WO2001068649A1 - 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 PDF

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WO2001068649A1
WO2001068649A1 PCT/KR2001/000399 KR0100399W WO0168649A1 WO 2001068649 A1 WO2001068649 A1 WO 2001068649A1 KR 0100399 W KR0100399 W KR 0100399W WO 0168649 A1 WO0168649 A1 WO 0168649A1
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formula
compound
salt
surfactant
base
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PCT/KR2001/000399
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French (fr)
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Bong Chan Kim
Yeong Dae Kim
Hoon Choi
Won Sup Kim
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Lg Life Sciences Ltd.
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Priority to AU41249/01A priority Critical patent/AU4124901A/en
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    • 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

Definitions

  • the present invention relates to a novel process for preparing quinoline carboxylic acid derivatives having a 7-(4-aminomethyl-3-oxime)pyrrolidine substituent represented by the following formula (3)
  • R represents hydrogen, methyl, or amino
  • R represents cyclopropyl, ethyl or phenyl which is substituted by one or more fluorine atoms
  • R 2 represents hydrogen, straight-chain or branched alkyl having 1 to 4 carbon atoms, aryl or allyl, and
  • R and R 4 independently of one another represent hydrogen or C- . -C 3 -alkyl, or together with the nitrogen atom to which they are attached may form a cycle, or a salt thereof which comprises coupling a compound represented by the following formula (1) in which
  • X represents a leaving group, preferably halogen, or a salt thereof, with a compound represented by the following formula (2):
  • R 2 , R 3 and R 4 are as defined for formula (3), or a salt thereof.
  • the compounds of formula (3) which are disclosed in Korean Patent Application 94-13604, are quinolone antimicrobials.
  • a particular compound of formula (3) which may be mentioned is (R,S)-7-(3-aminomethyl-4-5 «-methoxyimino-pyrrolidin-l-yl)-l- cyclopropyl-6-fluoro-4-oxo- 1 ,4-dihydro- 1 , 8-naphthyridine-3 -carboxylic acid (gemifloxac- in) and pharmaceutically acceptable salts thereof
  • Korean Patent Application No 98- 80504 discloses a preferred form of this compound namely (R_,S)-7-(3-aminomethyl-4-sy «- methoxyimino-pyrrolidin- 1 -yl)- 1 -cyclopropyl-6-fluoro-4-oxo- 1 ,4-dihydro- 1 , 8-naphthyrid- ine-3 -
  • the free base of formula (3) can therefore be considered as a key intermediate for the preparation of the salts of formula (3) and will exert a direct influence on the quality of the final product.
  • Attempts have been made to prepare the compounds of formula (3) with an improved purity using water as the solvent instead of a solvent mixture of acetonitrile/ water (see PCT/GBOO/03366)
  • the conventionally used solvents including water have the problem that the time required for filtration is longer than is desirable for use on a commercial scale where short cycle times are advantageous
  • the present inventors have conducted extensive studies to solve this problem in preparing a quinoline carboxylic acid derivative having a 7-(4-aminomethyl-3- oxime)pyrrolidine substituent and salts thereof As a result, we have found that by employing a new process where a surfactant is introduced into the reaction solution, the filtration time may be significantly reduced without any influence on the reactivity The present invention is based on this finding
  • the object of the present invention is to provide a process for preparing a quinoline carboxylic acid derivative having a 7-(4-aminomethyl-3-oxime)pyrrolidine substituent represented by the following formula (3)
  • Q represents C-H, C-F, C-Cl, C-OH, C-O-methyl, or N
  • R represents hydrogen, methyl, or amino
