Synthesis of Diazepam - Report Example

Introduction Diazepam commonly traded under the Valium is one of the chemicals found in a large groupof compounds known as Benzodiazepines. Benzodiazepines are mostly used as tranquilizers, skeletal muscle relaxants and anxiolytics. They have low toxicity as well as a extensive range of pharmacological profiles. Librium or Chlordiazepoxide was the first benzodiazepine to be synthesized. L. Sternbach and E. Reeder discovered it as they were submitting a sample of which to them was an antibiotic and they would throw it away anyway during a spring-cleaning. Accidentally, they found out the structure of the compound; it readjusted itself to Librium as synthesis was going on (RIVIERE& PAPICH, 2009, pg.356). Diazepam then came shortly after the discovery of Librium. Synthesis of Diazepam is from 5-chloro-isatoic anhydride which can be purchased in the market. Diazepam yield from this process is around 50%. Diazepam synthesis Synthesis of diazepam starting with commercially available 5-chloro-isatoic anhydride is the synthetic route mostly used because it gives the highest percentage yield of around 50%. Another reason is that 5-chloro-isatoic anhydride is easily available since it can be purchased. 5-Chloro-N-methyl-isatoic anhydride[1,2] 125ml of dimethyl-formamide, 6 grams of anhydrous sodium carbonate and 16 grams of methyl iodide is put into a solution of 12 grams of 5-chloroisatoic anhydride. The blend from the reaction is stirred for 20 hours at room temperature. It is later transferred into 650 ml of water giving out crude N- methyl-5-chloro-isatoic anhydride. After recrystallization of the crude N- methyl-5-chloro-isatoic anhydride from acetic acid, 80% product yield is collected. 7-Chloro-1-methyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione[1] A mixture consisting 5.20 grams of exceptionally ground 5-chloro-N-methylisatoic anhydride, 2.30 grams of glycine, 4.20 ml of triethylamine and 35 ml of water is stirred at room temp for five hours. Solid material completely disappears after 3 and half to 4 hours. Volatile material is wholly removed by the use of a rotary evaporator and the residue washed with 65ml ice-cold acetic acid and heated until recession for 4 and half hours. The mixture is then allowed to cool. As much as possible acetic acid is removed using the rotary evaporator. The residue is a tan oily substance that is then treated by the use of ether, 30 ml of ether is used. After the mixture is momentarily swirled, crystallization occurs and a colorless crystalline material was collecting after it had been kept overnight and by using 4.60 grams of ether at a melting point of between 176.5 and 178 °C the colorless crystalline material is washed. The two phase ethereal filtrate is diluted with adequate ethyl acetate to standardize it, double-washed by the use of dilute sodium carbonate, later with water, sieved through anhydrous sodium sulfate, and then concentrated. After recrystallization, 0.53 grams of crystalline residue gives 0.43 grams of product at a melting point of between 177 and 179 °C. 4-Acetyl-7-chloro-1-methyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione[1] 1.05 grams of 7-Chloro-1-methyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione which is the compound 2 above, and 3 ml of acetic anhydride in a mixture are heated to recession in a Craig tube for 2 and half hours. What was the original suspension goes into solution form more or less quickly, and after about 1 hour crystalline material starts to separate, and is cooled, let to stand through the night, and is later collected as 1.10 grams (92%) of pale prismatic blades at a melting point of between 207 and 208.5 °C. 5-Chloro-2-(glycylmethylamino)-benzophenone[1] 485mg finely ground 4-Acetyl-7-chloro-1-methyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5- dione (from experiment 3 above) suspended in 13 ml THF, recently recessed with and extracted from LiAlH4, is treated gradually for around 20 minutes while stirring with 1.00ml of 2.18 N commercial phenyl magnesium chloride at a room temperature of between 15 and 18°C.While adding, the delivery syringe’s tip is placed underneath the surface of the solution that had been stirred. Also on the course of the addition, the solution color turns deeply red, and the material suspended then forms a part of the solution. After the addition was complete, there is continued stirring for one and half hours. During the stirring, the solution lightens to a clear bright yellow color. The mixture from the reaction is treated with ammonium chloride solution and then extracted for four times using CH2Cl2. The extracts are filtered over anhydrous Na2SO4 and concentrated. The residue is pumped out at a temperature 100°C and limited pressure to obtain 686 mg yellow glass material. The yellow glass material contains mostly the product benzophenone and some smaller quantities of the starting material, in a ratio 10.8:1 as found out by the use of HPLC. 5-Chloro-2-(glycylmethylamino)-benzophenone oxime[1] 568 mg of crude 5-Chloro-2-(glycylmethylamino)-benzophenone obtained in the experiment 4 above and hydroxylamine hydrochloride (485mg) are