Hazardous solvents have a high potential for causing acute health risks, including serious health problems such as cancer. They should be avoided or limited in pharmaceutical and chemical synthesis owing to the health hazards and safety issues. A method of amide coupling reaction 

was developed employing the recommended solvents to replace the hazardous solvents. The reactions  were  observed  using  the  RP-HPLC  method  to  detect  reaction  rate  of  aniline  and benzoic  acid  to  produce  N-phenyl  benzamide.  68.33%,  79.25%  and  89.81%  yields  were 

synthesized using the solvents: acetone (Ace), dimethyl sulfoxide (DMSO), and ethanol (EtOH) respectively  while  87.60%  was  produced  by  hazardous  solvent:  N,  N-dimethyl  formamide (DMF). Using this approach, adjusting the pH10 of the organic solvent increases reaction yield 

up to 34.67%, 4.65%, and 3.84% for Ace, DMSO, and EtOH, respectively. In drug synthesis, the  proposed  method  can  be  applied  in  wide  range  to  get  the  protection  from  the  risks  of hazardous solvents. The method can be anticipated in future to be an exciting basic method in 

synthetic chemistry

Helal Uddin, A.B.M.

The International Islamic University Malaysia Repository

    PROCEEDINGS OF  III. INTERNATIONAL AGRICULTURAL, BIOLOGICAL & LIFE SCIENCE CONFERENCE AGBIOL 2021  SEPTEMBER 1-3, 2021   EDIRNE, TURKEY             PROCEEDINGS OF  III. INTERNATIONAL AGRICULTURAL, BIOLOGICAL & LIFE SCIENCE CONFERENCE AGBIOL 2021   1 – 3 SEPTEMBER 2021,  EDIRNE, TURKEY   Organized by  Trakya University  ISBN #: 978-975-374-300-6 Trakya University Publisher #:  257III. International Agricultural, Biological & Life Science Conference, Edirne, Turkey, 1-3 September 2021 3  WELCOME NOTES  You are welcome to our III. AGBIOL Conference that is organized by Trakya University. The aim of our conference is to present scientific subjects of a broad interest to the scientific community, by providing an opportunity to present their work as oral or poster presentations that can be of great value for global science arena. Our goal was to bring three communities, namely science, research and private investment together in a friendly environment of Edirne, Turkey in order to share their interests and ideas and to benefit from the interaction with each other but we have to organize as online due to Covid_19 stiuation again. I hope next one we could host you in Edirne. In September 2018, we organized the first AGBIOL Conference with more than 700 scientists and researchers from all over the world with over 800 scientific papers. Due to COVID-19 situation, II. AGBIOL 2020 has organized fully on-line event which was one of the biggest online conferences in recent years in the world with 499 papers and 1133 authors with 333 oral and 166 e-poster presentations from 55 countries. Therefore, this great interest gave ambition to organizers to make it a periodical event then we decided to organize 3rd one in this year.   The Organizing Committee of AGBIOL 2021 considers the health, safety, and security of its conference attendees and community as its top priority. Due to COVID-19 situation, which results in a very difficult travel restriction for most countries and the fact that there is no definite end in sight, with a careful consideration in all aspects, then AGBIOL 2021 has decided to move towards the organization of on-line again but with limited participation. There is a worldwide participation from 44 countries with 422 papers by contributing 1066 authors. Our AGBIOL 21 conference was organized with 288 oral, 134 e-poster presentations. The participants with paid conference fee will be able to access all the virtual presentation talks in each session, as well as to visit the virtual poster hall via preliminary provided participant ID and codes. The selected ABSTRACTs will be published in the Conference ABSTRACT and Proceedings Book. Participants might send us their full papers, which based on their preferences will be published either in our Conference ABSTRACT and Proceedings Book or in selected International Indexed Scientific Journals.  