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WO2005058914A1 - Cristal d'oxacepheme - Google Patents

Cristal d'oxacepheme Download PDF

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Publication number
WO2005058914A1
WO2005058914A1 PCT/JP2005/002607 JP2005002607W WO2005058914A1 WO 2005058914 A1 WO2005058914 A1 WO 2005058914A1 JP 2005002607 W JP2005002607 W JP 2005002607W WO 2005058914 A1 WO2005058914 A1 WO 2005058914A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl acetate
flomoxef
hydrate
crystal
crystals
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP2005/002607
Other languages
English (en)
Japanese (ja)
Inventor
Masaaki Uenaka
Koichi Noguchi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shionogi and Co Ltd
Original Assignee
Shionogi and Co Ltd
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 Shionogi and Co Ltd filed Critical Shionogi and Co Ltd
Priority to JP2005516398A priority Critical patent/JP4530287B2/ja
Publication of WO2005058914A1 publication Critical patent/WO2005058914A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D505/00—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D505/00—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D505/10—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D505/12—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 substituted in position 7
    • C07D505/14—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 substituted in position 7 with hetero atoms directly attached in position 7
    • C07D505/16—Nitrogen atoms
    • C07D505/18—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof
    • C07D505/20—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof with the acylating radicals further substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D505/24—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof with the acylating radicals further substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen further substituted by doubly-bound nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to the formation of oxacephem useful as an antibacterial agent.
  • a lyophilized preparation containing the Na salt is commercially available as an injection (trade name: Flumarin, Shionogi & Co., Ltd.).
  • the freeze-dried preparation is produced by using flomoxef as a main raw material and blending sodium chloride and a stabilizer (see Patent Document 1).
  • Flomoxef crystals are also known.For example, the corresponding protected carboxylic acid at the 4-position is treated with methylene chloride and alcohol, with a Lewis acid (TiCl or A: i) and then with ethyl acetate.
  • a Lewis acid TiCl or A: i
  • Patent Document 1 These crystal forms are not described in detail. However, according to the additional examination by the present inventors, methylene chloride-containing crystals can be obtained by the method of the literature.
  • Patent Document 1 JP-A-60-45514
  • Patent Document 2 JP-A-59-139385
  • Non-Patent Document 1 The Journal of Antibiotics (Apr. P466-476, 1985)
  • the present inventors have conducted intensive studies in view of the above problems, and as a result, have found a novel solvate-containing crystal of flomoxef, and have completed the present invention described below.
  • Equation (4)
  • the novel solvate of flomoxef of the present invention is preferably a crystal, which is advantageous for formulation with improved stability and handleability.
  • hydrate crystals do not contain organic solvents such as methylene chloride, so they may be directly formulated into injections by the powder filling method.
  • Methyl acetate hydrate crystals are more advantageous in terms of safety and environmental aspects than crystals containing methylene chloride, and can produce flomoxef industrially and efficiently. That is, these crystals can be used as a pharmaceutically active ingredient or an intermediate thereof.
  • the hydrate of flomoxef preferably contains one molecule of water per one molecule of flomoxef.
  • the hydrate is preferably crystalline.
  • the d-spacing is, for convenience, the main peak among the X-ray peaks, and the strength of the relative intensity is selected.
  • the force The crystal structure is necessarily limited only by these values. is not. That is, peaks other than these may be included. In general, when a crystal is measured by X-ray analysis, its peak may cause some measurement error depending on the measuring instrument, the measuring conditions, the presence of the attached solvent, and the like. Therefore, some errors should be taken into account in the identification of the crystal structure. All crystals characterized by a pattern are within the scope of the present invention.
  • the above hydrate can be obtained, for example, by adding flomoxef or its methylene chloride hydrate obtained according to the method described in JP-A-59-139385 or The Journal of Antibiotics (Apr. P466-476, 1985) in a small amount of a soluble solvent. After dissolving at room temperature or warming (preferably about 20-40 ° C), pour a larger amount of water than the soluble solvent at room temperature or under ice-cooling, and then add 0 ° C-about room temperature, preferably about 5- It is obtained by stirring or standing at 25 ° C for several hours and one day.
  • the amount of the soluble solvent to be used is preferably 0.1 to 10 mL, preferably 0.5 to 5 mL, more preferably 13 to 13 mL per 1 g of flomoxef.
