WO2015178663A1 - Procédé amélioré de préparation de zabofloxacine - Google Patents

Procédé amélioré de préparation de zabofloxacine Download PDF

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Publication number
WO2015178663A1
WO2015178663A1 PCT/KR2015/005009 KR2015005009W WO2015178663A1 WO 2015178663 A1 WO2015178663 A1 WO 2015178663A1 KR 2015005009 W KR2015005009 W KR 2015005009W WO 2015178663 A1 WO2015178663 A1 WO 2015178663A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
prepared
reacting
carboxylic acid
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PCT/KR2015/005009
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English (en)
Inventor
Dong-Rack Choi
Jae-Kyung Lim
Jung-Uk Choi
Dong-Hyuk Shin
Seung-Hwan Kim
Dae-Yeon Won
Jung-Hwan Kim
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Dong Wha Pharm. Co., Ltd.
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Application filed by Dong Wha Pharm. Co., Ltd. filed Critical Dong Wha Pharm. Co., Ltd.
Publication of WO2015178663A1 publication Critical patent/WO2015178663A1/fr

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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Definitions

  • the present invention relates to an improved manufacturing method of Zabofloxacin D-aspartate.
  • Zabofloxacin is a quinolone carboxylic acid antibacterial agent which exhibits excellent antibacterial activity against not only gram negative bacteria, but also against gram positive bacteria and, especially, show superior antibacterial activities against the existing quinolone-resistant strains and methicillin-resistant bacteria.
  • Zabofloxacin has a chemical name of 1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3,4]oct-6-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid, whose compound and its preparation method are disclosed in the United States Patent No. 6,313,299.
  • Zabofloxacin D-aspartate as represented by the following Formula 1 is disclosed in the United States Patent No. 8,324,238.
  • the following Zabofloxacin D-aspartate is known to have not only much higher solubility, but also excellent physicochemical properties such as stability, and to display little or no toxicity, as compared to the commonly prepared phosphate and hydrochloride forms.
  • the compound 1-benzyl-4-ethoxycarbonyl-pyrrolidin-3-one of Formula 8 is used to make the compound t-butyl-8-(methoxyimino)-2,6-diazaspiro[3,4]octane-2-carboxylate (TBDC) of Formula 9.
  • TBDC t-butyl-8-(methoxyimino)-2,6-diazaspiro[3,4]octane-2-carboxylate
  • the azide group is reduced by using Raney nickel under the pressure of hydrogen and the benzyl protecting group is removed by using palladium under the pressure of hydrogen, and therefore the duration of reaction process is long.
  • the two steps in this process use Raney nickel and palladium, which are very costly, and are proceeded under the high pressure of hydrogen, which make the process dangerous and inappropriate for commercial production.
  • the compound of Formula 9 prepared in above Reaction Scheme 1 is not stable in its liquid form, thus it is difficult for handling and storing, and when used in a substitution reaction at the chlorine position of the compound of Formula 3, 2.3 equivalents of the compound are used, which is very expensive.
  • the present inventors upon endeavoring to develop a preparation method of Zabofloxacin D-aspartate, have discovered a commercially feasible preparation method of the target compound with high yield and quality (HPLC purity ⁇ 99.5%) using a novel starting material, instead of the compound of Formula 9 used traditionally, to be substituted at the chlorine position of the compound of Formula 3, and upon further studies, have successfully completed the present invention.
  • One object of the present invention is to provide a novel starting material that is substituted at the chlorine position of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid (compound of Formula 3) in order to commercially prepare the target compound, Zabofloxacin D-aspartate, with high yield and quality (HPLC purity ⁇ 99.5%).
  • Another object of the present invention is to provide a preparation method of Zabofloxacin or Zabofloxacin D-aspartate using a novel manufacturing method of the above-mentioned starting material.
  • the present invention provides the following compound of Formula 6, 8-methoxyimino-2,6-diaza-spiro[3,4]octane-2-carboxylic acid t-butyl ester succinate (TBDCS), used in the preparation of Zabofloxacin D-aspartate, and a novel manufacturing method thereof.
  • TDCS 8-methoxyimino-2,6-diaza-spiro[3,4]octane-2-carboxylic acid t-butyl ester succinate
  • the compound of Formula 6 of the present invention when using the compound of Formula 6 of the present invention for substitution at the chlorine position of the compound of Formula 3, the compound of Formula 6 in its solid form is not only stable and easy to handle and store, but also can be used to commercially prepare Zabofloxacin D-aspartate with high yield and quality (HPLC purity ⁇ 99.5%).
  • the new manufacturing method of the compound of Formula 6 of the present invention is represented by the following Reaction Scheme 2.
  • Cbz- is a benzyloxycarbonyl group
  • Boc- is a t-butyloxycarbonyl group
  • Ms- is a methanesulfonyl group.
  • a mesylation reaction is carried out with the compound of Formula 13 using methanesulfonyl chloride to prepare the compound of the following Formula 14, 3-cyano-3-methanesulfonyloxymethyl-4-methoxyimino-pyrrolidine-1-carboxylic acid benzyl ester. Then, the nitrile group is subjected to a reduction reaction under a stream of nitrogen using sodium borohydride and lithium chloride to prepare the compound of the following Formula 15, 3-aminomethyl-3-methanesulfonyloxymethyl-4-methoxyimino-pyrrolidine-1-carboxylic acid benzyl ester.
  • sodium borohydride-lithium chloride mixture NaBH 4 -LiCl
  • sodium borohydride-cobalt chloride mixture NaBH 4 -CoCl 2
  • sodium borohydride-nickel chloride mixture NaBH 4 -NiCl 2
  • sodium borohydride-lithium chloride mixture NaBH 4 -LiCl
  • sodium borohydride-lithium chloride mixture NaBH 4 -LiCl is used in a reaction under a stream of nitrogen to prepare the product with a relatively high yield.
