2 분, 마지막 여과가 3분 걸림으로써 비교예 1에 비해 17배 가량 빨라지는 결과를 얻었다.In a 500 mL reactor, the compound of formula (1a) used in Comparative Example 1 (30.0 g, 106.14 mmol), and hydroxypropyl methylcellulose 2910, 60SH-50 300 mg (1.0 wt.% / Formula 1a), water as a surfactant (300 mL) , 10ml / g) was added 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. After heating this reaction solution to 40 degreeC, the compound (37.46g, 111.68 mmol) of General formula (2a) used by the comparative example 1 was put at 40 degreeC, and it stirred. After the reaction solution was cooled to room temperature for 40 minutes, the experiment was carried out in the same manner as in Example 1 to obtain 34.16 g of the title compound as a solid (7.4% residual solvent, 72% yield). At this time, the first filtration time was 3 minutes, the second filtration 2 minutes, and the last filtration took 3 minutes, which was 17 times faster than Comparative Example 1.

실시예 4: 40℃ 반응에서 염기인 트리에틸아민을 넣을 때 가능한 천천히 넣은 예Example 4 Example of adding as slowly as possible when adding triethylamine as a base in a 40 ° C reaction

7-(4-아미노메틸-3-메톡시이미노피롤리딘-1-일)-1-사이클로프로필-6-플루오로-4-옥소-1,4-디하이드로[1,8]나프티리딘-3-카르복실산의 제조7- (4-aminomethyl-3-methoxyiminopyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro [1,8] naphthyridine- Preparation of 3-carboxylic Acid

실시예 3과 동일한 방법으로 실험을 수행하되 염기인 트리에틸아민을 2시간 가량 천천히 적가하여 표제화합물을 고체로 34.52g(잔류용매 6.4%, 수율 78%) 수득하였다. 이때 여과시간은 처음 여과가 3 분, 두 번째 여과 3 분, 마지막 여과가 3분 걸림으로써 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 dropwise for about 2 hours to obtain 34.52 g of the title compound as a solid (6.4% residual solvent, 78% yield). In this case, the filtration time was about 15 times faster than Comparative Example 1 by taking 3 minutes of the first filtration, 3 minutes of the second filtration, and 3 minutes of the last filtration.

실시예 5: 40℃ 반응에서 계면활성제를 염기보다 먼저 넣고 상온에서 반응용액을 2∼3시간 숙성 시킨 예Example 5 Example in which the surfactant was added before the base in the reaction at 40 ° C. and the reaction solution was aged at room temperature for 2 to 3 hours

7-(4-아미노메틸-3-메톡시이미노피롤리딘-1-일)-1-사이클로프로필-6-플루오로-4-옥소-1,4-디하이드로[1,8]나프티리딘-3-카르복실산의 제조7- (4-aminomethyl-3-methoxyiminopyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro [1,8] naphthyridine- Preparation of 3-carboxylic Acid

실시예 3과 동일한 방법으로 실험을 수행하되 반응이 끝난 용액을 상온에서 2∼3시간 숙성시킨 후 표제화합물을 고체로 33.23g(잔류용매 6.5%, 수율 75%) 수득하였다. 이때 여과시간은 처음 여과가 3 분, 두 번째 여과 2 분, 마지막 여과가 2분 걸림으로써 비교예 1에 비해 20배 가량 빨라지는 결과를 얻었다.The experiment was carried out in the same manner as in Example 3, but the resultant 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). In this case, the filtration time of the first filtration was 3 minutes, the second filtration 2 minutes, the last filtration took 2 minutes, the result was about 20 times faster than Comparative Example 1.

Claims (10)

