The medicative chemical science synthesis path for industry of UK-427,857 is given and needs to be analysed for big scale fabrication. In order to give a critical analysis on the overall fabrication procedure, it is of import to analyze each and every reaction measure sing chemical science and technology facets of the reaction.

Industry of Intermediate 1.

The hydroxyl-amine hydrochloride used in the formation of oxime from the get downing stuff, the crystals of the hydroxyl-amine demands to be dissolved in pyridine foremost which can move as a dissolver every bit good as base for remotion of any acid formed during the reaction. The get downing stuff demands to be added easy in the reaction vas or a batch reactor to increase the given output of 96 % to about 99 % .

The hydroxyl aminoalkane used in this procedure is stable under normal conditions of usage and storage nevertheless it is to be noted that it can breathe toxic exhausts of HCl gas and Nitrogen Oxides, moreover it has been identifies as a harmful stuff if inhaled or swallowed and in conclusion it is caustic and therefore it requires a S.S. or glass-lined reactor for its usage in pharmaceuticals. ( 1 )

The pyridine used is a widely available dissolver for organic synthesis and besides helpful for scavenging acids formed during the reaction besides it can be easy recovered by distillment, but it is besides really flammable and can be harmful if swallowed or inhaled and therefore its handling and storage demands particular considerations. ( 2 )

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Since the reagents used can take to formation of toxicant gases the environmental impact on inadvertent release has to be considered before scaling up the procedure to fabricate in bulk measures.

In this reaction aminoalkane is formed from oxime, by refluxing n-pentanol in the presence of Na metal. Since aa‚¬ ” OH is non a good departure group the reaction mixture has to be refluxed for longer period of times to give higher rate of transition. Since Na as a metal is used it will most allow to maintain the Na metal in a jammed bed and reflux the reaction mixture from the bed to increase the transition and cut down the clip.

The Na metal used is extremely reactive in presence of H2O and big pieces of Na can besides detonate bring forthing toxic Na hydrated oxide and flammable H gas and therefore it is non advisable to utilize it on big scale fabrication of the coveted merchandise. ( 3 )

The usage of n-pentanol is really much crucial for accomplishing the desiered transition but it is extremely flammable and its bluess may organize explosive mixtures with air and moreover they are heavier than air. Therefore it is apparent that to utilize it in higher measures can be really much risky and therefore itaa‚¬a„?s option should be looked for.

In this reaction the add-on of butyric acid is added to acquire the coveted carboxylic group for its farther reaction. To accomplish this foremost butyric acid is assorted with Tri Ethyl-Amine ( ET3N ) and easy amide formed in the old measure is added along with the catalytic measure of Carbonyldiimidazole ( CDI ) which can ease ketone formation which is followed by add-on of DichloroMethane ( DCM ) which has really good solubility for HCl and H2O formed in the reaction. ( 4 ) Last since the reaction is reversible it is really much hard to run this procedure for fabricating majority measures, furthermore the output obtained is really low, and it is basically because the reaction is reversible and reaction clip ( RT ) is really high.

ET3N used as dissolver is widely used and available organic dissolver as it is cheaper in cost and besides can be easy removed by distillment. However attention should be taken while managing it in majority measures since it is a flammable liquid and besides caustic. ( 2 )

Carbonyldiimidazole ( CDI ) used plays a critical function in ketone formation, moreover it is a wet sensitive and therefore demands to be stored in a desiccator over P2O5. ( 2 )

Dichloro Methane ( DCM ) is a colorless impersonal liquid holding higher solubility for HCl and H2O and hence can cut down the concentration of HCl and H2O formed during the reaction, in conclusion it is to be noted that it is besides extremely volatile compound doing it risky if inhaled in higher measures, otherwise this compound is least toxic. ( 2 )

The formation of tri-azo compound is achieved utilizing ethyl hydrazine, which is a really widely used nucleophile and formation of aromatic ring can be achieved utilizing Phosphorus Oxychloride ( POCl3 ) . The output for this reaction is really less since the reagent ethyl hydrazine can non give higher transition in presence of aldehyde and ketone functional groups. ( 2 ) Therefore it is advisable to add para-Toluene Sulfonic acid ( p-TsOH ) with ethyl hydrazine foremost as it can besides move as a oxidizing agent to get down the reaction, after this add-on POCl3 in pyridine dissolver can take to formation of aromatic pealing emancipating HCl gas which can be absorbed by pyridine and the merchandise formed can be removed utilizing trichloromethane ( CHCl3 ) since it is comparatively un-reactive and mixable with most of the organic dissolver, and in conclusion HCl is added to precipitate out p-TsOH.