  • R 1 represents cyclopropyl, ethyl or phenyl which is substituted by one or more fluorine atoms
  • R represents hydrogen, straight-chain or branched alkyl having 1 to 4 carbon atoms, aryl or allyl, and R 3 and R 4 independently of one another represent hydrogen or C- . -C 3 -alkyl, or together with the nitrogen atom to which they are attached may form a cycle, or a salt thereof which comprises coupling a compound represented by the following formula (1)
  • X represents a leaving group, preferably halogen, or a salt thereof, with a compound represented by the following formula (2)
  • R 2 , R 3 and R 4 are as defined for formula (3), or a salt thereof, in a solvent in the presence of a base and a surfactant, and then filtering the resulting compound of formula (3), and optionally forming a pharmaceutically acceptable salt and/or hydrate thereof
  • a compound of formula (3) is typically prepared by introducing the compound of formula (1) into a solvent, e g water, adding dropwise a base, e g. triethylamine, to make a thoroughly clear solution, adding the compound of formula (2) into the reaction solution, and filtering the reaction solution after the completion of reaction
  • a solvent e g water
  • a base e g. triethylamine
  • the filtration time is reduced by 5 to 20 times, preferably 15 to 20 times, that obtained using the prior art method
  • the reaction time may also be reduced to 2-3 hours from 8-10 hours by raising the reaction temperature
  • the pharmaceutically acceptable salts of the compounds of formula (3) include those with acids generally known and used in the technical field to which quinolone derivatives or pyrrolidine derivatives pertain Salts with methanesulfonic acid may be specifically mentioned, methanesulfonates and hydrates thereof may be synthesised from the free base as described in Korean Patent Application No 98-80504
  • Salts of the compounds of formulae (1) and (2) which may be used in the process of the invention include salts known to those skilled in the art
  • Particular salts of the compounds of formula (2) which may be mentioned include the hydrochloride, trifluoroacetate and sulfate salts as described in PCT KR99/00099, and in particular the methanesulfonates as described in PCT/GB00/03358
  • the surfactant, base, solvent, etc used in the process of the present invention can be appropriately selected from those that do not adversely affect the reaction
  • the preferred reaction conditions including the amount and kind of the surfactant, base and solvent, reaction temperature, reaction order, etc are as follows
  • the preferred surfactant for use in the present invention is metolose which is a cellulose ether, i e , methyl cellulose or hydroxypropyl methyl cellulose, more specifically, methyl cellulose, SM-25 (Shinetsu) or hydroxypropyl methyl cellulose 2910, 60SH-50
  • the amount of surfactant ranges between 0 5 and 3 0% by weight with respect to the compound of formula (1)
  • an organic base such as triethylamine, pyridine, etc , preferably triethylamine, is used, preferably in an amount of 2 to 5 equivalents with respect to the compound of formula (1)
  • the solvent one or more selected from the group consisting of acetonitrile, water, alcohols, dimethylformamide and dimethylsulfoxide can be preferably used, but water is particularly preferable in view of the purity of the resulting product
  • the preferred reaction temperature is between about 0 and 40 ° C, and the surfactant will be selected according to the reaction temperature to obtain optimal results
  • the best result is obtained using methyl cellulose, SM-25 (reduction by about 10 times in the filtration time) and in the case of reaction at 40 ° C, the best result is obtained using hydroxypropyl methyl cellulose 2910, 60SH-50 (reduction by about 15 to 20 times in the filtration time).