heated while in 12ml pyridine below N2 in a bath kept at 70°C for 45 hours. Removal of pyridine is done as completely as possible on a rotary evaporator, and the residue is put into an ethereal solution of 3% HCl. The layers are divided, and the ether layer is extracted for 3 additional times with 3% HCl. The collective acid extracts are washed four times by the use of CH2Cl2. The CH2Cl2 backwashed just one time with 3% HCl, and the collective 3% HCl extracts turned basic by the use of excess ammonia. The basic material obtained, is then extracted for four times in CH2Cl2, filtered by passing it through anhydrous Na2SO4, concentrated and then pumped out yielding 259 mg of almost colorless glass. The almost colorless glass material crystallizes spontaneously (melting point between 202 and 204°C). The initial ether solution and the CH2Cl2 rinses of the 3% acid mixture are put together, sieved and concentrated yielding 250mg of a yellow glass material. This material’s TLC shows it to contain some amount of unchanged ketone. The yellow glass material is heated below N2 with 212 mg of hydroxylamine hydrochloride in 8 ml of pyridine at a temperature of 70°C for 43.5 hours. A workup that is similar to the one above yields 108 mg of extra oxime, at a melting point of between 201 and 203.5°C and 122 mg of a material that does not dissolve in an acid. The crystalline form of the oxime, when placed in most organic solvents is sparingly soluble. Numerous recrystallizations from methanol obtained colorless crystals with a melting point of between 212 and 213°C. Diazepam [1] The crude product (378 mg) obtained in experiment 6 above, in a mixture of 14ml of alcohol and 7ml of water is recessed for 12 hours with 1.13 grams of NaHSO3. A large amount of the alcohol is removed through vacuum while the residue is treated with ether and 3% HCl. 3% HCl is also used to wash the ether layer three more times. The collective acid fractions are extracted five times using CH2Cl2. After they have been filtered over anhydrous Na2SO4, the extracts are later concentrated. The orange-yellow residue weighing 302mg crystallizes freely on seeding with diazepam. Its melting point is between 129 and 131.5°C. Diazepam (alternative route from compound 4)[1I] After it dissolves in 28 ml of methanol, 504 mg of unpolished 5-Chloro-2-(aceturoylmethylamino)-benzophenone(which is the product from experiment 4) is then treated with 100% H2SO4 under recess for 3 and quarter hours. A large part of the methanol is removed under vacuum, while the residue is taken up to a mixture of 25 ml ether and 25ml of water. The layers are divided, and the ether layer washed for three times with a 3% HCl, and the collective aqueous layers turned basic by the use of ammonia and then extracted four times using methylene chloride. A little water amount washes the extracts, they are then sieved over anhydrous Na2SO4, and concentrated. 266 mg of a pale yellow glass is got after concentration is complete. This residue is put into around 2.5ml of alcohol and treated with 65% perchloric acid till it turns congo red. The sparingly soluble Diazepam Perchlorate begins to crystallize almost at once. It is sieved and washed using a little alcohol, yielding 255mg. The perchlorate is transformed to the freebase by allocating among methylene chloride and dilute ammonia for three extractions using CH2Cl2. The organic extracts after washing, filtering and concentrating, yields 191mg of extremely pale yellow glass that crystallizes freely, its melting point is between 130 and 131.5°C Thermodynamic calculations In this question, 5-Chloro-N-methyl-isatoic anhydride[1,2] acts as the major reactant while diazepam is the product. ΔHf for 5-Chloro-N-methyl-isatoic anhydride[1,2] = 119.38 kj mol−1 For the product {diazepam) = 219.96 kj ΔHf for dimethyl formamide = -174.87 kJ/mol sum of heat of formation for the reactants = sum of heat of formation of the products Hence heat of reaction = [sum of heat of formation of the products – sum of heat of formation of the reactants] ΔHrxn = [219.96 kJ) – [ [119.38 kJ) + (-174.87 kJ)] ΔHrxn = 275.45 kJ/mol Comment: The positive value obtained for the heat of reaction shows that the overall process was endothermic and irreversible. Further, the reaction was not spontaneous because there was no release of heat in the process. Kinetics and Mechanism rate of formation of diazepam valium = 1.02e-5 M s-1. 