WO2007128213A1 - Poudre solide de sel de sodium de pénicilline a pureté et/ou teneur élevée, et sa préparation - Google Patents

Poudre solide de sel de sodium de pénicilline a pureté et/ou teneur élevée, et sa préparation Download PDF

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Publication number
WO2007128213A1
WO2007128213A1 PCT/CN2007/001405 CN2007001405W WO2007128213A1 WO 2007128213 A1 WO2007128213 A1 WO 2007128213A1 CN 2007001405 W CN2007001405 W CN 2007001405W WO 2007128213 A1 WO2007128213 A1 WO 2007128213A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
sodium
solid
butanol
Prior art date
Application number
PCT/CN2007/001405
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English (en)
Chinese (zh)
Inventor
Qiming Ma
Original Assignee
Qiming Ma
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 Qiming Ma filed Critical Qiming Ma
Publication of WO2007128213A1 publication Critical patent/WO2007128213A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/04—Preparation
    • C07D499/14—Preparation of salts
    • C07D499/16—Preparation of salts of alkali or alkaline earth metals
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/04—Preparation
    • C07D499/18—Separation; Purification

Definitions

  • the present invention relates to a high purity and/or high content of barium sulphate sodium salt solid powder, a pharmaceutical composition containing the same, and a process for the preparation thereof.
  • the sodium penicillin salt is exemplified by the following: sodium salt of ticarcillin and carbenicillin.
  • Ticarcillin and carbenicillin are broad-spectrum semisynthetic penicillin antibiotics, which are carboxypenicillins, as shown in formula I, wherein Ar is thiophen-3-yl (tencacillin) or phenyl (carboxylin).
  • Ar is thiophen-3-yl (tencacillin) or phenyl (carboxylin).
  • its disodium salt (Formula II, Ar is a thiophen-3-yl or phenyl group) and a ⁇ -lactamase inhibitor, such as potassium clavulanate, are prepared into a variety of preparations for various Treatment of bacterial infections.
  • the solid powder of the compound of the formula II is prepared by converting the compound of the formula I into an aqueous solution of the compound of the formula II and then lyophilizing it (US Pa tent 4, 066, 664), mainly because the compound of formula II is very water-soluble.
  • the lyophilization method usually causes impurities in the aqueous solution to be difficult to be removed during the conversion, and all the impurities are precipitated together with the product after lyophilization, resulting in a large amount of impurities in the frozen powder and a relatively low purity, which affects the quality of the product.
  • the content of ticarcillin disodium salt lyophilized powder produced by freeze-drying method is generally 90%, and the purity is 93%. about. Summary of the invention
  • the object of the invention is to obtain high purity and/or high content of the compound of formula I I
  • the first aspect of the invention relates to a solid powder of the compound of formula I I in an amount of at least 97%,
  • Ar is thiophen-3-yl or phenyl.
  • a further aspect of the invention relates to a solid powder of a compound of formula I I having a purity of at least 98%,
  • Ar is thiophen-3-yl or phenyl.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a solid powder of a compound of formula II in an amount of at least 97% and/or a purity of at least 98%, and a pharmaceutically acceptable carrier or excipient.
  • the invention further relates to a process for the preparation of a solid powder of a compound of formula II in an amount of at least 97% and/or a purity of at least 98%, which comprises: a) dropwise addition of an aqueous solution of a compound of formula II to an organic solvent such as an alcohol or a ketone organic solvent To precipitate a solid, filter and vacuum dry to give a solid of the compound of formula II; or b) in a solution of a compound of formula I in a fat-soluble organic solvent such as an ester or ether, adding a small amount of water, alcohol or ketone to the organic solvent And a sodium-containing salt or hydroxide, the compound of formula I is converted to the sodium salt of the compound of formula II and precipitated, and the solid of the compound of formula II is obtained by filtration and vacuum drying.
  • the method has the advantages of less solvent usage and simple process operation.
  • the invention further relates to the use of a compound of formula I I at a level of at least 97% and/or a purity of at least 98%, alone or in combination with a beta-lactamase inhibitor, for the preparation of an antibiotic.
  • the organic solvent used in the production method a) of the present invention is a water-miscible alcohol solvent and a ketone solvent, for example: ethanol, propanol, isopropanol, n-butanol, 2-butanol, Isobutanol, tert-butanol, acetone, butanone, etc., preferably isopropanol and acetone, more preferably isopropanol; b) alcohol solvent used in the process, including methanol, ethanol, propanol, isopropanol, n-butanol, 2-butanol, isobutanol, tert-butanol, ketone solvents include acetone, butanone and ester solvents or ether solvents, examples of fat-soluble organic solvents such as: methyl acetate, ethyl acetate, acrylic acid Ester, butyl acetate, isopropyl acetate, is
  • the alcohol in the solvent is preferably decyl alcohol, ethanol or isopropanol; the ester is preferably ethyl acetate; and the ether is preferably methyl tert-butyl ether and tetrahydrofuran.
  • the sodium-containing salt used in the production method of the present invention includes an inorganic salt or an organic salt containing sodium, such as, for example, sodium carbonate, sodium hydrogencarbonate, sodium isooctanoate, etc.; Speak, such as sodium hydroxide.
  • Sodium hydrogencarbonate and sodium carbonate are preferred.
  • the compound of the formula I I is at least 97% by weight in the solid powder of the compound of the formula I I, for example: 97.1%, 97.5%, 97.2%, 98. 1%,
  • the compound of the formula I I of the present invention has a purity of at least 98% by weight in the solid powder of the compound of the formula I I, for example: 98. 03%, 98.80%, 98.96%, 99. 21%,
  • the compounds of formula I used in the present invention can be prepared by methods known in the art, such as in U.S. Patent No. 4,066,664.
  • the pharmaceutical composition of the present invention may further contain a ⁇ -lactamase inhibitor such as potassium clavulanate for the treatment of various infectious diseases.
  • a ⁇ -lactamase inhibitor such as potassium clavulanate
  • the high content and/or high purity solid powder of the compound of the invention may be combined with a beta-lactam inhibitor.
  • Example 1 Preparation of 98.7% and purity 99.68% of ticarcillin disodium solid powder
  • the water is separated from the aqueous solution, and the aqueous solution is added to the aqueous solution of the aqueous solution, and the aqueous solution is adjusted to a pH of 6.5. Floor.
  • the aqueous layer was slowly added dropwise to 100 mL of isopropanol, filtered, and the cake was washed with a small amount of isopropanol, and the white powdery solid of ticarcillin disodium was 7. 9 g, yield 93%.
  • the purity was 99.68% (HPLC), and the content was 98.7%.
  • Example 2 Preparation 98.5% and purity 99. 25% Preparation of ticarcillin disodium solid powder
  • Ticarcillin sodium 300 g (calculated as ticarcillin)
  • Example 1 of the present invention The content and purity of the compound of Example 1 of the present invention and the commercially available ticarcillin disodium salt were compared by the method of the fifth edition of the European Pharmacopoeia. The results are shown in Table 1.
  • Table 1 Commercially available ticarcillin disodium salt and the implementation of the present invention Example 1 compound *1 purity and content comparison * 2