  • the compound of formula (1) or salt thereof is introduced into a solvent, a base is added (ideally to make a thoroughly clear solution), a surfactant is added, the reaction temperature is optionally raised, the compound of formula (2) or salt thereof is added, and then the reaction solution is filtered after the reaction is completed, or
  • the compound of formula (1) or salt thereof and a surfactant are introduced into a solvent, a base is added (preferably dropwise, if desired, the base may be slowly added over about 2 hours), the reaction temperature is optionally raised, the compound of formula (2) or salt thereof is added, and then the reaction solution is filtered after the reaction is completed and, optionally after the reaction solution is allowed to stand for 2 to 3 hours at room temperature
  • a compound of the following formula (la) (30 Og, 106 14mmol) and water(300 mi, 10 mi/g) were introduced into a 500 mi reactor and the mixture was stirred at room temperature(24 ⁇ 26 ° C ) 3 4 Equivalents of triethylamine(36 5 lg, 360 81 mmol) was added thereto at room temperature, with the temperature being raised to about 30°C, stirred for 10 minutes for making a clear solution, and then the temperature was cooled to 16 — 20 ° C
  • a compound of the following formula (2a) (37 46g, 111 68mmol)
  • Example 1 and water (300 mi, 10 ml/g) were introduced into a 500 mi reactor, and the resulting mixture was stirred at room temperature(24 ⁇ 26 ° C ) 3 4
  • Equivalents of triethylamine (36 51g, 360 81 mmol) was added thereto at room temperature, with the temperature being raised to about 30°C, and stirred for 10 minutes for making a clear solution 300mg (1 0wt%/Compound(la)) of methyl cellulose, SM-25, a surfactant, was added and stirred for lOminutes
  • the compound of formula (2a) 37 46g, 111 68mmol) used in Comparative Example 1 was added thereto at room temperature and stirred After stirring for 16 5 hours, the reaction was completed (HPLC analysis that the content of the compound of formula (la) in the reaction solution is decreased to 2% or less, is regarded to show the completion of reaction)
  • the mixture after completion of reaction was filtered through a glass filter, consecutively washed with water(
  • Example 1 was added thereto at room temperature and stirred Thereafter, the same procedure as Example 1 was carried out except that the reaction time was 15 hours to give the title compound (32 25g, content of residual solvent 7 49%, Yield 72%) as a solid
  • the first filtration time was 6 minutes, the second 5 minutes, and the third 6 minutes, respectively, the total time of which was about 8 times shorter than that of Comparative Example 1
  • Example 3 The same procedure as Example 3 was carried out except that the base triethylamine is slowly added over 2 hours and the reaction time was 2 5 hours to give the title compound (34 52g, content of residual solvent 6 4%, Yield 78%) as a solid
  • the first filtration time was 3 minutes, the second 3 minutes, and the third 3 minutes, respectively, the total time of which was about 15 times shorter than that of Comparative Example 1
  • Example 3 The same procedure as Example 3 was carried out except that the reaction time was 2 5 hours and the reaction solution was allowed to stand for 2-3 hours after reaction completion to give the title compound (33 23g, content of residual solvent 6 5%, Yield 75%) as a solid
  • the first filtration time was 3 minutes, the second 2 minutes, and the third 2 minutes, respectively, the total time of which was about 20 times shorter than that of Comparative Example 1

Abstract

The present invention relates to a novel process for preparing quinoline carboxylic acid antimicrobials having a 7-(4-aminomethyl-3-oxime)pyrrolidine substituent, e.g. gemifloxacin, or salt thereof, wherein a specific surfactant is used so that the filtration time can be significantly reduced compared with the prior art method.

Description

NOVEL PROCESS FOR THE PREPARATION OF A QUINOLINE
CARBOXYLIC ACID DERIVATIVE HAVING A 7-(4-
AMINOMETHYL-3-OXIME)PYRROLIDINE SUBSTITUENT
TECHNICAL FIELD
The present invention relates to a novel process for preparing quinoline carboxylic acid derivatives having a 7-(4-aminomethyl-3-oxime)pyrrolidine substituent represented by the following formula (3)
Figure imgf000002_0001
in which Q represents C-H, C-F, C-Cl, C-OH, C-O-methyl, or N, R represents hydrogen, methyl, or amino, R represents cyclopropyl, ethyl or phenyl which is substituted by one or more fluorine atoms, R2 represents hydrogen, straight-chain or branched alkyl having 1 to 4 carbon atoms, aryl or allyl, and
R and R4 independently of one another represent hydrogen or C-.-C3-alkyl, or together with the nitrogen atom to which they are attached may form a cycle, or a salt thereof which comprises coupling a compound represented by the following formula (1)
Figure imgf000003_0001
in which
Q, R and R1 are as defined for formula (3), and
X represents a leaving group, preferably halogen, or a salt thereof, with a compound represented by the following formula (2):
Figure imgf000003_0002
in which
R2, R3 and R4 are as defined for formula (3), or a salt thereof.