화학식 (1)의 화합물 또는 그의 염을 용매중에서 염기 및 계면활성제의 존재하에 화학식 (2)의 화합물 또는 그의 염과 반응시킨 후 여과함을 특징으로 하여 화학식 (3)의 화합물 또는 그의 염을 제조하는 방법:A compound of formula (3) or a salt thereof is characterized by 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, followed by filtration. Way: [화학식 1][Formula 1] [화학식 2][Formula 2] [화학식 3][Formula 3] 상기 식에서,Where 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, R1은 사이클로프로필, 에틸 또는 하나이상의 불소원자로 치환된 페닐이고,R 1 is cyclopropyl, ethyl or phenyl substituted with one or more fluorine atoms, R2는 수소, C1-C4의 직쇄 또는 측쇄 알킬, 아릴 또는 알릴이며,R 2 is hydrogen, C 1 -C 4 straight or branched alkyl, aryl or allyl, R3및 R4는 각각 독립적으로 수소 또는 C1-C3알킬이거나, 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. 제 1 항에 있어서, 화학식 (1)의 화합물 또는 그의 염을 용매중에 도입하고, 염기를 첨가한 후, 계면활성제를 첨가하여 화학식 (2)의 화합물 또는 그의 염과 반응시킨 후 여과함을 특징으로 하여 화학식 (3)의 화합물을 제조하는 방법.A compound of formula (1) or a salt thereof is introduced into a solvent, a base is added, and then a surfactant is added to react with a compound of formula (2) or a salt thereof, followed by filtration. To prepare a compound of formula (3). 제 1 항에 있어서, 화학식 (1)의 화합물 또는 그의 염 및 계면활성제를 함께 용매중에 도입하고, 염기를 첨가한 후, 화학식 (2)의 화합물 또는 그의 염을 도입하여 반응시킨 후 여과함을 특징으로 하여 화학식 (3)의 화합물 또는 그의 염을 제조하는 방법.A compound according to claim 1, wherein the compound of formula (1) or a salt thereof and a surfactant thereof are introduced together in a solvent, a base is added, and then the compound of formula (2) or a salt thereof is introduced to react, followed by filtration. To prepare a compound of formula (3) or a salt thereof. 제 1 항에 있어서, 계면활성제가 셀룰로스에테르인 방법.The method of claim 1 wherein the surfactant is cellulose ether. 제 4 항에 있어서, 셀룰로스에테르가 하이드록시프로필 메틸셀룰로스 또는 메틸셀룰로스인 방법.The method of claim 4 wherein the cellulose ether is hydroxypropyl methylcellulose or methylcellulose. 제 1 항에 있어서, 계면활성제가 화학식 (1)의 화합물에 대해 0.5 내지 3.0중량%의 양으로 사용되는 방법.The method of claim 1 wherein the surfactant is used in an amount of 0.5 to 3.0% by weight relative to the compound of formula (1). 제 1 항에 있어서, 반응온도가 0 내지 40℃인 방법.The method according to claim 1, wherein the reaction temperature is 0 to 40 ° C. 제 1 항에 있어서, 염기가 트리에틸아민이고, 용매가 물인 방법.The method of claim 1 wherein the base is triethylamine and the solvent is water. 제 3 항에 있어서, 염기를 천천히 첨가하는 방법.The method of claim 3 wherein the base is added slowly. 제 3 항에 있어서, 반응 온도를 40℃ 로 하고, 여과하기 전 온도를 상온으로 낮춰 2 내지 3시간동안 숙성시키는 방법.The method according to claim 3, wherein the reaction temperature is 40 DEG C, and the temperature is lowered to room temperature before filtration and aged for 2 to 3 hours.
KR1020000013011A 2000-03-15 2000-03-15 Novel process for the preparation of quinoline carboxylic acid derivatives having 7-(4-aminomethyl-3-oxime)pyrrolidine substituent KR20010091379A (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
KR1020000013011A KR20010091379A (en) 2000-03-15 2000-03-15 Novel process for the preparation of quinoline carboxylic acid derivatives having 7-(4-aminomethyl-3-oxime)pyrrolidine substituent
KR10-2002-7011999A KR100498004B1 (en) 2000-03-15 2001-03-14 Novel process for the preparation of a quinoline carboxylic acid derivative having a 7-(4-aminomethyl-3-oxime)pyrrolidine substituent
PCT/KR2001/000399 WO2001068649A1 (en) 2000-03-15 2001-03-14 Novel process for the preparation of a quinoline carboxylic acid derivative having a 7-(4-aminomethyl-3-oxime)pyrrolidine substituent
AU41249/01A AU4124901A (en) 2000-03-15 2001-03-14 Novel process for the preparation of a quinoline carboxylic acid derivative having 7-(4-aminomethyl-3-oxime)pyrrolidine substituent

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
KR1020000013011A KR20010091379A (en) 2000-03-15 2000-03-15 Novel process for the preparation of quinoline carboxylic acid derivatives having 7-(4-aminomethyl-3-oxime)pyrrolidine substituent