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

Abstract

Poudre solide de sel de sodium de pénicilline, notamment de sel de sodium de ticarcilline et de sel de sodium de carbénicilline à pureté et/ou teneur élevées, sa composition médicamenteuse la contenant et sa préparation.
PCT/CN2007/001405 2006-05-08 2007-04-26 Poudre solide de sel de sodium de pénicilline a pureté et/ou teneur élevée, et sa préparation WO2007128213A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200610076501.3 2006-05-08
CNA2006100765013A CN101070326A (zh) 2006-05-08 2006-05-08 高纯度和/或高含量青霉素钠盐固体粉末及其制备方法

Publications (1)

Publication Number Publication Date
WO2007128213A1 true WO2007128213A1 (fr) 2007-11-15

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ID=38667428

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2007/001405 WO2007128213A1 (fr) 2006-05-08 2007-04-26 Poudre solide de sel de sodium de pénicilline a pureté et/ou teneur élevée, et sa préparation

Country Status (2)

Country Link
CN (1) CN101070326A (fr)
WO (1) WO2007128213A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103030649B (zh) * 2012-12-28 2014-09-03 吴秋萍 一种替卡西林钠化合物及其与克拉维酸钾化合物的组合物

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PL84872B1 (fr) * 1972-03-30 1976-04-30
PL87153B1 (pl) * 1973-07-13 1976-12-15 Tarchomińskie Zakłady Farmaceutyczne Sposób otrzymywania krystalicznej soli dwusodowej penicyliny a-karboksybenzylowej
PL93437B1 (fr) * 1974-03-07 1977-05-30
CN1720915A (zh) * 2005-07-20 2006-01-18 夏中宁 抗β－内酰胺酶抗菌素复方制剂

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PL84872B1 (fr) * 1972-03-30 1976-04-30
PL87153B1 (pl) * 1973-07-13 1976-12-15 Tarchomińskie Zakłady Farmaceutyczne Sposób otrzymywania krystalicznej soli dwusodowej penicyliny a-karboksybenzylowej
PL93437B1 (fr) * 1974-03-07 1977-05-30
CN1720915A (zh) * 2005-07-20 2006-01-18 夏中宁 抗β－内酰胺酶抗菌素复方制剂

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Columbus, Ohio, US; abstract no. 87:201515 *
CHEMICAL ABSTRACTS, Columbus, Ohio, US; abstract no. 88:6875 *
CHEMICAL ABSTRACTS, Columbus, Ohio, US; abstract no. 90:121587 *

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CN101070326A (zh) 2007-11-14

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