BACKGROUND ART
The compounds of formula (3), which are disclosed in Korean Patent Application 94-13604, are quinolone antimicrobials. A particular compound of formula (3) which may be mentioned is (R,S)-7-(3-aminomethyl-4-5 «-methoxyimino-pyrrolidin-l-yl)-l- cyclopropyl-6-fluoro-4-oxo- 1 ,4-dihydro- 1 , 8-naphthyridine-3 -carboxylic acid (gemifloxac- in) and pharmaceutically acceptable salts thereof Korean Patent Application No 98- 80504 discloses a preferred form of this compound namely (R_,S)-7-(3-aminomethyl-4-sy«- methoxyimino-pyrrolidin- 1 -yl)- 1 -cyclopropyl-6-fluoro-4-oxo- 1 ,4-dihydro- 1 , 8-naphthyrid- ine-3 -carboxylic methanesulfonate and hydrates thereof, in particular the sesquihydrate.
The free base of formula (3) can therefore be considered as a key intermediate for the preparation of the salts of formula (3) and will exert a direct influence on the quality of the final product. Attempts have been made to prepare the compounds of formula (3) with an improved purity using water as the solvent instead of a solvent mixture of acetonitrile/ water (see PCT/GBOO/03366) However, the conventionally used solvents including water have the problem that the time required for filtration is longer than is desirable for use on a commercial scale where short cycle times are advantageous
DISCLOSURE OF INVENTION
Thus, the present inventors have conducted extensive studies to solve this problem in preparing a quinoline carboxylic acid derivative having a 7-(4-aminomethyl-3- oxime)pyrrolidine substituent and salts thereof As a result, we have found that by employing a new process where a surfactant is introduced into the reaction solution, the filtration time may be significantly reduced without any influence on the reactivity The present invention is based on this finding
Therefore, the object of the present invention is to provide a process for preparing a quinoline carboxylic acid derivative having a 7-(4-aminomethyl-3-oxime)pyrrolidine substituent represented by the following formula (3)
Figure imgf000004_0001
in which
Q represents C-H, C-F, C-Cl, C-OH, C-O-methyl, or N, R represents hydrogen, methyl, or amino,
R1 represents cyclopropyl, ethyl or phenyl which is substituted by one or more fluorine atoms,
R represents hydrogen, straight-chain or branched alkyl having 1 to 4 carbon atoms, aryl or allyl, and R3 and R4 independently of one another represent hydrogen or C-.-C3-alkyl, or together with the nitrogen atom to which they are attached may form a cycle, or a salt thereof which comprises coupling a compound represented by the following formula (1)
Figure imgf000005_0001
in which
Q, R and R1 are as defined for formula (3), and
X represents a leaving group, preferably halogen, or a salt thereof, with a compound represented by the following formula (2)
Figure imgf000005_0002
in which
R2, R3 and R4 are as defined for formula (3), or a salt thereof, in a solvent in the presence of a base and a surfactant, and then filtering the resulting compound of formula (3), and optionally forming a pharmaceutically acceptable salt and/or hydrate thereof
BEST MODE FOR CARRYING OUT THE INVENTION
According to the prior art method a compound of formula (3) is typically prepared by introducing the compound of formula (1) into a solvent, e g water, adding dropwise a base, e g. triethylamine, to make a thoroughly clear solution, adding the compound of formula (2) into the reaction solution, and filtering the reaction solution after the completion of reaction However, according to the present invention, the compound of formula (3) is prepared as depicted in the following Reaction Scheme (1)
Reaction Scheme (1)
Figure imgf000006_0001
Using the process of the present invention, the filtration time is reduced by 5 to 20 times, preferably 15 to 20 times, that obtained using the prior art method The reaction time may also be reduced to 2-3 hours from 8-10 hours by raising the reaction temperature Thereby, the cycle time, which is a very important economical factor in a commercial process, can be significantly reduced
