The medicinal chemistry synthesis route for manufacture of UK-427,857 is given and needs to be analysed for large scale manufacturing. In order to give a critical analysis on the overall manufacturing process, it is important to analyse each and every reaction step considering chemistry and engineering aspects of the reaction.
Manufacture of Intermediate 1.
The hydroxyl-amine hydrochloride used in the formation of oxime from the starting material, the crystals of the hydroxyl-amine needs to be dissolved in pyridine first which can act as a solvent as well as base for removal of any acid formed during the reaction. The starting material needs to be added slowly in the reaction vessel or a batch reactor to increase the given yield of 96 % to approximately 99 %.
The hydroxyl amine used in this process is stable under normal conditions of use and storage however it is to be noted that it can emit toxic fumes of HCl gas and Nitrogen Oxides, moreover it has been identifies as a harmful material if inhaled or swallowed and lastly it is corrosive and therefore it requires a S.S. or glass-lined reactor for its use in pharmaceuticals. (1)
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The pyridine used is a widely available solvent for organic synthesis and also helpful for scavenging acids formed during the reaction also it can be easily recovered by distillation, but it is also very flammable and can be harmful if swallowed or inhaled and therefore its handling and storage needs special considerations. (2)
Since the reagents used can lead to formation of poisonous gases the environmental impact on accidental release has to be considered before scaling up the process to manufacture in bulk quantities.
In this reaction amine is formed from oxime, by refluxing n-pentanol in the presence of Na metal. Since ââ‚¬"OH is not a good leaving group the reaction mixture has to be refluxed for longer period of times to give higher rate of conversion. Since Na as a metal is used it will most appropriate to keep the Na metal in a packed bed and reflux the reaction mixture from the bed to increase the conversion and reduce the time.
The Na metal used is highly reactive in presence of water and large pieces of Na can also explode producing toxic sodium hydroxide and flammable hydrogen gas and therefore it is not advisable to use it on large scale manufacturing of the desired product. (3)
The use of n-pentanol is very much crucial for achieving the desiered conversion but it is highly flammable and its vapours may form explosive mixtures with air and moreover they are heavier than air. Therefore it is evident that to use it in higher quantities can be very much risky and thus itââ‚¬â„¢s alternative should be looked for.
In this reaction the addition of butyric acid is added to get the desired carboxylic group for its further reaction. To achieve this firstly butyric acid is mixed with Tri Ethyl-Amine (ET3N) and slowly amide formed in the previous step is added along with the catalytic quantity of Carbonyldiimidazole (CDI) which can facilitated ketone formation which is followed by addition of DichloroMethane (DCM) which has very good solubility for HCl and water formed in the reaction. (4) Lastly since the reaction is reversible it is very much difficult to operate this process for manufacturing bulk quantities, moreover the yield obtained is very low, and it is essentially because the reaction is reversible and reaction time (RT) is very high.
ET3N used as solvent is widely used and available organic solvent as it is cheaper in cost and also can be easily removed by distillation. However care should be taken while handling it in bulk quantities since it is a flammable liquid and also corrosive. (2)
Carbonyldiimidazole (CDI) used plays a vital role in ketone formation, moreover it is a moisture sensitive and thus needs to be stored in a desiccator over P2O5. (2)
Dichloro Methane (DCM) is a colourless neutral liquid having higher solubility for HCl and water and therefore can reduce the concentration of HCl and water formed during the reaction, lastly it is to be noted that it is also highly volatile compound making it hazardous if inhaled in higher quantities, otherwise this compound is least toxic. (2)
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The formation of tri-azo compound is achieved using ethyl hydrazine, which is a very widely used nucleophile and formation of aromatic ring can be achieved using Phosphorus Oxychloride (POCl3). The yield for this reaction is very less since the reagent ethyl hydrazine cannot give higher conversion in presence of aldehyde and ketone functional groups. (2) Therefore it is advisable to add para-Toluene Sulfonic acid (p-TsOH) with ethyl hydrazine firstly as it can also act as a oxidising agent to start the reaction, after this addition POCl3 in pyridine solvent can lead to formation of aromatic ring liberating HCl gas which can be absorbed by pyridine and the product formed can be removed using chloroform (CHCl3) since it is relatively un-reactive and miscible with most of the organic solvent, and lastly HCl is added to precipitate out p-TsOH.
