WO2010097675A1 - Procédé de préparation amélioré pour le cefpodoxime proxétil - Google Patents

Procédé de préparation amélioré pour le cefpodoxime proxétil Download PDF

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Publication number
WO2010097675A1
WO2010097675A1 PCT/IB2010/000330 IB2010000330W WO2010097675A1 WO 2010097675 A1 WO2010097675 A1 WO 2010097675A1 IB 2010000330 W IB2010000330 W IB 2010000330W WO 2010097675 A1 WO2010097675 A1 WO 2010097675A1
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Prior art keywords
minutes
undec
ene
diazabicyclo
acetate
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PCT/IB2010/000330
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English (en)
Inventor
Rajendra Kumar Dubey
Sandeep Singh
Manish Dhanuka
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Dhanuka Laboratories Ltd.
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Publication of WO2010097675A1 publication Critical patent/WO2010097675A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/02—Preparation
    • C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents

Definitions

  • the present invention relates to an improved process for the preparation of cefpodoxime proxetil from cefpodoxime acid.
  • cefpodoxime proxetil is l-isopropoxycarbonyloxyethyl(6R,7R)-7-[2-(2- aminothiazol-4-yl)-2-(Z)-(methoxyimino)acetamido]-3-(methoxymethyl)-3-cephem-4- carboxylate of Formula 1 and is disclosed in U.S. Patent No. 4, 486,425.
  • Cefpodoxime proxetil is one of the limited class of third generation cephalosporin derivatives which can be administered orally as it is readily adsorbed through the digestive tract and which is then readily hydrolyzed and converted in vivo to the corresponding carboxylic acid which, in turn, shows outstanding antibacterial activity against both gram-positive and gram-negative bacteria.
  • Pharmaceutical compounds are required in highly pure form because of the fear of unknown and potentially harmful effects of impurities. For purposes of patients' safety, it is highly desirable to limit the amount of impurities present in any medicament administered to a patient. This is achieved by either devising a process for or by additional purification steps like chromatography or recrystallization etc. The purity of intermediates and raw materials is essential for obtaining the target pharmaceutical compounds in high yield and purity.
  • WO 2004/060896Ai teaches a process for the preparation of Cefpodoxime proxetil free of impurities having a isomeric ratio ranging between 0.5 - 0.6.
  • US 2006/0009639Ai describes an improved process of the preparation of
  • Cefpodoxime proxetil having purity of 99.22% (HPLC) and ⁇ 3 -isomer of 0.36%.
  • Cefpodoxime proxetil having an assay upto98%.
  • Cefpodoxime proxetil prepared using various prior art processes have yields ranging from 42% - 92% ,HPLC purity 92% - 99.22%, assay up to 98% and R/R+S ratio ranging between 0 .51 to 0.54, more particularly when Diisopropyl ethylamine, Tetramethyl Guanidine is used as a base in the preparation, yield of the product ranged from 81% to 92%.
  • few of the processes described in the prior art did not reveal important parameters viz. R/R+S ratio or assay of the product Cefpodoxime proxetil obtained to establish its conformity with pharmacopial grade for establishing its commercial utility.
  • the present invention has met such need by providing a process for the preparation of cefpodoxime proxetil having enhanced assay and yield.
  • the present invention relates to processes for the preparation of cefpodoxime proxetil (I) by reacting cefpodoxime acid (II) with 1-iodoethylisopropyl corbonate (III) in presence of mixture of organic and inorganic bases, followed by workup to yield crude cefpodoxime proxetil, which is subsequently converted into its methane sulfonate salt followed by basifying the salt thus obtained up to pH 4.5 to yield cefpodoxime proxetil (I) having enhanced yield and assay .
  • An embodiment of present invention provides a process wherein in step (b) the temperature preferably ranges between -10 0 C to -15°C
  • step (b) organic base used is selected from a group consisting of tetramethyl guanidine(TMG) and 1, 8- diazabicyclo-undec-7-ene(DBU)
  • step (b) inorganic base used is selected from a group consisting of sodium acetate, sodium carbonate, potassium acetate, potassium carbonate, calcium acetate and calcium carbonate .