1.15e-6 = k [5-Chloro-N-methyl-isatoic anhydride[1,2]]x [I-]y [H+]z 1.15e-6 k (0.010)x(0.010)y(0.0050)z  exprmt 1 1 1 ----------- = ------------------------------------- ---- = --- 2.30e-6 k (0.020)x(0.010)y(0.0050)z  exprmt 2 2 2 x = 1 Thurs, rate = 1.15e-6 = k (0.010)(0.010) from exprmt 1 k = 1.15e-6 M s-1 / (0.010)(0.010) M3 = 0.0115 M-1 s-1 And the rate law is therefore, – d [5-Chloro-N-methyl-isatoic anhydride[1,2] k rate = ————— = 0.0115 [H2O2] [I-] a differential rate law d t total order 2 The rate when [H2O2] = [5-Chloro-N-methyl-isatoic anhydride[1,2]= [H+] = 1.0 M: A = k eEa / R T = 1e-10 s-1 exp (111000 J mol-1 / (8.314 J mol-1 K –1*300 K)) = 2.13e9 s-1 k = 2.13e9 s-1 exp (– 111000 J mol-1) / (8.314 J mol-1 K –1*273 K) = 1.23e-12 s-1 T = Ea / [R* ln (A/k)] = 111000 J mol-1 / (8.314*46.8) J mol-1 K-1 = 285 K Reactor selection The types of reactors to be used in this process include Batch, CSTR, and PFR to help in manipulating chemical rates, materials balance, and reactor design. The three aspects are important in the waste treatment process involved: Batch Reactor This reactor makes use of the mechanism of fully mixed reactor with no flow in or out of the reactor. For the synthesis process, perfect mixing was done to ensure total distribution of the tracer as shown in the following model for the diazepam synthesis: Plug Flow Reactor In this case there is flow through, but in the absence of longitudinal mixing. The model used was in the form of a garden hose with continuous flow inwards. The elements coming in together are subjected to leaving together with the same residence time for all. The following is the model used for diazepam synthesis: The presence of reaction occurring is depicted as follows: Cai > Ca > Cao CSTR (Continuously Stirred Tank Reactor) a chemical engineering term: In this reator, the flow through is completely mixed indifference to the other two. Generally, in a CSTR the concentration in the reactor Ca = Cao The following is the model used for diazepam synthesis: Calculations Batch reactor r = dC/dt or r = -dC/dt for a zero order reaction, Cin – Cout = kt For a first order reaction, Cout/Cin= e-kt CSTR For zero order reaction, Cin – Cout = k For first order reaction, (Cin – Cout)/ Cout = k The following are the operating conditions for the diazepam valium synthesis as studied by “University of las palmas, Canaria; diazepam studied, influence on efflux, porin synthesis mar phenotype revealed” retrieved from: http://search.proquest.com/docview/205655577?accountid=45049 kmax = 0.05 hr-1 Ks = 100 mg/L AS = 5 hr TF = 0.2 hr (industrial) MAS = 5,000 mg/L (MLSS) MTF = 50,000 mg/L Estimating the K value for the reaction and then using the given reaction equation in calculating effluent concentration of the process: First order equation for CSTR: (Cin – Cout)/ Cout = k (200 - Cout)/ Cout = (2.5 hr-1) (5 hr) ; Cout = 14.8 mg/L Actual Materials balance: Assume steady state dC/dt = 0 QCin – QCout –rV = 0 Waste identification and proposed treatment Waste water is the major waste product during the synthesis of diazepam considering that large amount of water was used in washing various chemicals. Large amounts of chemicals are required during the synthesis of medical products. This implies that the waste water produced contains a variety of substances that are not easy to isolate from the sewage sludge. Also, sedimentation tanks nowadays occupy large areas and therefore need fairly longer periods of purification and this makes it hard for most companies to adhere to the statutory limit values for waste water. Waste water from diazepam synthesis therefore must be finely treated and this is done through the present waste water treatment processes. These processes consist of three stage processes: an activated sludge process, trickling filtration and anaerobic reactors. Solids are separated from the waste water by the application of rake screens and the waste water is processed more by defatting to remove fatty acids. KOH is added to the waste water as neutralization pretreatment for solid-liquid isolation. After that, the waste water is exposed to an activated sludge process where the extra mixed alcohol releases into settling tanks and later the treated supernatant is let out to undergo more treatment before being released. Sedimentation is also done, where suspended solids in water are let to settle by the influence of gravitational force(HENZE, 2002, pg.131) Some amount of the settled material is reverted to the aeration system to re-seed the new waste water arriving in the tank. At the final phase of treatment, the waste water is directed to a clarifier where it causes flocculated substances to precipitate and this leaves behind water that is already treated. After these processes the treated waste water is then left behind for re-using. PFR process flow reactor for the first synthesis of diazepam Process flow diagram for the selected route Retrieved: http://www.ilo.org/oshenc/part-xii/pharmaceutical-industry/item/385-pharmaceutical-industry Bibliography AFTALION, F. (2001). A history of the international chemical industry: from the "early days" to 2000. Philadelphia, Chemical Heritage Press. FUHRHOP, J.-H., & LI, G. (2003). Organic synthesis: concepts and methods. Weinheim, Wiley-VCH. VARDANYAN, R. S., & HRUBY, V. J. (2006). Synthesis of essential drugs. Amsterdam, Elsevier. http://public.eblib.com/EBLPublic/PublicView.do?ptiID=270363. RIVIERE, J. E., & PAPICH, M. G. (2009). Veterinary pharmacology and therapeutics. Ames, Iowa, Wiley-Blackwell. HENZE, M. (2002). Wastewater treatment: biological and chemical processes. Berlin [u.a.], Springer. WIKLUND, P. (2004). Synthesis of heterocycles from anthranilic acid and its derivatives. University of las palmas, Canaria; diazepam studied, influence on efflux, porin synthesis mar phenotype revealed. (2005). Biotech Week, , 1097. Retrieved from http://search.proquest.com/docview/205655577?accountid=45049 . Read More