Conference Topics: Agriculture, Forestry, Life Sciences, Agricultural Engineering, Aquaculture and Biosystems, Animal Science, Biomedical science, Biochemistry and Molecular Biology, Biology, Bioengineering, Biomaterials, Biomechanics, Biophysics, Bioscience, Biotechnology, Botany, Chemistry, Chemical Engineering, Earth Sciences, Environmental Science, Food Science, Genetics and Human Genetics, Medical Science, Machinery, Pharmaceutical Sciences, Physics, Soil Science. We would like to thank all of you for joining this conference and we would like to give also special thanks to our sponsors and collaborators for giving us a big support to organize this event.              Prof Dr Yalcin KAYA Head of the Organizing Committee III. International Agricultural, Biological & Life Science Conference, Edirne, Turkey, 1-3 September 2021 266  METHODOLOGY FOR THE ALTERATION OF HAZARDOUS SOLVENTS IN DRUG SYNTHESIS Tariqul Islam, Md. Zaidul Islam Sarker*, ABM Helal Uddin  Faculty of Pharmacy, International Islamic University Malaysia, 25200 Kuantan, Pahang, Malaysia  *Corresponding author: zaidul@iium.edu.my  ABSTRACT Hazardous solvents have a high potential for causing acute health risks, including serious health problems such as cancer. They should be avoided or limited in pharmaceutical and chemical synthesis owing to the health hazards and safety issues. A method of amide coupling reaction was developed employing the recommended solvents to replace the hazardous solvents. The reactions were observed using the RP-HPLC method to detect reaction rate of aniline and benzoic acid to produce N-phenyl benzamide. 68.33%, 79.25% and 89.81% yields were synthesized using the solvents: acetone (Ace), dimethyl sulfoxide (DMSO), and ethanol (EtOH) respectively while 87.60% was produced by hazardous solvent: N, N-dimethyl formamide (DMF). Using this approach, adjusting the pH10 of the organic solvent increases reaction yield up to 34.67%, 4.65%, and 3.84% for Ace, DMSO, and EtOH, respectively. In drug synthesis, the proposed method can be applied in wide range to get the protection from the risks of hazardous solvents. The method can be anticipated in future to be an exciting basic method in synthetic chemistry. Keywords: N-phenyl benzamide, Hazardous solvent, amide coupling reaction, Reaction yield, RP-HPLC method.          Research TitleMethodology for the Alteration of Hazardous Solvents in Drug SynthesisIII. INTERNATIONAL AGRICULTURAL, BIOLOGICAL &LIFE SCIENCE CONFERENCE1-3 September, 2021, Edirne, TurkeyTariqul Islam, Md. Zaidul Islam Sarker*, ABM Helal UddinPresented byTariqul IslamOutlines 11. Background2. Objective3. Methodology Flowchart of methodology Solvent selection by Kamlet Taft (KT) parameters Synthesis procedure4. Result and Discussion KT properties of pure solvents and solvent-pair mixtures Curve for KT properties Comparison of HPLC chromatograms between normal pH and pH adjusted synthesis Reaction conversion curve of pure solvents Yield curve of pure solvents Reaction conversion curve of solvent-pair mixtures Yield curve of solvent-pair mixtures5. ConclusionBackground1. Solvents are an unavoidable part of pharmaceutical and chemical synthesis2. 80-90% solvents of the non-aqueous volume is used in the synthesis of APIs in routine GSK development processes3. 83% of the 680000 amidation reactions performed by DMF, DCM4. Majority of crucial solvents have a high potential for causing acute health risks, including safety and environmental hazards and also makes the problem in pharmaceutical preparationSolvent Concern (comment)Most used solvents Pfizer GSK Sanofi ICHDMF Undesirable Major issues Substitution requested To be limitedDMAC Undesirable Major issues Substitution requested To be limitedNMP Undesirable Major issues Substitution requested To be limitedDCM Undesirable Major issues Substitution advisable To be limitedChloroform Undesirable Major issues No comment To be limitedDioxane Undesirable Major issues Substitution requested To be limitedPyridine Undesirable No comment Substitution advisable To be limitedIPE Undesirable Major issues Substitution advisable Unknown2Objectives Our target to replace the dipolar aprotic solvents containing hydrogen bond acceptor solvent (HBA) Since present HBA solvents (e.g. NMP, DMF) are used for processing API have both severe health andsafety issues, we propose to study one or more common amide coupling reactions with solvent-pairmixtures and pure solvent to understand the comparison of solvent replacement according to reactionkinetics. Application of pure solvent and solvent-pair mixture in N-phenylbenzamide synthesis3MethodologyList