  • Still another embodiment of the present invention provides a process wherein in step(b) the mixture of base used is selected from a group of tetramethyl guanidine-sodium acetate, tetramethyl guanidine- sodium carbonate, tetramethyl guanidine- potassium acetate, tetramethyl guanidine- potassium carbonate, tetramethyl guanidine- calcium acetate, tetramethyl guanidine- calcium carbonate,, 1 ,8- diazabicyclo-undec-7-ene- sodium acetate, 1 ,8 diazabicyclo-undec-7-ene - sodium carbonate, 1,8- diazabicyclo-undec-7-ene - potassium acetate, 1,8- diazabicyclo-undec- 7-ene - potassium Carbonate, 1,8- diazabicyclo-undec-7-ene - calcium acetate and 1 ,8- diazabicyclo-undec-7-ene
  • An embodiment of the present invention provides a process wherein most preferred mixture of base used is 1,8- diazabicyclo-undec-7-ene-sodium acetate
  • Another embodiment of the present invention provides a process wherein the molar ratio of 1, 8- diazabicyclo-undec-7-ene-sodium acetate and tetramethyl guanidine- sodium acetate ranges from 0.9:.0.15 to 0.75:.30.
  • the process of present invention has provided an exemplified results by obtaining cefpodoxime proxetil product having an enhanced yield and assay up to 99.25% with concomitant control in the formation of ⁇ 3 impurity to less than 0.3%, which could not be achieved by adapting any of the prior art processes described.
  • Cefpodoxime acid was prepared as per the procedure described in US patent document no.4,486,425.
  • Cefpodoxime acid (40.0 gm; 0.0936 moles) was dissolved in dimethylacetamide (200 ml) and cooled to -10° C. (12.10 g ; 0.0796 moles) of l ,8-diazabicyclo[5,4,0]undec-7- ene was added drop wise maintaining the temperature in the range of -10 to -15° C in 10 minutes , stirred for 5 minutes. Anhydrous sodium acetate((1.54 g; 0.0188 moles) was added and stirred for 10 minutes., followed by addition of 1-iodoethylisopropyl carbonate(26.58 gm; 0.1030 moles) at -10 to -15°C over a period of 10 minutes.
  • reaction mixture was stirred for further 30 minutes
  • the reaction mixture was worked up by adding hydrochloric acid (4 ml) in (40 ml) water maintaining the temperature in the range of -15 0 C to +1O 0 C. followed by adding solution of (8.0 gm) of sodium thiosulphate in (800 ml) water and ethyl acetate (400ml).
  • the aqueous and organic layers were separated.
  • Aqueous layer is again extracted with ethyl acetate (200 ml). Combined both ethyl acetate layer and washed with 10% brine solution (300 ml x 3) at 10 0 C.
  • Organic layer was treated with activated carbon (8.0 gm) and sodium dithionite (2.0 gm) for 60 minutes and filtered.
  • the organic layer was concentrated under vacuum at 25°C.up to (140 ml) and cooled to 10 0 C.
  • the solution of crude cefpodoxime proxetil in ethyl acetate was treated with a solution of methanesulfonic acid (12.0 gm 0.125 moles) in water (400 ml) and stir for 15 minutes at 15°C, cyclohexane (100 ml) was added to the reaction mixture and stirred for 15 minutes.
  • the organic and aqueous layer was separated. The aqueous layer was de-gas under vacuum for 30 minutes at 25°C.
  • Cefpodoxime acid (10.0 g; 0.0234 moles) was dissolved in dimethylacetamide (50 ml) and cooled to -10° C.
  • Anhydrous sodium acetate (2.020 g ; 0.0246 moles) was added at 30 0 C to35°C. stirred for 10 minutes.
  • 1-iodoethylisopropyl carbonate (6.64 g; 0.0257 moles) was added at -10 to -15°C within 10 minutes. The reaction mixture was stirred for further 30 minutes and worked up as per example no.
  • EXAMPLE (5) Cefpodoxime acid (20.0 gm; 0.0468 moles) was dissolved in dimethylacetamide (100 ml) and cooled to -10° C. (6.05 g ; 0.0398 moles) of l,8-diazabicyclo[5,4,0]undec-7- ene was added drop wise over -10 0 C to -15°C in 10 minutes . Stirred for 5 minutes. Anhydrous sodium acetate(0.768g; 0.00936 moles) was added and stirred for 10 minutes. 1-iodoethylisopropyl carbonate(13.29gm; 0.0515 moles) was added at -10 to - 15°C within 10 minutes.
  • reaction mixture was stirred for further 30 minutes and hydrochloric acid (2 ml) in (20 ml) was added was added at -15°C to +10 0 C.
  • a solution of sodium thiosulphate (4.0 gm) in (400 ml) water was added followed by ethyl acetate (200ml) at 10 0 C.