  • phthalic acid is used to prepare a compound of the following Formula 16, 8-methoxyimino-2,6-diaza-spiro[3,4]octane-6-carboxylic acid benzyl ester phthalic acid.
  • inorganic acid such as phosphoric acid and sulfuric acid
  • organic acid such as methanesulfonic acid, p -toluenesulfonic acid, oxalic acid, maleic acid, tartaric acid, fumaric acid, mandelic acid, benzoic acid and phthalic acid
  • inorganic acid such as phosphoric acid and sulfuric acid
  • organic acid such as methanesulfonic acid, p -toluenesulfonic acid, oxalic acid, maleic acid, tartaric acid, fumaric acid, mandelic acid, benzoic acid and phthalic acid
  • the compound of Formula 6 can be prepared in its free base form, or can be prepared in its organic acid salt form by reacting with organic acid such as methanesulfonic acid, p -toluenesulfonic acid, acetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid and glucuronic acid.
  • organic acid such as methanesulfonic acid, p -toluenesulfonic acid, acetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid and glucuronic acid.
  • succinate the compound of Formula 6, especially provides a favorable result as stable solid state.
  • the compound of Formula 6 (TBDCS) prepared by using the new method can be reacted with the compound of the following Formula 3, 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid, to prepare the final target compound Zabofloxacin D-aspartate of Formula 1.
  • the resulting compound is subjected to neutralization reaction using an inorganic base such as sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, potassium hydroxide and lithium hydroxide to prepare the compound of Formula 2, 1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3,4]oct-6-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid (Zabofloxacin). And then, D-aspartic acid is used to prepare the final target compound of Formula 1.
  • an inorganic base such as sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, potassium hydroxide and lithium hydroxide
  • the present invention provides another starting material for the preparation of Zabofloxacin D-aspartate, the compound of the following Formula 4, 2-(2,2,2-trifluoro-acetyl)-2,6-diaza-spiro[3,4]octan-8-one O -methyloxime methanesulfonate (TDMOS), and a novel manufacturing method thereof.
  • TMOS 2-(2,2,2-trifluoro-acetyl)-2,6-diaza-spiro[3,4]octan-8-one O -methyloxime methanesulfonate
  • Boc- is a t-butyloxycarbonyl group and Ms- is a methanesulfonyl group.
  • a mesylation reaction is carried out with the compound of Formula 18 using methanesulfonyl chloride to prepare the compound of the following Formula 19, 3-cyano-3-methanesulfonyloxymethyl-4-methoxyimino-pyrrolidine-1-carboxylic acid t-butyl ester. Then, the nitrile group is reduced under a stream of nitrogen using sodium borohydride and lithium chloride to prepare the compound of the following Formula 20, 3-aminomethyl-3-methanesulfonyloxymethyl-4-methoxyimino-pyrrolidine-1-carboxylic acid t-butyl ester.
  • sodium borohydride-lithium chloride mixture NaBH 4 -LiCl
  • sodium borohydride-cobalt chloride mixture NaBH 4 -CoCl 2
  • sodium borohydride-nickel chloride mixture NaBH 4 -NiCl 2
  • the compound of Formula 21 is treated with trifluoroacetic anhydride in order to protect the amine group of its azetidine ring with a trifluoroacetyl group, resulting in a compound of the following Formula 22, 8-methoxyimino-2-(2,2,2-trifluoro-acetyl)-2,6-diaza-spiro[3,4]octane-6-carboxylic acid t-butyl ester.
  • t-butyloxycarbonyl group of the compound of Formula 22 is subjected to a deprotection reaction by using methanesulfonic acid to prepare the compound of Formula 4, 2-(2,2,2-trifluoro-acetyl)-2,6-diaza-spiro[3,4]octan-8-one O -methyloxime methanesulfonate (TDMOS).
  • TMOS 2-(2,2,2-trifluoro-acetyl)-2,6-diaza-spiro[3,4]octan-8-one O -methyloxime methanesulfonate
  • the compound of Formula 4 can be prepared in the form of a free base, or as organic acid salts by reacting with the following organic acids: methanesulfonic acid, p -toluenesulfonic acid, acetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, and glucuronic acid.
  • methanesulfonate which is the compound of Formula 4 especially provides a favorable result as stable solid state.
  • the compound of Formula 4 (TDMOS) prepared by the novel method can be reacted with the compound of Formula 3, 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dehydro[1,8]naphthyridine-3-carboxylic acid, to prepare the final target compound Zabofloxacin D-aspartate of Formula 1.
  • step iv) The aforementioned compound of Formula 4 prepared in step iv) above is reacted with the compound of Formula 3 in a substitution reaction to first prepare the compound of Formula 5.
  • inorganic base such as sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium bicarbonate, potassium hydroxide, and lithium hydroxide are used.
  • compound of Formula 2 1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3,4]oct-6-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid (Zabofloxacin), is prepared.
  • D-aspartic acid the final target compound Zabofloxacin D-aspartate can be prepared.
  • the present invention provides a novel preparation method of 8-methoxyimino-2,6-diaza-spiro[3,4] octane-2-carboxylic acid t-butyl ester succinate (TBDCS), the starting material for preparing Zabofloxacin D-aspartate, such that it is prepared with high yield and high quality (HPLC purity ⁇ 99.5%) and in a way that is suitable for mass production.
  • TDCS 8-methoxyimino-2,6-diaza-spiro[3,4] octane-2-carboxylic acid t-butyl ester succinate
  • the present invention provides a novel preparation method of 2-(2,2,2-trifluoro-acetyl)-2,6-diaza-spiro[3.4]octan-8-one O -methyloxime methanesulfonate (TDMOS), a different starting material for preparing Zabofloxacin D-aspartate, such that it is prepared with high yield and high quality (HPLC purity ⁇ 99.5%) and in a way that is suitable for mass production.
  • TMOS 2-(2,2,2-trifluoro-acetyl)-2,6-diaza-spiro[3.4]octan-8-one O -methyloxime methanesulfonate
  • the present invention provides a method which uses only 1.0 ⁇ 1.1 equivalents of TBDCS or TDMOS during the substitution reaction, significantly reducing the unit cost of production, thus suitable for mass production of Zabofloxacin D-aspartate.