Phosphorus Oxychloride (POCl3) used is very toxic and corrosive as well also it can react violently with alcohol and water liberating HCl, Phosphorus acid and large amout of heat. Therefore handling and storage needs special considerations for using it in bulk quantities. (5)
Chloroform (CHCl3) used is an excellent solvent but its handling needs special considerations since it is easily oxidised by air and sunlight resulting in formation of highly poisonous Phosgene gas, also it is a cancer suspect agent. So its use in bulk quantities should be avoided. (2)
Ethyl Hydrazine (AcNHNH2) used is a colourless liquid and very widely used nucleophile, but handling it in bulk quantities is not advisable since it is a potential carcinogen and highly toxic as well as it can be easily absorbed by skin. (2)
para-Toluene Sulfonic acid (p-TsOH) is a powerful oxidizing agent but also it is highly toxic and therefore it needs special considerations for handling it in bulk quantities. (2)
The removal of phenyl group can be removed very efficiently with the use of Ammonium Formate in the presence of Palladium (II) Hydroxide (Pd(OH)2). Generally the removal is very difficult but the use of Pd(OH)2 greatly increases the reaction yield. (5)
The reagents used in this synthesis can be used on large since they do not come out to be potential toxic substances.
Manufacture of Intermediate 2.
The use of Dimethylamino sulphur triflouride can react with carboxylic acid or aldehyde compounds to give the desired diflourocyclohexame carboxylic acid. The reaction has to be carried out at around 5oC since the flash point of triflouride compound is 9oC, and therefore the reactor system needs to be supplied with efficient cooling system. Tetrahydrofuran (THF) used in the later stage is a very good solvent for many of the organometallic compounds and lastly sodium hydroxide used provides the necessary basic conditions for the reactions.
In this given process for synthesis of intermerdiate 2. The only reagent which needs careful considerations is Dimethyl amino sulphur-triflouride as it has a very low flash point of 9oC, its storage needs to be isolated and maintained at lower temperatures and any proximity of flammable substance should thus be avoided. (6)
Manufacture of UK-427,857
The stereo-chemical arrangement of the amine group is first protected with the use of Carboxybenzyle which is an excellent protecting group for amine and can also be removed easily by hydrogenation or reacting with HBr. L-Tartaric acid used helps in maintaining the stereochemistry of the product formed and since the solvents used are easily separable from the reaction mixture the separation can be carried out in the same reactor once the reaction is completed. (5)
The reagents used in this reactions are not any potential toxic or carcinogenic substance moreover the solvents used are easily separable as discussed in the previous section, furthermore the 100 % yield obtained adds up to the merits of the reaction. (2)
Since the reactive Amine group is now protected the etheric group present can be replaced by ketone using Sodium Hydroxide solution, also it is to be noted that the dissolution of NaOH is an exothermic process and therefore it should be added slowly to the reactor to avoid liberation of excess amount of heat, making the process safer. Lastly the 90 % yield obtained is satisfactory considering the reactivity and exothermic properties of NaOH. (5)
Sodium Hydroxide used as a reagent in this process can cause permanent burns on the skin if it comes in contact with the skin and therefore providing suitable safety equipments to people handling the operation it can be taken care of.
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The formation of alchol from ketone is achieved using Borane in THF solution. The reaction is to be carried out at around 0 to -10OC for 8-10 hours under refluxing conditions. (2) Despite this the yield obtained is only 70 % and therefore it is advisable to use Hydrogen Peroxide instead of THF as a solvent to increase the yield of the reaction.
The reagent BH3.THF used is extremely flammable liquid and also it has to be stored under Nitrogen atmosphere at 0OC, which can incur much higher storage cost while running this process for getting bulk quantities of product and therefore it is strongly advisable to look for an alternative method or reagents to reduce operating cost. (2)
The conversion of alchol to aldehyde is achieved using sulphur trioxide pyridine complex which can act as a strong electrophile and has to be dissolved in the solvent before adding it up to the reactor also it is to be noted to maintain the higher yield of the reaction it should be added at the bottom of the reactor to achieve efficient mixing and conversion. The yield obtained in this reaction is nearly 100% and therefore proves to be beneficial. Dimethyl Sulfoxide (DMSO) used has higher boiling point and can be used for separation of product from other solvents and hence it plays a vital role to telescope the formed product. (7)
The Sulfur trioxide pyridine used is highly moisture sensitive and therefore it needs to be stored under inert gas which can incur cost for handling it on large scale.
DMSO used is readily absorbed by skin and can further lead to fatality and therefore its handling on large scale can be dangerous. (2)
Dichloro Methane as discussed in the earlier sections is highly volatile and itââ‚¬â„¢s use should be as minimal as possible. The use of benzo trifluoride should be promoted which can be an important substitute for DCM. (7) (9)
The addition of the first intermediate is achieved by ammination reaction in the presence of Sodium triAcetoxy Borohydrate (NaBH(OAc)3) as a reducing agent and Acetic acid which is a catalyst for the formation of Amine. To achieve this formation firstly catalyst and reducing agent are to mixed in a solvent of DCM and has to be added to the reactor, while mixing borohydrate there is a possibility of Hydrogen gas formation, thus it has to be carried out under Vacuum, and finally intermediate 1 in p-TsOH solution is added and reaction mixture stirred for 23 hours to achieve the desired conversion. (2) The yield obtained for this reaction is 80% which is satisfactory considering the longer residence time of the reaction.