Publications (1)

Publication Number Publication Date
KR20010091379A true KR20010091379A (en) 2001-10-23

Family

ID=19655350

Family Applications (2)

Application Number Title Priority Date Filing Date
KR1020000013011A KR20010091379A (en) 2000-03-15 2000-03-15 Novel process for the preparation of quinoline carboxylic acid derivatives having 7-(4-aminomethyl-3-oxime)pyrrolidine substituent
KR10-2002-7011999A KR100498004B1 (en) 2000-03-15 2001-03-14 Novel process for the preparation of a quinoline carboxylic acid derivative having a 7-(4-aminomethyl-3-oxime)pyrrolidine substituent

Family Applications After (1)

Application Number Title Priority Date Filing Date
KR10-2002-7011999A KR100498004B1 (en) 2000-03-15 2001-03-14 Novel process for the preparation of a quinoline carboxylic acid derivative having a 7-(4-aminomethyl-3-oxime)pyrrolidine substituent

Country Status (3)

Country Link
KR (2) KR20010091379A (en)
AU (1) AU4124901A (en)
WO (1) WO2001068649A1 (en)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9920919D0 (en) 1999-09-03 1999-11-10 Sb Pharmco Inc Novel compound
GB9920917D0 (en) 1999-09-03 1999-11-10 Sb Pharmco Inc Novel process
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)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK0688772T3 (en) * 1994-06-16 1999-11-01 Lg Chemical Ltd Quinoline Carboxylic Acid Derivatives with 7- (4-Aminomethyl-3-oxime) -pyrrolidine Substituents and Process 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

Also Published As

Publication number Publication date
KR100498004B1 (en) 2005-07-01
WO2001068649A1 (en) 2001-09-20
KR20030017475A (en) 2003-03-03
AU4124901A (en) 2001-09-24

Similar Documents

Publication Publication Date Title
TWI829771B (en) Manufacture of compounds and compositions for inhibiting the activity of shp2
KR20180022125A (en) Acid addition salts of diamine derivatives compound and preparation thereof
KR20010091379A (en) Novel process for the preparation of quinoline carboxylic acid derivatives having 7-(4-aminomethyl-3-oxime)pyrrolidine substituent
KR101127814B1 (en) Novel intermediate and process for preparing sildenafil or its salt using the same
KR19990007390A (en) Quinolone Carboxylic Acid Derivatives
KR101313842B1 (en) A manufacturing method of esamlodipine besilate and its hydrate
GB2126212A (en) Process for the production of (+/-)-4-oxo-1,2,3,6,7,11b-hexahydro- 4H-pyrazino(2,1-a]isoquinoline derivatives
KR20020015313A (en) Novel synthesis of piperazine ring
JPH0841030A (en) Production of 1-(hetero)aryl-3-hydroxypyrazole
KR0132188B1 (en) Preparation process of pyridobenzoxazine carboxylic acid derivatives
JPH07121931B2 (en) Benzo [b] furan derivative
KR960010351B1 (en) Process for the preparation of benzoxazine derivative
KR970004048B1 (en) Processes for preparation of chephalosporin derivatives
JP2552101B2 (en) Novel pyridonecarboxylic acid derivative and method for preparing the same
KR20000055711A (en) A method of preparing 5-halobutyl-1-cyclohexyltetrazole
US5250682A (en) Process for the preparation of 6-[3-substitutedaminopropionyl]-7-deacetylforskolin derivatives
KR100440192B1 (en) Method of preparing optical active quinolonecarboxylic acid derivatives
KR0132189B1 (en) Preparation process of -3(s)-methyl pyridobenzoxazine carboxylic acid derivatives
KR100868160B1 (en) Method of preparing s---amlodipine or salt thereof and intermediate used therein
JPH04270272A (en) Production of aminoalkylmorpholine derivative
JP4192526B2 (en) Production of coumarin compounds
WO1990006909A1 (en) Vinyl tricarbonyl compounds and methods of making the same
KR100516383B1 (en) New manufacturing process of dihydrocarbostyril derivatives
KR20020068140A (en) Method for Preparing [(2-Oxo-3-tetrahydrothienylcarbamoyl)-methyl thio] acetic acid
KR0183439B1 (en) Novel camptothecin derivatives with antitumor effect

Legal Events

Date Code Title Description
A201 Request for examination