  • the amount of water used is preferably 1 to 100 mL, preferably 5 to 50 mL, more preferably 10 to 30 mL per lg of Flomoxef.
  • the soluble solvent examples include alcohols such as methanol, ethanol, 2-propanol, 2-methoxyethanol, ethylene glycol, methoxyethanol, glycerin, and propylene glycol, and ethers such as dioxane, tetrahydrofuran, dimethoxyethane, and diethylene dimethyl ether.
  • alcohols such as methanol, ethanol, 2-propanol, 2-methoxyethanol, ethylene glycol, methoxyethanol, glycerin, and propylene glycol
  • ethers such as dioxane, tetrahydrofuran, dimethoxyethane, and diethylene dimethyl ether.
  • the crystals thus obtained are then separated from the solvent by conventional separation means (eg, filtration, centrifugation, etc.) and subjected to conventional purification means (eg, washing, air drying, drying under reduced pressure). Can be isolated.
  • conventional separation means eg, filtration, centrifugation, etc.
  • purification means eg, washing, air drying, drying under reduced pressure
  • the above hydrate is obtained by heating and dissolving an extraction residue containing Flomoxef or an organic solvate thereof in water, which is also capable of obtaining a reaction liquid obtained by deprotecting the Flomoxef intermediate. For several hours and several days.
  • the methyl acetate solvate of flomoxef preferably contains 0.5 to 1.0, more preferably 0.5, methyl acetate molecules per one molecule of flomoxef.
  • the methyl acetate solvate is preferably crystalline.
  • the methyl acetate hydrate is obtained, for example, as follows. After dissolving Flomoxef or its methylene chloride hydrate in methyl acetate under heating (preferably at about 20-40 ° C), the solvent is distilled off. The residue is heated and dissolved in methyl acetate (preferably about 20-40 ° C), and then stirred at 0 ° C-room temperature for several hours and several days. It is obtained by filtering the precipitated crystals, preferably washing with cold methyl acetate, and air-drying.
  • the amount of methyl acetate used in the first and second times is preferably 0.1 to 20 mL, preferably 0.5 to 15 mL, more preferably 110 to 10 mL, per 1 g of flomoxef.
  • the amount of water used is preferably 1 to 100 mL, preferably 5 to 50 mL, and more preferably 10 to 30 mL, per 1 g of Flomoxef.
  • the methyl acetate hydrate can also be obtained in the same manner as described above, using the extraction residue of the reaction solution obtained by deprotecting the intermediate of flomoxef as a raw material.
  • the above hydrate or methyl acetate solvate can be converted to another solvate or crystal if desired. It can also be formulated alone or, if desired, together with a pH adjuster, stabilizer and the like by freeze-drying method, powder filling method and the like. In particular, hydrates are advantageous for formulation, since they can be preferably formulated by the powder filling method.
  • Non-Patent Document 1 (The Journal of Antibiotics (Apr. P466-476, 1985)) describes an intermediate of mouth moxef (benzhydryl at the 4-position of flomoxef, hydroxy on 3-position tetrazole methylbenzyloxycarbo) (405 mg), methylene chloride (2.5 ml) and tromethane (0.5 ml) were cooled to 30 ° C and contained ethanol (0.11 ml) and SnCl (0.17 ml). Mix the methylene chloride (2 ml) solution and stir for 3 hours and a half.
  • the reaction mixture was poured into a mixture of 1N hydrochloric acid, ethyl acetate and methyl ethyl ketone, and the separated organic layer was mixed with an aqueous solution of sodium hydrogen carbonate, the aqueous layer was acidified with concentrated hydrochloric acid, and ethyl acetate and methyl ethyl were added. Extracted with a mixture of ketones. The extract was washed with a saturated saline solution, dried over magnesium sulfate, and dried under reduced pressure to obtain a foamy reaction extract residue containing methylene chloride hydrate of flomoxef.
  • the reaction extraction residue obtained in Reference Example 1 was dissolved in a soluble solvent at room temperature or with heating under the conditions shown in Table 2 below, and water was added at room temperature or with ice cooling. The mixture was stirred or allowed to stand at 5-25 ° C for several hours a day. All the obtained crystals contained no organic solvent by NMR, and were confirmed to be monohydrate by elemental analysis. Also, the same powder X-ray diffraction pattern as in Example 1 was shown.
  • the reaction extraction residue lOOOOmg obtained in Reference Example 1 was dissolved by heating in 5 mL of methyl acetate, and the solvent was distilled off. The residue was heated and dissolved in 2 mL of methyl acetate, and then stirred at 5 ° C for 1 day. The precipitated crystals were filtered and washed with 2 mL of cold methyl acetate. After air drying, 784 mg (82%) of crystals of 0.5 methyl acetate hydrate were obtained.
  • FIG. 1 shows a powder X-ray diffraction pattern of a monohydrate crystal of flomoxef obtained in Example 1.
  • FIG. 2 shows a powder X-ray diffraction pattern of 0.5-methyl acetate solvate of flomoxef obtained in Example 3.
  • FIG. 2 shows a powder X-ray diffraction pattern of 0.5-methyl acetate solvate of flomoxef obtained in Example 3.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