  • the aqueous and organic layers were separated.
  • Aqueous layer is again extracted with ethyl acetate (100 ml). Combined ethyl acetate layer and washed with 10% brine solution (150 ml x 3) at 10 0 C.
  • Washed organic layer was treated with activated carbon (4.0 gm) and sodium dithionite (1.0 gm) for 60 minutes and filtered.
  • EXAMPLE (6) Cefpodoxime acid (20.0 gm; 0.0468 moles) was dissolved in dimethylacetamide (100 ml) and cooled to -10° C. (6.05 g ; 0.0398 moles) of l,8-diazabicyclo[5,4,0]undec-7- ene was added drop wise over -10 to -15° C over a period of 10 minutes . Stirred for 5 minutes. Anhydrous sodium acetate(0.768 g; 0.00936 moles) was added and stirred for 10 minutes.1-iodoethylisopropyl carbonate( 13.29 gm; 0.0515 moles) was added at - 10 0 C to -15°C within 15 minutes.
  • reaction mixture was stirred for further 30 minutes and hydrochloric acid (2.0 ml )in (20 ml) water was added maintaining the temperature between -15°C to +10 0 C.
  • hydrochloric acid 2.0 ml )in (20 ml) water was added maintaining the temperature between -15°C to +10 0 C.
  • the aqueous and organic layers were separated. Aqueous layer was again extracted with ethyl acetate (100 ml). Combined ethyl acetate layer washed with 10% brine solution (150 ml x 3) at 10 0 C. Washed ethyl acetate layer was treated with activated carbon (4.0 gm) and sodium dithionite (1.0 gm) for 60 minutes and filtered.
  • EXAMPLE (7) Cefpodoxime acid (30.0 gm; 0.07025 moles) was dissolved in dimethylacetamide (150 ml) and cooled to -10° C. Tetramethyl guanidine (7.92gm, 0.0688mols) was added drop wise over -10 to -15° C in 10 minutes . Stirred for 5 minutes. 1 -iodoethylisopropyl carbonate( 19.94 gm; 0.07728 moles) was added at -10 to -15°C within 10 minutes. The reaction mixture was stirred for further 30 minutes and hydrochloric acid (3.0 ml) in (30 ml) water was added at -15°C to +10 0 C.
  • Cefpodoxime acid (20.0 gm; 0.0468 moles) was dissolved in dimethylacetamide (100 ml) and cooled to -10° C.
  • Tetramethyl guanidine ( 5.28gm,0.0459mols) was added drop wise at a temperature ranging between -10 0 C to -15° C in 10 minutes Stirred for 5 minutes.
  • 1-iodoethylisopropyl carbonate (13.29gm; 0.0515 moles) was added at -10 0 C to -15°C within 15 minutes.
  • the reaction mixture was stirred for further 30 minutes and hydrochloric acid (2.0 ml)in (20 ml) water was added at -15°C to +10 0 C.
  • Cefpodoxime acid (20.0 gm; 0.0468 moles) was dissolved in dimethylacetamide (100 ml) and cooled to -10° C. (4.58 gm, 0.0398moles) of tetramethyl guanidine as added drop wise maintaining the temperature in the range of -10 0 C to -15°C in 10 minutes , stirred for 5 minutes.
  • Anhydrous sodium acetate((0.768 g; 0.00936 moles) was added and stirred for 10 minutes., followed by addition of 1-iodoethylisopropyl carbonate( 13.29 gm; 0.0515 moles) at -10°C to -15 0 C over a period of 15 minutes.
  • reaction mixture was stirred for further 30 minutes
  • the reaction mixture was worked up by adding hydrochloric acid (2 ml ) in (20 ml) water maintaining the temperature in the range of -15°C to +10 0 C. followed by adding solution of (4.0 gm) of sodium thiosulphate in water (400 ml) and ethyl acetate (200ml).
  • the aqueous and organic layers were separated.
  • Aqueous layer is again extracted with ethyl acetate ( 100 ml). Combined both ethyl acetate layer and washed with 10% brine solution (150 ml x 3) at 10 0 C.
  • Organic layer was treated with activated carbon (4.0 gm) and sodium dithionite (1.0 gm) for 60 minutes and filtered.
  • the organic layer was concentrated under vacuum at 25°C.up to volume (70 ml) and cooled to 10 0 C.
  • the solution of crude cefpodoxime proxetil in ethyl acetate was treated with a solution of methanesulfonic acid (6.0 gm 0.0625 moles) in water (200 ml) and stir for 15 minutes at 15°C, cyclohexane (50 ml) was added to the reaction mixture and stirred for 15 minutes.