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

Abstract

La présente invention concerne un procédé amélioré de préparation de D-aspartate de zabofloxacine. La présente invention concerne un nouveau procédé de préparation de succinate d'ester t-butylique de l'acide 8-méthoxyimino-2,6-diaza-spiro[3,4]octane-2-carboxylique (TBDCS) ou de méthanesulfonate de 2-(2,2,2-trifluoro-acétyl)-2,6-diaza-spiro[3,4]octan-8-one-O-méthyl-oxime (TDMOS), qui sont séparément les matières de départ pour la préparation de D-aspartate de zabofloxacine. Le procédé de préparation selon la présente invention est approprié pour une préparation en masse de D-aspartate de zabofloxacine, car il permet une préparation avec un rendement élevé et une pureté élevée (pureté HPLC ≥ 99,5 %) ainsi que la réduction du coût unitaire de préparation à l'aide de seulement 1,0 à 1,1 équivalent de TBDCS ou TDMOS dans une réaction de substitution.
PCT/KR2015/005009 2014-05-20 2015-05-19 Procédé amélioré de préparation de zabofloxacine WO2015178663A1 (fr)

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KR1020140060112A KR102213991B1 (ko) 2014-05-20 2014-05-20 개선된 자보플록사신의 제조방법
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108623608A (zh) * 2018-08-06 2018-10-09 北京汇林思生物科技有限公司 扎布沙星中间体的制备方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113278021B (zh) * 2021-05-29 2022-09-23 天津全和诚科技有限责任公司 1,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯及其草酸盐的制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4822801A (en) * 1984-07-20 1989-04-18 Warner-Lambert Company 4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivative as antibacterial agents
US5633262A (en) * 1994-06-16 1997-05-27 Lg Chemical Ltd. Quinoline carboxylic acid derivatives having 7-(4-amino-methyl-3-oxime) pyrrolidine substituent and processes for preparing thereof
US6313299B1 (en) * 1997-06-26 2001-11-06 Dong Wha Pharmaceutical Industrial Co., Ltd. Quinolone carboxylic acid derivatives
US20100184795A1 (en) * 2007-04-13 2010-07-22 Dong Wha Pharmaceutical Ind. Co. Ltd Aspartate of 1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3.4]oct-6-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid, method for preparing the same, and antimicrobial pharmaceutical composition comprising the same

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4822801A (en) * 1984-07-20 1989-04-18 Warner-Lambert Company 4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivative as antibacterial agents
US5633262A (en) * 1994-06-16 1997-05-27 Lg Chemical Ltd. Quinoline carboxylic acid derivatives having 7-(4-amino-methyl-3-oxime) pyrrolidine substituent and processes for preparing thereof
US6313299B1 (en) * 1997-06-26 2001-11-06 Dong Wha Pharmaceutical Industrial Co., Ltd. Quinolone carboxylic acid derivatives
US20100184795A1 (en) * 2007-04-13 2010-07-22 Dong Wha Pharmaceutical Ind. Co. Ltd Aspartate of 1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3.4]oct-6-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid, method for preparing the same, and antimicrobial pharmaceutical composition comprising the same

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108623608A (zh) * 2018-08-06 2018-10-09 北京汇林思生物科技有限公司 扎布沙星中间体的制备方法

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KR20150133433A (ko) 2015-11-30

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