L'invention concerne de nouveaux cristaux de flomoxef avantageux d'un point de vue environnemental et permettant de formuler des préparations pharmaceutiques. L'invention concerne également des cristaux d'hydrate ou de solvate de flomoxef associés à un acétate méthylique.
PCT/JP2005/002607 2004-02-20 2005-02-18 Cristal d'oxacepheme Ceased WO2005058914A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2005516398A JP4530287B2 (ja) 2004-02-20 2005-02-18 オキサセフェムの結晶

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2004043824 2004-02-20
JP2004-043824 2004-02-20
JP2004053283 2004-02-27
JP2004-053283 2004-02-27

Publications (1)

Publication Number Publication Date
WO2005058914A1 true WO2005058914A1 (fr) 2005-06-30

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PCT/JP2005/002607 Ceased WO2005058914A1 (fr) 2004-02-20 2005-02-18 Cristal d'oxacepheme

Country Status (5)

Country Link
JP (1) JP4530287B2 (fr)
KR (1) KR100832757B1 (fr)
CN (2) CN101440098B (fr)
TW (1) TWI338008B (fr)
WO (1) WO2005058914A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9585961B2 (en) 2003-10-24 2017-03-07 Adhesives Research, Inc. Rapidly disintegrating films for delivery of pharmaceutical or cosmetic agents

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102952149B (zh) * 2012-11-09 2015-06-24 浙江新和成股份有限公司 一种氟氧头孢中间体的一锅合成法
KR101314500B1 (ko) * 2012-12-28 2013-10-07 제일약품주식회사 안정성이 개선된 옥사세펨 제제 및 그 제조방법
CN105801601B (zh) * 2016-04-02 2018-01-26 丽珠医药集团股份有限公司 一种氟氧头孢钠合成方法
CN108424418A (zh) * 2017-02-15 2018-08-21 山东致纯医药科技有限公司 一种氟氧头孢钠杂质

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59139385A (ja) * 1982-12-23 1984-08-10 Shionogi & Co Ltd フルオロメチルチオオキサセフアロスポリン
JPH03279329A (ja) * 1990-03-27 1991-12-10 Banyu Pharmaceut Co Ltd セファマイシンおよびセファロスポリンからなる抗菌剤

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59231090A (ja) * 1983-06-14 1984-12-25 Shionogi & Co Ltd フルオロメチルチオオキサセフアロスポリン

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59139385A (ja) * 1982-12-23 1984-08-10 Shionogi & Co Ltd フルオロメチルチオオキサセフアロスポリン
JPH03279329A (ja) * 1990-03-27 1991-12-10 Banyu Pharmaceut Co Ltd セファマイシンおよびセファロスポリンからなる抗菌剤

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9585961B2 (en) 2003-10-24 2017-03-07 Adhesives Research, Inc. Rapidly disintegrating films for delivery of pharmaceutical or cosmetic agents

Also Published As

Publication number Publication date
JP4530287B2 (ja) 2010-08-25
JPWO2005058914A1 (ja) 2007-07-12
TW200533672A (en) 2005-10-16
KR20060120253A (ko) 2006-11-24
CN101440098A (zh) 2009-05-27
KR100832757B1 (ko) 2008-05-27
CN100509819C (zh) 2009-07-08
TWI338008B (en) 2011-03-01
CN1922191A (zh) 2007-02-28
CN101440098B (zh) 2011-07-13

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