The pharmaceutically acceptable salts of the compounds of formula (3) include those with acids generally known and used in the technical field to which quinolone derivatives or pyrrolidine derivatives pertain Salts with methanesulfonic acid may be specifically mentioned, methanesulfonates and hydrates thereof may be synthesised from the free base as described in Korean Patent Application No 98-80504
Salts of the compounds of formulae (1) and (2) which may be used in the process of the invention include salts known to those skilled in the art Particular salts of the compounds of formula (2) which may be mentioned include the hydrochloride, trifluoroacetate and sulfate salts as described in PCT KR99/00099, and in particular the methanesulfonates as described in PCT/GB00/03358
The surfactant, base, solvent, etc used in the process of the present invention can be appropriately selected from those that do not adversely affect the reaction The preferred reaction conditions including the amount and kind of the surfactant, base and solvent, reaction temperature, reaction order, etc are as follows
The preferred surfactant for use in the present invention is metolose which is a cellulose ether, i e , methyl cellulose or hydroxypropyl methyl cellulose, more specifically, methyl cellulose, SM-25 (Shinetsu) or hydroxypropyl methyl cellulose 2910, 60SH-50
(Shinetsu) can be mentioned For optimal filtration, generally, the amount of surfactant ranges between 0 5 and 3 0% by weight with respect to the compound of formula (1)
As the base, an organic base such as triethylamine, pyridine, etc , preferably triethylamine, is used, preferably in an amount of 2 to 5 equivalents with respect to the compound of formula (1)
As the solvent, one or more selected from the group consisting of acetonitrile, water, alcohols, dimethylformamide and dimethylsulfoxide can be preferably used, but water is particularly preferable in view of the purity of the resulting product
The preferred reaction temperature is between about 0 and 40 °C, and the surfactant will be selected according to the reaction temperature to obtain optimal results For example, in the case of room temperature reaction, the best result is obtained using methyl cellulose, SM-25 (reduction by about 10 times in the filtration time) and in the case of reaction at 40 °C, the best result is obtained using hydroxypropyl methyl cellulose 2910, 60SH-50 (reduction by about 15 to 20 times in the filtration time).
Under the conditions mentioned above, the process of the present invention may be carried out according to one of the following procedures
a) the compound of formula (1) or salt thereof is introduced into a solvent, a base is added (ideally to make a thoroughly clear solution), a surfactant is added, the reaction temperature is optionally raised, the compound of formula (2) or salt thereof is added, and then the reaction solution is filtered after the reaction is completed, or
b) the compound of formula (1) or salt thereof and a surfactant are introduced into a solvent, a base is added (preferably dropwise, if desired, the base may be slowly added over about 2 hours), the reaction temperature is optionally raised, the compound of formula (2) or salt thereof is added, and then the reaction solution is filtered after the reaction is completed and, optionally after the reaction solution is allowed to stand for 2 to 3 hours at room temperature
All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth
The present invention will be more specifically explained by the following examples However, it should be understood that those examples are intended to illustrate the present invention but not in any manner to limit the scope of the present invention
Comparative Example 1 Preparation of 7-(4-aminomethyl-3-methoxyiminopyrrolidin-l-yl)-l-cyclo- propyl-6-fluoro-4-oxo-l,4-dihydro[l,8]naphthyridine-3-carboxylic acid according to the prior art method
