Introduction
Diazepam commonly traded under the name Valium is one of the chemicals found in a large class of compounds known as Benzodiazepines. Benzodiazepines are mostly used as tranquilizers, skeletal muscle relaxants and anxiolytics. They have low toxicity as well as a wide variety of pharmacological profiles. Librium or Chlordiazepoxide was the first benzodiazepine to be synthesized. As a testing sample was submitted to carry out further testing, the establishment of this antibiotic was discovered by L. Sternbach and E. Reeder. In addition, during synthesis, the compound structure was determined to have Librium.
Diazepam then came shortly after the discovery of Librium. Synthesis of Diazepam is from an available starting material 5-chloroisatoic anhydride. Diazepam yield is around 50%.
Diazepam synthesis
Synthesis of diazepam starting with commercially available 5-chloroisatoic 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-methylisatoic anhydride (C9H6ClNO3):
In preparation for the above formulation require addition of 18 grams of methyl iodide, and 120mL of dimethylformamide and 7grams of anhydrous sodium carbonate is to be added to 13 grams of 5-chloro-isotioc anhydride. Following this addition the mixture require to be kept at room temperature and stirred for 20 hours. In order to complete the process, it requires pouring 700mL of water to produce N-methyl-5-chloroisatioc anhydride. As a result, 85% yields achieved from product recrystallization.
7-chloro-1-methyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione(C10H9ClN2O2):
This combination consisting of 5.19 grams 5-chloro-N-methylisatoic anhydride, 2.25 grams of glycine, 4.15 ml of triethylamine and 30 ml water which is stimulated in a normal room temp within 5 hours. After 3 and half to 4 hours the materials which are solid disappears. All volatile material is removed by the use of a rotary evaporator and the remains get treated with 60 ml glacial acetic acid it also gets heated to reflux for 4 and half hours. The combination is left cool down. Acetic acid gets 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 quick swirling of the combination, crystallization occurs which showed a clearly colorless crystalline material was taken in the following night and was washed with 4.60 grams of ether at a melting point of between 176.5 and 178 °C. There was dilution of etheral filtrate (two phases) with ethyl acetate to make it homogenous, it was cleaned two times with dilute sodium carbonate, water, it was cleaned through anhydrous sodium sulfate, and then concentrated. After recrystallization, at a melting point of 177°C and 179°C, 0.53 grams of crystalline residue gives 0.43 grams of product.
4-Acetyl-7-chloro-1-methyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione[1]
A combination of 1.0 gram of 7-Chloro-1-methyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione (compound 2 above), with 3 ml of acetic anhydride gets heated in order to reflux in a craig tube for 2.5 h. In a quick way the original suspension turns into solution form, in an 1 hour time the crystalline material starts to divide, then gets cooled down, its then stand for overnight, then gets collected as 1.12 grams (94%) of colorless prismatic blades at a melting point of between 207 and 208.5 °C.
5-chloro-2-methylamino benzophenone (C14H12ClNO):
A suspension of 483mg (1.82mmol) smooth ground 4-Acetyl-7-chloro-1-methyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5- dione (from experiment 3 above) in 12 ml of THF, freshly refluxed with and distilled from LiAlH4, is treated and added slowly for more than 20 minutes and stirred continuously with 1.00ml (2.18 mmol, 1.2 equiv) of 2.18 N commercial (Fisher) phenylmagnesium chloride and this is carried out at room temperature of between 15 and 18°C. In the route of the addition, the tip of the delivery syringe must be kept below the surface of the stirred solution. Furthermore, solution color changes to deep red and the suspended material mixes well with the solution. During this process the solution must be stirred continuously up to 1.5hours once the addition is completed (color must become lighter and change to yellow).
The reaction mixture is to be treated using ammonia chloride solution and should be extracted 4 times using CH2C12. The extracts are filtered through anhydrous Na2SO4 and concentrated. The remaining residue is to be purged at temperature 100°C with decreased pressure in order to give 684mg of yellow glass. Following this steps, material consists predominantly of the product benzophenone using small quantity of the initial material using ratios of 10.8:1 as described by HPLC. However, the extra runs must be carried out in different ratios between 7:1 and 10:1.