  • the organic and aqueous layer was separated. The aqueous layer was de-gas under vacuum for 30 minutes at 25°C.
  • Cefpodoxime acid (20.0 gm; 0.0468 moles) was dissolved in dimethylacetamide (100 ml) and cooled to -10° C. (6.62 g ; 0.0435 moles) of l,8-diazabicyclo[5,4,0]undec-7- ene was added drop wise over -10 0 C to -15 0 C in 10 minutes . Stirred for 10 minutes. 1 - iodoethylisopropyl carbonate(1 1.70gm; 0.0453 moles) was added at -10 to - 15°C within 10 minutes.
  • reaction mixture was stirred for further 30 minutes and hydrochloric acid (1 ml) in (10 ml) was added was added at -15°C to +10°C.
  • a solution of sodium thiosulphate (2.0 gm) in (200 ml) water was added followed by ethyl acetate (100ml) at 10 0 C.
  • the aqueous and organic layers were separated.
  • Aqueous layer is again extracted with ethyl acetate (50 ml). Combined ethyl acetate layer and washed with 10% brine solution (75 ml x 3) at 10 0 C.
  • Washed organic layer was treated with activated carbon (2.0 gm) and sodium dithionite (0.5 gm) for 60 minutes and filtered.
  • the organic layer was concentrated under vacuum at 25°C.up to (35 ml) and cooled to 10 0 C.
  • the solution of crude cefpodoxime proxetil in ethyl acetate was treated with a solution of methanesulfonic acid (3.0 gm 0.03125 moles) in water (100 ml) and stir for 15 minutes at 15°C, cyclohexane (25 ml) was added to the reaction mixture and stirred for 15 minutes.
  • the organic and aqueous layer was separated. The aqueous layer was de-gas under vacuum for 30 minutes at 25°C.
  • Cefpodoxime acid (10.0 gm; 0.0234 moles) was dissolved in dimethylacetamide (50 ml) and cooled to -10° C. (3.56 g ; 0.0234 moles) of l,8-diazabicyclo[5,4,0]undec-7- ene was added drop wise over -10 0 C to -15°C in 10 minutes . Stirred for 10 minutes.
  • 1- iodoethylisopropyl carbonate (16.34 gm; 0.0245 moles) was added at -10 to -15 0 C within 10 minutes.
  • reaction mixture was stirred for further 30 minutes and hydrochloric acid (1 ml) in (10 ml) was added was added at -15°C to +10 0 C.
  • a solution of sodium thiosulphate (2.0 gm) in (200 ml) water was added followed by ethyl acetate (100ml) at 10 0 C.
  • the aqueous and organic layers were separated.
  • Aqueous layer is again extracted with ethyl acetate (50 ml). Combined ethyl acetate layer and washed with 10% brine solution (75 ml x 3) at 1O 0 C.
  • Washed organic layer was treated with activated carbon (2.0 gm) and sodium dithionite (0.5 gm) for 60 minutes and filtered.
  • the organic layer was concentrated under vacuum at 25°C.up to (35 ml) and cooled to 10 0 C.
  • the solution of crude cefpodoxime proxetil in ethyl acetate was treated with a solution of methanesulfonic acid (3.0 gm 0.03125 moles) in water (100 ml) and stir for 15 minutes at 15°C, cyclohexane (25 ml) was added to the reaction mixture and stirred for 15 minutes.
  • the organic and aqueous layer was separated. The aqueous layer was de-gas under vacuum for 30 minutes at 25°C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

La présente invention concerne un procédé amélioré pour la préparation de cefpodoxime proxétil de formule (I) à partir d'acide cefpodoxime (II) par réaction du carbonate de 1-iodoéthyl-isopropyle (III) dans un solvant aprotique en présence d'un mélange constitué de base organique ou inorganique à une température dans la plage de 0° à ‑20 °C pendant une durée de 10 minutes à 60 minutes. Plus particulièrement, l'invention concerne un procédé, caractérisé en ce que le cefpodoxime proxétil obtenu a une impureté d'isomère Δ3 inférieure à 0,3 % et un rapport R/R+S compris entre 0,5 et 0,6 avec un rendement et un essai améliorés.