Sodium triAcetoxy Borohydrate is a better reducing agent as comparted to other for Reductive Amination, moreover it has to be stored under inert gas as it can liberate Hydrogen gas under normal conditions, making it difficult for its application on larger volumes. (5)
Acetic acid used can also be used to recrystallise the product formed. The acid is also corrosive and flammabel in nature and can cause permanent eye damage and therefore proper care should be taken for handling large quantities of acetic acid. (2)
The removal of Amine protecting group can be achieved by hydrogenation over Palladium catalyst using Methanol as a solvent. The key factor for this conversion is the hydrogen pressure and the contact of hydrogen gas with the reaction mixture, therefore the gas has to be introduced at the bottom of the stirrer to increase the mass transfer rate and thereby reaction yield as well. (5)
The storage of hydrogen gas needs special control system and the storage and reaction vessels needs to be designed well otherwise it can lead to catastrophic results.
Addition of intermediate 2. Is achieved in presence of Sodium Carbonate which can help in alkylation of Amines and can also act as a neutralizing agent. The yield obtained in this reaction is significantly low and can be improved by prior mixing of Sodium Carbonate and the reactant in the reaction vessels and the addition of intermediate 2. In DCM can be done slowly to achieve the desired conversion.
An Overview on assessment of the given Med-Chem Synthesis.
Figure An overview on given Med-Chem Sytnthesis Route
Comparison of the modified Synthesis route.
The modified synthesis route is more appropriate for scale-up and manufacturing bulk quantities of given cost sensitive product. The advantages of using this route over the Med-Chem route are as follows.
The use of majority of flammable and moisture sensitive solvents such as BH3.THF, CDI is avoided, which can reduce the storage and handling cost of the materials to a great extent.
DCM widely used in the earlier synthesis route is very much minimized as the handling of large quantities of DCM can lead to catastrophic results and also it is not allowed by regulatory authorities.
Lesser number of reaction steps reduces the total amount of time required to get the product.
The addition of diflourocyclohexane carboxylic acid in the very first step reduces the use of NH2 protecting group.
Also the hydrogenation step is avoided which otherwise could incur greatly in the production cost of the material and its operation on large quantities is not considered as safe.
The solvents used such as Ethyl Acetate,Toluene and other are lesser toxic, commercially available and can be easily separated.
The requirements of reactors and other equipments are not diverse as most of the reactions can be carried out using a Batch or Continious Stirred Tank Reactor (CSTR) which gives this process a greater flexibility to operate in bulk quantities.
There is no requirement for application of high pressure to the system, as it can be cost determining for manufacturing products in bulk quantities.
Higher yield is obtained which is very much beneficial and thus waste generation and its further treatment is greatly reduced. (10)
Oxidation of Intermediate 3.
Potential Scale-up Problems concerning the above shown conversion.
Solvent Selection: - DCM used as a solvent has a very wide range of solubility, but it has to be noted that it is highly volatile and its handling can incur higher operational cost as it has to be used in bulk quantities.
It is therefore advisable to use Acetonitrile as it is also a very good solvent for organic synthesis as replacement to DCM which is widely available and lesser toxic as compared to DCM. (9)
Reaction Kinetics: -Sodium hypochlorite (NaOCl) used is a very strong oxidizing agent and therefore it generates heat during oxidation reaction. In order to control the heat of reaction an efficient cooling system is required around the reactor system to avoid any thermal shocks. (2)
Likely Side Reactions: - Since NaOCl is very strong oxidizing agent it can also react with oxygen nearer to Amine group giving undesired side products, this can be controlled by continuously removing the product formed and keeping its concentration low in the reactor system. Lastly the product formed should be separated from the solvents to avoid any reverse reaction, this can be taken care of by the addition of Sodium thiosulfate which can act as an anionic surfactant in the dispersed solution.
Reagent Addition order or equivalence: - The proposed method of mixing reagents and its addition to the reactor seems to be justified and the exothermicity of the reaction can be controlled by using higher amount of Na2HCO3 and by slower addition of NaOCl.
Equipment Issues: - Since the generation of heat is going to be significantly higher, the conventional Batch or CSTR reactor system may not be able to serve the required purpose.
Alternative approach to carry out the given reaction.
It has to be noted that we need to carry out this reaction on the continuous basis to avoid any side reactions and maintain the concentration gradient towards the desired product formation.
For operating reaction under given conditions it is not advisable to use CSTR since the difference in Total Volume (m3) of the liquid present in the reactor and the Surface Area (m2) for heat transfer to is too high making the control of heat generation extremely difficult and can also lead to thermal runaway. (11)
Figure Continious Stirred Tank Reactor
Whereas using a Plug Flow Reactor (PFR) can serve the given purpose as they have higher Volumetric Conversions and heat transfer rate can be efficiently maintained by reducing or increasing the thickness of the tubes as well as by increasing or decreasing number of cooling coils around the tubes. (11)