- How the chemical and physical properties can be exploited?
- How the solvent use be minimized and/or eliminated? It impacts process productivity?
- Can the solvent use be limited to one in addition to water?
- How the conversion of each reaction step can be improved by applying chemical kinetics fundamentals?
To a solution of piperazine (224.0 gm) dissolved in methanol (600.0 ml) under an atmosphere of nitrogen, 1-chloro-2-nitrobenzene (100.0 gm) was slowly added while the temperature was maintained at 30.degree. C. The temperature of the reaction mass was raised to 70.degree. C. (70-100.degree. C.) and the contents maintained at this temperature for 24 hours (20-24 hours). After the reaction was complete the reaction solution was distilled under vacuum below 50.degree. C. Charged water (600 ml) and toluene (600 ml) into the crude. The pH of the reaction mass was adjusted to below 1.0 with hydrochloric acid. The organic layer and aqueous layer were separated. The aqueous layer was taken and the reaction mass pH was adjusted to 7.0-8.0 with sodium carbonate solution. The obtained aqueous layers were extracted with dichloromethane (300 ml and 150 ml), and the organic layer dried with sodium sulphate. The organic layers were collected and concentrated under reduced pressure at 45.degree. C. to furnish the title compound (120.0 gm) as brown viscous oil which was used for the next step without further purification.
1-(2-nitrophenyl) piperazine (100.0 gm) was dissolved in DMF (200.0 ml) and toluene (500 ml) at room temperature. The contents were cooled to 0.degree. C. followed by addition of potassium carbonate (160.0 gm) and benzyl chloride (73.0 gm) while maintaining the temperature at 0.degree. C. The temperature was raised to 100.degree. C. (100-120.degree. C.) and the reaction mixture maintained at this temperature for 2 hours (2-4 hours). On completion of the reaction (monitored by TLC), the contents were brought to room temperature and slowly poured into ice water (1000 ml) with vigorous stirring. The organic layer was washed successively with water (2.times.400 ml), brine (400 ml), dried over anhydrous sodium sulphate and solvent removed under reduced pressure to furnish the title compound (140 gm) as thick orange oil. The product was used for the next step without further purification.
First two steps for Vortioxetine process
1- (2-Nitrophenyl) piperazine
MP, o C
BP, o C
Moles/ mole 1-Chloro-2-nitrobenzene
Moles/ mole 1-(2-Nitrophenyl) piperazine
Theoretical yield, gm
Actual exp. Yield
Step 2: Preparation of (2-bromophenyl)(2,4-dimethylphenyl) sulfane
Lupin Limited USP 10,227,317
First two steps for Vortioxetine
2-4 dimethyl thiophenol
MP, o C
BP, o C
Moles/ mole 2-4 dimethyl thiophenol
S- (2,4-Dimethylphenyl) ethanethioate
Theoretical yield, gm
Actual exp. Yield
This is an interesting patent. It uses oxidative properties of bleach in a reaction. Since the oxidative properties of bleach have been used in the past, I am wondering about the validity of this patent. Patent claims:
1. A process for the preparation of Levothyroxine of formula (II) comprising iodination of compound of formula (III) with sodium iodide and sodium hypochlorite in the presence of an aliphatic amine.
3. The process according to claim 1, wherein said iodination reaction is carried out in suitable solvent comprising water, dioxane, methanol, ethanol, or mixtures thereof.
In the suggested process two moles of sodium iodide per mole thyronine are needed. Bleach acts as the oxidizing agent. Some excess of sodium iodide is necessary but not the quantity mentioned in the patent. Quantity of bleach has to be optimized. For a commercial process, I would prefer water-based chemistry as they are commercial. This is suggested because at Sherwin Williams Chemicals in late sixties used a similar chemistry to produce isatoic anhydride from phthalic anhydride by a continuous process using bleach and sodium hydroxide after phthalic anhydride had been converted to phthalimide. Bayer AG was granted a USP 3, 687,951.
Intent here is not to challenge the Lupin patent but present that substitution reactions using bleach and an alkali salt have been commercial for over fifty years. The outlined process can be economized and if executed properly Lupin using modular operation can produce global demand for Levothyroxine from a single plant that would require multiple plants to formulate.
Syntheses proposed by chemists are a laboratory pathway to a product. However, optimization and careful pruning of the laboratory process is necessary to have an economic commercial process. There are many routes. Creativity and imagination are necessary in the simplification process. Careful exploitation of mutual social behavior of the chemicals and unit operations is necessary for creating an economic process. Underlying goal of the chemists and chemical engineers has to be that the commercial process they will create is their best ever and the most economic. It is a challenge because the product demand dictates the type of process they will create.
Another factor which is latent is that how API manufacturing process impact our environment. We may not have the necessary empathy but we need to recognize that active pharmaceutical ingredients are organic chemicals that are toxins that kill disease causing bacteria, a living organism. We don’t know the toxicity of every chemical and other reaction byproducts. Thus, if we can minimize their presence in the environment, we will make a difference while curing illness. Their presence impacts mammal, aquatic and bird life.
Girish Malhotra, PE
1. Malhotra, Girish: Chemical Process Simplification: Improving Productivity and Sustainability John Wiley & Sons, February 2011
2. Malhotra, Girish: Focus on Physical Properties To Improve Processes: Chemical Engineering, Vol. 119 No. 4 April 2012, pgs 63-66
3. Communication with Dr. Charles Kausch, Senior Scientist, OMNOVA Solutions, Akron, April 16, 2019