PCT/IB2010/000330 2009-02-27 2010-02-22 Procédé de préparation amélioré pour le cefpodoxime proxétil WO2010097675A1 (fr)

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Cited By (19)

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Publication number Priority date Publication date Assignee Title
EP2520578A1 (fr) * 2011-05-06 2012-11-07 Lupin Limited Procédé pour la purfication de céphalosporines
US9012491B2 (en) 2011-08-31 2015-04-21 Rempex Pharmaceuticals, Inc. Heterocyclic boronic acid ester derivatives and therapeutic uses thereof
US9101638B2 (en) 2013-01-04 2015-08-11 Rempex Pharmaceuticals, Inc. Boronic acid derivatives and therapeutic uses thereof
US9132140B2 (en) 2013-01-04 2015-09-15 Rempex Pharmaceuticals, Inc. Boronic acid derivatives and therapeutic uses thereof
US9156858B2 (en) 2012-05-23 2015-10-13 Rempex Pharmaceuticals, Inc. Boronic acid derivatives and therapeutic uses thereof
WO2015179308A1 (fr) 2014-05-19 2015-11-26 Rempex Pharmaceuticals, Inc. Dérivés d'acide boronique et leurs utilisations thérapeutiques
US9241947B2 (en) 2013-01-04 2016-01-26 Rempex Pharmaceuticals, Inc. Boronic acid derivatives and therapeutic uses thereof
US9296763B2 (en) 2010-08-10 2016-03-29 Rempex Pharmaceuticals, Inc. Cyclic boronic acid ester derivatives and therapeutic uses thereof
US9642869B2 (en) 2013-01-04 2017-05-09 Rempex Pharmaceuticals, Inc. Boronic acid derivatives and therapeutic uses thereof
US9687497B1 (en) 2014-05-05 2017-06-27 Rempex Pharmaceuticals, Inc. Salts and polymorphs of cyclic boronic acid ester derivatives and therapeutic uses thereof
WO2018005662A1 (fr) 2016-06-30 2018-01-04 Rempex Pharmaceuticals, Inc. Dérivés d'acide boronique et leurs utilisations thérapeutiques
CN109232609A (zh) * 2018-09-27 2019-01-18 浙江普洛得邦制药有限公司 一种制备高纯度头孢泊肟酯的方法
US10206937B2 (en) 2014-07-01 2019-02-19 Qpex Biopharma, Inc. Boronic acid derivatives and therapeutic uses thereof
US10385074B2 (en) 2014-05-05 2019-08-20 Rempex Pharmaceuticals, Inc. Synthesis of boronate salts and uses thereof
WO2019204419A1 (fr) 2018-04-20 2019-10-24 The Medicines Company (San Diego), Llc Dérivés d'acide boronique et leurs utilisations thérapeutiques
US10561675B2 (en) 2012-06-06 2020-02-18 Rempex Pharmaceuticals, Inc. Cyclic boronic acid ester derivatives and therapeutic uses thereof
US10618918B2 (en) 2015-03-17 2020-04-14 Qpex Biopharma, Inc. Substituted boronic acids as antimicrobials
US10662205B2 (en) 2014-11-18 2020-05-26 Qpex Biopharma, Inc. Cyclic boronic acid ester derivatives and therapeutic uses thereof
US11286270B2 (en) 2017-10-11 2022-03-29 Qpex Biopharma, Inc. Boronic acid derivatives and synthesis thereof

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US10639318B2 (en) 2010-08-10 2020-05-05 Rempex Pharmaceuticals, Inc. Therapeutic uses of pharmaceutical compositions comprising cyclic boronic acid ester derivatives
US9694025B2 (en) 2010-08-10 2017-07-04 Rempex Pharmaceuticals, Inc. Cyclic boronic acid ester derivatives and therapeutic uses thereof
US9296763B2 (en) 2010-08-10 2016-03-29 Rempex Pharmaceuticals, Inc. Cyclic boronic acid ester derivatives and therapeutic uses thereof
US10183034B2 (en) 2010-08-10 2019-01-22 Rempex Pharmaceuticals, Inc. Therapeutic uses of pharmaceutical compositions comprising cyclic boronic acid ester derivatives
US10172874B2 (en) 2010-08-10 2019-01-08 Rempex Pharmaceuticals, Inc. Pharmaceutical compositions comprising cyclic boronic acid ester derivatives
US10004758B2 (en) 2010-08-10 2018-06-26 Rempex Pharmaceuticals, Inc. Cyclic boronic acid ester derivatives and methods of making the same