of pure solventsAcidity, basicity and polarity determination by Kamlet-Taft parametersAcidity, basicity and polarity determination using Kamlet-Taft parametersPrepare solvent-pair mixture (1:1)Result justification of solvent/solvent-pairs using GSK2016 health & safety scores and Chem21 guidelinepH measurementApply the solvent/solvent-pair to the synthesisReaction?NoYes: Final selectionFlowchart44List of pure solventsAcidity, basicity and polarity determination by Kamlet-Taft parametersAcidity, basicity and polarity determination using Kamlet-Taft parametersPrepare solvent-pair mixture (1:1)Result justification of solvent/solvent-pairs using GSK2016 health & safety scores and Chem21 guidelinepH measurementApply the solvent/solvent-pair to the synthesisReaction?Yield observationFinal selection of solvent/solvent mixture for specific drug synthesisKamlet-Taft (KT) solvatochromic parameters (For 10 pure solvents and 16 solvent-pairs)• Indicator 1: Polarity (π) = (28.10 – Vmax1) / 3.52                           (eq. 1)• Indicator 2: Basicity (β) = (0.984Vmax1 + 3.49 – Vmax2) / 2.759         (eq. 2)• Indicator 3: Acidity (α) = (1.318Vmax1 – 47.7 + Vmax3) / 5.47 (eq. 3)The wavenumber (Vmax) from wavelength (nm) is converted into KiloKaiser unit (1KK = 1000 cm-1 =10000/λmax (nm) require to calculate the π*, β, α.Methodology1. Double beam UV-VIS spectrophotometer with 0.2 nm resolution was applied to determine theabsorbance of the solvent with indicator at temperature of 25 ± 0.1 °C.2. The concentration was for indicator 1: N,N-dimethyl-4-nitroaniline (0.03 mM to 0.05 mM),indicator 2: 4-nitroaniline (0.03 mM to 0.05 mM), and indicator 3: 2,6-diphenyl-4-(2,4,6-triphenyl-1-pyridinio) phenolate (0.1mM) in the solvent or solvent mixture.5MethodologySynthesis procedure of N-phenylbenzamide (N-PBA)At room temperature, benzoic acid (24.448 mg), a amide coupling reagent (1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU, 132.455 mg)) and then abase N,N-Diisopropylethylamine (DIPEA, 69.400 µL) were added in the solvent mixture (1:1, 15.5 mL) respectively.Then, aniline (10.637 µL) was added in the mixture after 15 min proper stirring. Reactions were observed using theHPLC at 0 hour (approx. 1 min.), 1 h, 2 h, 3 h, 4 h, 6 h, 8 h and 24 h.The procedure was applied to the synthesis of N-PBA with 8 solvent-pair mixtures and 4 pure solvents in triplicateNH2+OOHNHO             Solvent (15.5ml), RTCOMU (132.455mg)DIPEA (69.400µl)  Benzanilide or. N-phenylbenzamideAniline(10.637µl)Benzoic acid(24.448mg)6Result and DiscussionKT solvatochromic properties(π*, β, α) of the pure solvent(10) and solvent-pairs (16)0.000.200.400.600.801.001.201.40EtOH MeOH Ace ACN IPA DMSO DMF THF DCM H2Oπ*,β, αvalues  of  solvent  Pure solventPolarity (π*) Basicity (β) Acidity (α) 0.000.200.400.600.801.001.201.40π*,β, αvalues  of  solvent mixtureSolvent-pair mixture (HBD-HBA)Polarity (π*) Basicity (β) Acidity (α) 7Results and DiscussionKT properties (π*, β, α) of the organic solvents8Result and DiscussionHPLC chromatograms of N-PBA synthesis using the H2O-THF mixture (Normal pH 7.10)1 min 1 h 2 h7.50%35.90%31.18%82.80%9HPLC chromatograms of N-PBA synthesis using the H2O-THF solvent (pH 10.80 adjust)1 min 1 h 2 h100%73.01%65%30%Result and Discussion 10Yield comparison between the two types of synthesis (Normal pH and pH 10.80 adjusted solvent)0102030405060708090100DMSO Ace EtOH DMF74.6033.6685.97 87.6079.2568.3389.81Percent yieldSolventNormal pHpH 10.80 adjustResults and Discussion 12Mean (n=3), *P values of 0.05 or less were regarded as significant.0102030405060708090100H2O-THF H2O-DMSO H2O-Ace H2O-DMF EtOH-DMF EtOH-DMSO H2O-IPA H2O-EtOH35.933.08.815.821.733.37.61.373.058.173.543.181.867.9 66.347.0Percent yieldSolvent-pairNormal pHpH 10.80 adjustResults and DiscussionYield comparison between the two types of synthesis (Normal pH and pH 10.80 adjusted solvent media)14Mean (n=3), *P values of 0.05 or less were regarded as significant.Conclusion1. Solvent-pair mixture/ HBD solvent able to replace the hazardous solvents2. pH adjustment also increase the yield of reactionIt can be concluded that……..15

METHODOLOGY FOR THE ALTERATION OF HAZARDOUS SOLVENTS IN 

DRUG SYNTHESIS

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METHODOLOGY FOR THE ALTERATION OF HAZARDOUS SOLVENTS IN DRUG SYNTHESIS

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