A compound of the following formula (la) (30 Og, 106 14mmol)
Figure imgf000009_0001
and water(300 mi, 10 mi/g) were introduced into a 500 mi reactor and the mixture was stirred at room temperature(24 ~ 26 °C ) 3 4 Equivalents of triethylamine(36 5 lg, 360 81 mmol) was added thereto at room temperature, with the temperature being raised to about 30°C, stirred for 10 minutes for making a clear solution, and then the temperature was cooled to 16 — 20 °C A compound of the following formula (2a) (37 46g, 111 68mmol)
Figure imgf000009_0002
2MSA was added at 16~20°C and stirred at room temperature After stirring for 15 5 hours, the reaction was completed (HPLC analysis that the content of the compound of formula (la) in the reaction solution is decreased to 2% or less, is regarded to show the completion of reaction) After the reaction was completed, the mixture was filtered through a glass filter, consecutively washed with water(150 mi) and ethanol(150 mi), and then dried under nitrogen gas stream to give the title compound (37 32g, Content of residual solvent 10 7%, Nield 81%) as a solid The first filtration time was 52 minutes, the second 43 minutes, and the third 42 minutes, respectively
Example 1
Preparation of 7-(4-aminomethyl-3-methoxyiminopyrrolidin-l-yl)-l-cyclo- propyl-6-fluoro-4-oxo-l,4-dihydro[l,8]naphthyridine-3-carboxylic acid wherein surfactant is added after base and the reaction is carried out at room temperature
The compound of formula (la) (30 Og, 106 14mmol) used in Comparative
Example 1 and water (300 mi, 10 ml/g) were introduced into a 500 mi reactor, and the resulting mixture was stirred at room temperature(24 ~ 26 °C ) 3 4 Equivalents of triethylamine (36 51g, 360 81 mmol) was added thereto at room temperature, with the temperature being raised to about 30°C, and stirred for 10 minutes for making a clear solution 300mg (1 0wt%/Compound(la)) of methyl cellulose, SM-25, a surfactant, was added and stirred for lOminutes Then, the compound of formula (2a) (37 46g, 111 68mmol) used in Comparative Example 1 was added thereto at room temperature and stirred After stirring for 16 5 hours, the reaction was completed (HPLC analysis that the content of the compound of formula (la) in the reaction solution is decreased to 2% or less, is regarded to show the completion of reaction) The mixture after completion of reaction was filtered through a glass filter, consecutively washed with water(150 ml) and ethanol(150 mi), and then dried under nitrogen gas stream to give the title compound (34 31g, content of residual solvent 6 5%, Yield 78%) as a solid The first filtration time was 5 minutes, the second 5 minutes, and the third 5 minutes, respectively, the total time of which was about 9 times shorter than that of Comparative Example 1
Example 2 Preparation of 7-(4-aminomethyl-3-methoxyiminopyrroIidin-l-yl)-l-cyclo- propyl-6-fluoro-4-oxo-l,4-dihydro[l,8]naphthyridine-3-carboxylic acid wherein surfactant is added before base and the reaction is carried out at room temperature
The compound of formula (la) (30 Og, 106 14mmol) used in Comparative Example 1, 300mg (1 Owt %/Compound(la)) of hydroxypropyl methyl cellulose 2910,
60SH-50 as a surfactant, and water(300 mi, 10 mi/g) were introduced into a 500 mi reactor, and the resulting mixture was stirred at room temperature(24 ~ 26 °C ) 3 4 Equivalents of triethylamine (36 51g, 360 81 mmol) was added thereto at room temperature, with the temperature being raised to about 30°C, and stirred for 10 minutes for making a clear solution The compound of formula (2a) (37 46g, 111 68mmol) used in Comparative
Example 1 was added thereto at room temperature and stirred Thereafter, the same procedure as Example 1 was carried out except that the reaction time was 15 hours to give the title compound (32 25g, content of residual solvent 7 49%, Yield 72%) as a solid