US11090319B2 (en) 2010-08-10 2021-08-17 Melinta Subsidiary Corp. Therapeutic uses of pharmaceutical compositions comprising cyclic boronic acid ester derivatives
US11684629B2 (en) 2010-08-10 2023-06-27 Melinta Subsidiary Corp. Therapeutic uses of pharmaceutical compositions comprising cyclic boronic acid ester derivatives
EP2520578A1 (fr) * 2011-05-06 2012-11-07 Lupin Limited Procédé pour la purfication de céphalosporines
US9012491B2 (en) 2011-08-31 2015-04-21 Rempex Pharmaceuticals, Inc. Heterocyclic boronic acid ester derivatives and therapeutic uses thereof
US9156858B2 (en) 2012-05-23 2015-10-13 Rempex Pharmaceuticals, Inc. Boronic acid derivatives and therapeutic uses thereof
US11007206B2 (en) 2012-06-06 2021-05-18 Melinta Subsidiary Corp. Cyclic boronic acid ester derivatives and therapeutic uses thereof
US10561675B2 (en) 2012-06-06 2020-02-18 Rempex Pharmaceuticals, Inc. Cyclic boronic acid ester derivatives and therapeutic uses thereof
US9642869B2 (en) 2013-01-04 2017-05-09 Rempex Pharmaceuticals, Inc. Boronic acid derivatives and therapeutic uses thereof
US9241947B2 (en) 2013-01-04 2016-01-26 Rempex Pharmaceuticals, Inc. Boronic acid derivatives and therapeutic uses thereof
US9132140B2 (en) 2013-01-04 2015-09-15 Rempex Pharmaceuticals, Inc. Boronic acid derivatives and therapeutic uses thereof
US9101638B2 (en) 2013-01-04 2015-08-11 Rempex Pharmaceuticals, Inc. Boronic acid derivatives and therapeutic uses thereof
US9687497B1 (en) 2014-05-05 2017-06-27 Rempex Pharmaceuticals, Inc. Salts and polymorphs of cyclic boronic acid ester derivatives and therapeutic uses thereof
US10385074B2 (en) 2014-05-05 2019-08-20 Rempex Pharmaceuticals, Inc. Synthesis of boronate salts and uses thereof
US10669292B2 (en) 2014-05-05 2020-06-02 Rempex Pharmaceuticals, Inc. Synthesis of boronate salts and uses thereof
US9963467B2 (en) 2014-05-19 2018-05-08 Rempex Pharmaceuticals, Inc. Boronic acid derivatives and therapeutic uses thereof
WO2015179308A1 (fr) 2014-05-19 2015-11-26 Rempex Pharmaceuticals, Inc. Dérivés d'acide boronique et leurs utilisations thérapeutiques
US10206937B2 (en) 2014-07-01 2019-02-19 Qpex Biopharma, Inc. Boronic acid derivatives and therapeutic uses thereof
US10662205B2 (en) 2014-11-18 2020-05-26 Qpex Biopharma, Inc. Cyclic boronic acid ester derivatives and therapeutic uses thereof
US10618918B2 (en) 2015-03-17 2020-04-14 Qpex Biopharma, Inc. Substituted boronic acids as antimicrobials
US10570159B2 (en) 2016-06-30 2020-02-25 Qpex Biopharma, Inc. Boronic acid derivatives and therapeutic uses thereof
WO2018005662A1 (fr) 2016-06-30 2018-01-04 Rempex Pharmaceuticals, Inc. Dérivés d'acide boronique et leurs utilisations thérapeutiques
US11180512B2 (en) 2016-06-30 2021-11-23 Qpex Biopharma, Inc. Boronic acid derivatives and therapeutic uses thereof
US10294249B2 (en) 2016-06-30 2019-05-21 Qpex Biopharma, Inc. Boronic acid derivatives and therapeutic uses thereof
US11999759B2 (en) 2016-06-30 2024-06-04 Qpex Biopharma, Inc. Boronic acid derivatives and therapeutic uses thereof
US11286270B2 (en) 2017-10-11 2022-03-29 Qpex Biopharma, Inc. Boronic acid derivatives and synthesis thereof
WO2019204419A1 (fr) 2018-04-20 2019-10-24 The Medicines Company (San Diego), Llc Dérivés d'acide boronique et leurs utilisations thérapeutiques
US12016868B2 (en) 2018-04-20 2024-06-25 Qpex Biopharma, Inc. Boronic acid derivatives and therapeutic uses thereof
CN109232609A (zh) * 2018-09-27 2019-01-18 浙江普洛得邦制药有限公司 一种制备高纯度头孢泊肟酯的方法

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