5-Chloro-2-(glycylmethylamino)-benzophenone oxime[1]
From experiment 4, results obtained for Crude 5-Chloro-2-(glycylmethylamino)-benzophenone (568 mg) and 485mg hydroxylamine hydrochloride are heated in 10ml of pyridine under N2 in a bath maintained at 70°C for 45 hours. Using the rotary evaporator, the pyridine must be removed and purged completely, and remaining fraction is used up by ethereal solution of 3% HC. The layers are separated, and the ether layer was extracted three more times with 3% HCl. Furthermore, the joint acid extracts is then washed 4 more times using CH2C12 which is then backwashed once again using 3% HCl and this results in combining extracts of HCl with excess ammonia.
The liberated basic material is to be used into CH2C12, then filtered through Na2SO4 and concentrated and then purged to yield 259mg which gives a colorless glass that which is crystallizes spontaneously (melting point between 202 and 204°C). The original ether raffinate and the CH2C12 is combined with 3% acid solution for a wash, filtered and concentrated to give yield 248 mg of a yellow glass, as a result the TLC still shows some contents of some unchanged ketone. Furthermore, the solution is heated under N2 using 210 mg of hydroxylamine hydrochloride in 7 ml of pyridine at 70°C for more than 43.5 hours. A similar plan yield of 106 mg more oxime at the following conditions such as at a boiling point between 201 – 203.5°C and 122 mg of acid-insoluble material. Oxime can be very sparingly soluble when it’s crystallized in most organic solvents: therefore, after several recrystallizations from methanol to colorless crystals with a melting point of between 212 and 213°C is obtained.
Diazepam [1]
An amount of 378g of crude powder was obtained and mixed for further 12 Hours with 1.13g of NaHSO3, in addition, it was further mixed with 15mL of Alcohol added with 7.5mL of water. As part of separation, alcohol is removed under vacuum and the left over is treated with 3% of HCl. Furthermore, ether layer is washed 3 more times using 3% of HCl and also above mixture is combined with acid fractions and remixed for 5 more times using CH2C12. Also, the removed solution is filtered through anhydrous Na2SO4 and then is concentrated. The orange-yellow residue (303mg) crystallizes freely on seeding with diazepam at a melting point of between 129 and 131.5°C.
Diazepam (alternative route from compound 4)[1I]
In experiment 4, a 502mg of crude 5-Chloro-2-(aceturoylmethylamino)-benzophenone is treated with 100% H2SO4 and pre-dissolved in 25mL of methanol under a reflux for 3 more hours and 25minutes. Experimentally, large percentage of methanol is removed under vacuum, also, the remaining solution, is mixed with 25mL water and 25mL of ether. As the layers are separated, it will require 3 times washing using 3% HCl solution so that the combined aqueous and ammonia as well as extraction can be done in 4 times using methylene chloride.
The remaining extracts are purified and washed with a small quantity of water and then filtered through Na2SO4 anhydrous to be concentrated of 264 mg of a pale yellow glass. The residue is then to be added into 2-3ml of alcohol and to be tested with 60% perchloric acid slowly until acid colour changes to congo red. The crystallization begins to sprinkle slowly of Diazepam Perchlorate as it’s washed and filtered using a small amount of alcohol, yielding 225mg. The Perchlorate is formed to freebase by reassessing between diluted ammonia and methylene chloride. Resulted solution is to be filtered, washed and concentrated organic extracts yields of 191mg of very pale yellow glass which 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 (reactant)
ΔHf for the product diazepam = 219.96 kj/mol (product)
ΔHf for dimethyl formamide = -174.87 kj/mol (reactant)
by knowing that:
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:
The following calculations are the operating conditions for the diazepam valium synthesis as studied by ‘University of las palmas,Cnaria; diazepam studied, influence on efflux
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:
k=(k_max ×C)/(K_s+C) ≅ (k_max×C)/K_s By assuming that K_s≫C
Multiply by biomass concentration to find out it is effect on k
kM= (k_max MC)/K_s
k=2.5 hr^(-1)
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
Where,
r= (Mk_(max ) C)/(K_s+C)
So,
Q/V (C_in- C_out )= (Mk_(max ) C)/(K_s+C)
(200 mg/L- C_out)/Θ= ( (5000 mg)/L ×0.05 hr^(-1)× C_out)/(100+ C_out )
C_out=171 mg/l
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.
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