Optimization of AR-3 synthesis

Andrzej Leś 1,2Katarzyna Badowska-Rosłonek 1Marta Łaszcz 1Agata E. Kamieńska-Duda 1Piotr Baran 1Łukasz S. Kaczmarek 1

1. Pharmaceutical Research Institute (IF), Rydygiera 8, Warszawa 01-793, Poland
2. Warsaw University, Faculty of Chemistry, Pasteura 1, Warszawa 02-093, Poland

Abstract

The reaction of quinolinone derivative 1 with piperazine derivative 2 giving AR-3 was carried out at laboratory scale (10 mmol of 1 ) under various conditions in order to achieve high yield and purity of the product. The reaction parameters (1 : 2 ratio, amount of base, volume of ethanol and the reaction timing) were sampled guided by the D-optimal plans. Molar content of crude reaction product was predicted theoretically with the use of the mass balance and the corresponding HPLC parameters. The theoretical predictions were verified with the potentiometric and thermogravimetric analysis for selected samples. Based on the predicted molar content of reaction mixtures a series of reaction response surfaces was calculated. From analysis of these surfaces it appears that there exists an optimal set of reaction parameters for AR-3 synthesis for a high conversion ratio of about 99 % and 99.5 % purity of the product.

Keywords: optimization, synthesis, reaction response surface

 

 

 

 

 

 

Related papers
  1. Hplc study of Cilostazol tablets: assay and release profile determination
  2. Application of the new data processing method for photodiode array detector in the analysis of drug substances
  3. Improved manufacturing process of bosentan monohydrate.
  4. Characterization of dutasteride polymorphic forms
  5. Bioequivalence study of ondansetron film-coated tablets in healthy volunteers
  6. Validation of HPLC methods for analyzing the chemical purity of cilostazol
  7. Identification of degradation products of cilostazol drug substance
  8. Capecitabine molecular structure in the liquid state as predicted from NMR measurements and theoretical calculations.
  9. Preparation and physicochemical properties of crystalline forms and amorphous pemetrexed disodium
  10. Comparison of bisoprolol pharmacokinetics after 10 mg oral administration of Bisocard and reference formulation to healthy subjects
  11. Bioequivalence study of 500 mg cefuroxime film-coated tablets in healthy volunteers
  12. An application of accelerator mass spectrometry (AMS) in pediatric clinical studies. Paracetamol, midazolam and spironolactone radiosynthesis and certification.
  13. HPLC methods for in–process control and chemical purity determination of olopatadine
  14. An improved process for the preparation of 2-amino-N-tert-butyl-2-cyanoamide hydrochlorie.
  15. Efficient preparation of a key intermediate in the exemestane synthesis
  16. Physicochemical characterization of sunitinib and its impurities
  17. Distinguishing between polymorphic forms of linezolid by solid-phase electronic and vibrational circular dichroism
  18. Preparation of protoaescigenin from escin.
  19. Analytical control of synthesis and determination of BR-S by HPLC
  20. Optimization of BR-8 synthesis
  21. Opimisation of preparation of TZ-6
  22. Validation of a HPLC method for LI-S analysis
  23. HPLC Methods for Stress Testing of ZL-S Drug Substances
  24. Structural characterization of PX-S
  25. Quantification of active substance in drug by Rietveld analysis
  26. Zolmitriptan synthesis and in-process control by HPLC methods
  27. The determination of chromatografic purity of Pramipexole Dihydrohloride Monohydrate
  28. The cytotoxic activity of glycosides of indolo[2,3-b]quinoline derivatives.
  29. Disubstituted indolo[2,3-b]quinoline derivatives - the cytotoxic activity in vitro against various human tumor cell lines.
  30. Mono substituted 5H- and 6H-indolo[2,3-b]quinoline derivatives and their ability to overcome the barrier of drug resistance.
  31. Validation of an analytical procedure – control of residual 8 solvents in a pharmaceutical substance
  32. Application of confidence intervals to bioanalytical method validation
  33. High-yielded method of synthesis of voriconazole.
  34. Development of HPLC and GC methods for analysis of Zolmitriptan of pharmaceutical purity
  35. CHARACTERIZATION OF ARIPIPRAZOLE SOLVATE WITH ETHANOL AND POLYMORPHIC FORMS PRODUCED DURING ITS HEATING
  36. HPLC SEPARATION AND DETERMINATION OF ZIPRASIDONE
  37. THE VALIDATION OF ANALYTICAL METHODS OF A PHARMACEUTICAL ACTIVE SUBSTANCE PRODUCED IN SMALL SCALE PLANT (SSP). THE EXAMPLE OF PIOGLITAZONE HYDROCHLORIDE.
  38. OPTIMIZATION OF CHIRAL SEPARATION ON VARIOUS POLISACCHARIDE STATIONARY PHASES
  39. OPTIMIZATION OF THE CHROMATOGRAPHIC SEPARATION BY HPLC METHOD AND CONFIRMATION OF THE IDENTITY OF CHOSEN ESCITALOPRAM OXALATE INTERMEDIATE PRODUCTS
  40. SYNTHESIS OF GLIMEPIRIDE - CRYSTAL STRUCTURE ANALYSIS STEP BY STEP
  41. GC METHOD FOR QUANTITATIVE DETER- MINATION OF RESIDUAL 2-(2-CHLORO- ETOXY)ETHANOL (CEE) AND N-METHYL- 2-PYRROLIDINONE (NMP) IN PHARMACEU- TICAL ACTIVE SUBSTANCE
  42. THE CYTOTOXIC GLYCOSIDES OF INDOLO[2,3-B]QUINOLINE DERIVATIVES. IN VITRO AND IN VIVO STUDIES
  43. MONO SUBSTITUTED 5H-INDOLO[2,3-B]- QUINOLINE DERIVATIVES AND THEIR ABILITY TO OVERCOME THE BARRIER OF DRUG RESISTANCE.
  44. DISUBSTITUTED INDOLO[2,3-b]QUINOLINE DERIVATIVES. THE CYTOTOXIC ACTIVITY IN VITRO AGAINST VARIOUS HUMAN TUMOR CELL LINE.
  45. SYNTHESIS OF PIOGLITAZONE HYDROCHLORIDE OF PHARMACEUTICAL PURITY AT SMALL PLANT SCALE
  46. NEW IMPROVED METHOD OF POLYMORPHIC α FORM OF IMATINIB MESYLATE (GLEEVEC®) SYNTHESIS.
  47. 1H AND 13C NMR DATA FOR INDOLO[2,3-b]QUINOLINES - AMINOGLYCOSIDE HYBRIDS, A NOVEL POTENT ANTICANCER DRUG FAMILY .
  48. NEW SYNTHESIS OF 11-(1-PIPERAZINYL)- DIBENZO[b,f][1,4]THIAZEPINE, A CRUCIAL INTERMEDIATE IN QUETIAPINE PRODUCTION.

Presentation: Poster at VI Multidyscyplinarna Konferencja Nauki o Leku, by Katarzyna Badowska-Rosłonek
See On-line Journal of VI Multidyscyplinarna Konferencja Nauki o Leku

Submitted: 2008-03-10 15:08
Revised:   2009-06-07 00:48