The first filtration time was 6 minutes, the second 5 minutes, and the third 6 minutes, respectively, the total time of which was about 8 times shorter than that of Comparative Example 1
Example 3
Preparation of 7-(4-aminomethyl-3-methoxyiminopyrrolidin-l-yl)-l-cyclo- propyl-6-fluoro-4-oxo-l,4-dihydro[l,8]naphthyridine-3-carboxylic acid wherein surfactant is added before base and the reaction is carried out at 40 °C
The compound of formula (la) (30 Og, 106 14mmol) used in Comparative Example 1, 300mg (1 Owt %/Compound(la)) of hydroxypropyl methyl cellulose 2910, 60SH-50 as a surfactant, and water(300 ml, 10 i/g) were introduced into a 500 mi reactor, and the resulting mixture was stirred at room temperature(24~26°C) 3 4 Equivalents of triethylamine (36 51g, 360 81 mmol) was added thereto at room temperature, with the temperature being raised to about 30°C, and stirred for 10 minutes for making a clear solution After the temperature of this reaction solution was raised to 40 °C , the compound of formula (2a) (37 46g, 111 68mmol) used in Comparative Example 1 was added thereto at the same temperature, stirred, and reacted for 3 5 hours The reaction solution was cooled to room temperature over 40 minutes and then filtered, washed and dried according to the same procedure as Example 1 to give the title compound (34 16g, content of residual solvent 7 4%, Yield 77%) as a solid The first filtration time was 3 minutes, the second 2 minutes, and the third 3 minutes, respectively, the total time of which was about 17 times shorter than that of Comparative Example 1
Example 4
Preparation of 7-(4-aminomethyl-3-methoxyiminopyrrolidin-l-yl)-l-cyclo- propyl-6-fluoro-4-oxo-l,4-dihydro[l,8]naphthyridine-3-carboxylic acid wherein base is added as slowly as possible and the reaction is carried out at 40 °C
The same procedure as Example 3 was carried out except that the base triethylamine is slowly added over 2 hours and the reaction time was 2 5 hours to give the title compound (34 52g, content of residual solvent 6 4%, Yield 78%) as a solid The first filtration time was 3 minutes, the second 3 minutes, and the third 3 minutes, respectively, the total time of which was about 15 times shorter than that of Comparative Example 1
Example 5 Preparation of 7-(4-aminomethyl-3-methoxyiminopyrrolidin-l-yI)-l-cyclo- propyl-6-fluoro-4-oxo-l,4-dihydro[l,8]naphthyridine-3-carboxylic acid wherein surfactant is added before base, the reaction solution is allowed to stand for 2-3 hours after reaction completion at room temperature, and the reaction is carried out at 40 "C
The same procedure as Example 3 was carried out except that the reaction time was 2 5 hours and the reaction solution was allowed to stand for 2-3 hours after reaction completion to give the title compound (33 23g, content of residual solvent 6 5%, Yield 75%) as a solid The first filtration time was 3 minutes, the second 2 minutes, and the third 2 minutes, respectively, the total time of which was about 20 times shorter than that of Comparative Example 1

Claims

A process for preparing a compound represented by the following formula (3)
Figure imgf000013_0001
in which
Q represents C-H, C-F, C-Cl, C-OH, C-O-methyl, or N,
R represents hydrogen, methyl, or amino,
R1 represents cyclopropyl, ethyl or phenyl which is substituted by one or more fluorine atoms,
R2 represents hydrogen, straight- chain or branched alkyl having 1 to 4 carbon atoms, aryl or allyl, and
R3 and R4 independently of one another represent hydrogen or Cι-C3-alkyl, or together with the nitrogen atom to which they are attached may form a cycle, or a salt thereof which comprises coupling a compound represented by the following formula (1)
Figure imgf000013_0002
in which
Q, R and R1 are as defined for formula (3), and X represents a leaving group, preferably halogen, or a salt thereof, with a compound represented by the following formula (2)
Figure imgf000013_0003
in which
R2, R3 and R4 are as defined for formula (3), or a salt thereof, in a solvent in the presence of a base and a surfactant, and then filtering the resulting compound of formula (3), and optionally forming a pharmaceutically acceptable salt and/or hydrate thereof
2 The process of claim 1 wherein the compound of formula (1), or a salt thereof, is introduced into a solvent to which a base, a surfactant and the compound of formula (2) or a salt thereof are added consecutively, and then the reaction solution is filtered
3 The process of claim 1 wherein the compound of formula (1), or a salt thereof, and a surfactant are introduced into a solvent to which a base and the compound of formula (2) or a salt thereof are added consecutively, and then the reaction solution is filtered
4 The process of claim 3 wherein the base is added dropwise
5 The process of claim 3 wherein the reaction temperature is 40 °C and the reaction solution is allowed to stand for 2 to 3 hours at room temperature before filtration
6 The process of any one of the preceding claims wherein the surfactant is a cellulose ether
7 The process of claim 6 wherein the cellulose ether is hydroxypropyl methyl cellulose or methyl cellulose
8 The process of any one of the preceding claims wherein the surfactant is used in an amount of 0 5 to 3 0% by weight with respect to the compound of formula (1)
9 The process of any one of the preceding claims wherein the reaction temperature is between 0 and 40 °C
10. The process of any one of the preceding claims wherein the base is triethylamine and the solvent is water
11. The process of any one of the preceding claims wherein the compound of formula
(3 ) is (R, S)-7-(3 -aminomethyl-4-5y«-methoxyimino-pyrrolidin- 1 -yl)- 1 -cyclopropyl-6- fluoro-4-oxo-l,4-dihydro-l,8-naphfhyridine-3 -carboxylic acid or a pharmaceutically acceptable salt thereof.
12. The process of claim 11 wherein the compound of formula (3) is (R,S)-7-(3- aminomethy l-4-_vy«-methoxyimino-pyrrolidin- 1 -yl)- 1 -cyclopropyl-6-fluoro-4-oxo- 1 ,4- dihydro- l,8-naphthyridine-3 -carboxylic methanesulfonate or a hydrate thereof.
13. The process of claim 12 wherein the compound of formula (3) is (R,S)-7-(3- amino methyl-4-5y«-methoxyimino-pyrrolidin- 1 -yl)- 1 -cyclopropyl-6-fluoro-4-oxo- 1 ,4- dihydro- 1 , 8-naphthyridine-3 -carboxylic methanesulfonate sesquihydrate.
PCT/KR2001/000399 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 WO2001068649A1 (en)

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WO2004092129A1 (en) * 2003-03-07 2004-10-28 Lg Life Sciences Ltd. New process for preparing 4-aminomethyl-3-alkoxyiminopyrrolidine methanesulfonate
US7232907B2 (en) 1999-09-03 2007-06-19 Lg Life Sciences Limited Process for production of naphthyridine-3-carboxylic acid derivatives
US7361762B2 (en) 2002-04-08 2008-04-22 Lg Life Sciences Ltd. Process for preparing acid salts of Gemifloxacin
JP2018099116A (en) * 2016-12-20 2018-06-28 アース製薬株式会社 Method for increasing plant chlorophyll and method for inhibiting pest colonization, and composition applicable to methods

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Publication number Priority date Publication date Assignee Title
US6703512B1 (en) 1999-09-03 2004-03-09 Sb Pharmco Puerto Rico Inc. Of The United States Corporation Company Intermediates for the production of quinolone carboxylic acid derivatives
US6803467B2 (en) 1999-09-03 2004-10-12 Lg Life Sciences Limited Intermediates for the production of quinolone carboxylic acid derivatives
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JP2018099116A (en) * 2016-12-20 2018-06-28 アース製薬株式会社 Method for increasing plant chlorophyll and method for inhibiting pest colonization, and composition applicable to methods
JP2020168001A (en) * 2016-12-20 2020-10-15 アース製薬株式会社 Method for increasing plant chlorophyll and method for inhibiting pest colonization, and composition applicable to methods

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