Phosphorus Oxychloride ( POCl3 ) used is really toxic and caustic every bit good besides it can respond violently with intoxicant and H2O emancipating HCl, Phosphorus acid and big amout of heat. Therefore managing and storage demands particular considerations for utilizing it in majority measures. ( 5 )

Chloroform ( CHCl3 ) used is an first-class dissolver but its handling needs particular considerations since it is easy oxidised by air and sunlight ensuing in formation of extremely toxicant Phosgene gas, besides it is a malignant neoplastic disease suspect agent. So its usage in majority measures should be avoided. ( 2 )

Ethyl Hydrazine ( AcNHNH2 ) used is a colourless liquid and really widely used nucleophile, but managing it in majority measures is non advisable since it is a possible carcinogen and extremely toxic every bit good as it can be easy absorbed by tegument. ( 2 )

para-Toluene Sulfonic acid ( p-TsOH ) is a powerful oxidizing agent but besides it is extremely toxic and therefore it needs particular considerations for managing it in majority measures. ( 2 )

The remotion of phenyl group can be removed really expeditiously with the usage of Ammonium Formate in the presence of Palladium ( II ) Hydroxide ( Pd ( OH ) 2 ) . By and large the remotion is really hard but the usage of Pd ( OH ) 2 greatly increases the reaction output. ( 5 )

The reagents used in this synthesis can be used on big since they do non come out to be possible toxic substances.

Industry of Intermediate 2.

The usage of Dimethylamino sulphur triflouride can respond with carboxylic acid or aldehyde compounds to give the coveted diflourocyclohexame carboxylic acid. The reaction has to be carried out at around 5oC since the brassy point of triflouride compound is 9oC, and hence the reactor system needs to be supplied with efficient chilling system. Tetrahydrofuran ( THF ) used in the ulterior phase is a really good dissolver for many of the organometallic compounds and in conclusion sodium hydrated oxide used provides the necessary basic conditions for the reactions.

In this given procedure for synthesis of intermerdiate 2. The lone reagent which needs careful considerations is Dimethyl amino sulphur-triflouride as it has a really low flash point of 9oC, its storage demands to be isolated and maintained at lower temperatures and any propinquity of flammable substance should therefore be avoided. ( 6 )

Industry of UK-427,857

The stereo-chemical agreement of the aminoalkane group is foremost protected with the usage of Carboxybenzyle which is an first-class protecting group for aminoalkane and can besides be removed easy by hydrogenation or responding with HBr. L-Tartaric acid used helps in keeping the stereochemistry of the merchandise formed and since the dissolvers used are easy dissociable 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 non any possible toxic or carcinogenic substance moreover the dissolvers used are easy dissociable as discussed in the old subdivision, furthermore the 100 % output obtained adds up to the virtues of the reaction. ( 2 )

Since the reactive Amine group is now protected the etheric group nowadays can be replaced by ketone utilizing Sodium Hydroxide solution, besides it is to be noted that the disintegration of NaOH is an exothermal procedure and therefore it should be added easy to the reactor to avoid release of extra sum of heat, doing the procedure safer. Last the 90 % output obtained is satisfactory sing the responsiveness and exothermal belongingss of NaOH. ( 5 )

Sodium Hydroxide used as a reagent in this procedure can do lasting Burnss on the tegument if it comes in contact with the tegument and hence supplying suited safety equipments to people managing the operation it can be taken attention of.

The formation of alchol from ketone is achieved utilizing Borane in THF solution. The reaction is to be carried out at about 0 to -10OC for 8-10 hours under refluxing conditions. ( 2 ) Despite this the output obtained is merely 70 % and therefore it is advisable to utilize Hydrogen Peroxide alternatively of THF as a dissolver to increase the output of the reaction.

The reagent BH3.THF used is highly flammable liquid and besides it has to be stored under Nitrogen atmosphere at 0OC, which can incur much higher storage cost while running this procedure for acquiring bulk measures of merchandise and therefore it is strongly advisable to look for an alternate method or reagents to cut down runing cost. ( 2 )

The transition of alchol to aldehyde is achieved utilizing sulphur trioxide pyridine composite which can move as a strong electrophile and has to be dissolved in the dissolver before adding it up to the reactor besides it is to be noted to keep the higher output of the reaction it should be added at the underside of the reactor to accomplish efficient commixture and transition. The output obtained in this reaction is about 100 % and hence proves to be good. Dimethyl Sulfoxide ( DMSO ) used has higher boiling point and can be used for separation of merchandise from other dissolvers and hence it plays a critical function to telescope the formed merchandise. ( 7 )

The Sulfur trioxide pyridine used is extremely moisture sensitive and therefore it needs to be stored under inert gas which can incur cost for managing it on big graduated table.

DMSO used is readily absorbed by tegument and can farther take to human death and therefore its managing on big graduated table can be unsafe. ( 2 )

Dichloro Methane as discussed in the earlier subdivisions is extremely volatile and itaa‚¬a„?s usage should be every bit minimum as possible. The usage of benzo trifluoride should be promoted which can be an of import replacement for DCM. ( 7 ) ( 9 )

The add-on of the first intermediate is achieved by ammination reaction in the presence of Sodium triAcetoxy Borohydrate ( NaBH ( OAc ) 3 ) as a reduction agent and Acetic acid which is a accelerator for the formation of Amine. To accomplish this formation foremost accelerator and cut downing agent are to blend in a dissolver of DCM and has to be added to the reactor, while blending borohydrate there is a possibility of Hydrogen gas formation, therefore it has to be carried out under Vacuum, and eventually intermediate 1 in p-TsOH solution is added and reaction mixture stirred for 23 hours to accomplish the coveted transition. ( 2 ) The output obtained for this reaction is 80 % which is satisfactory sing the longer abode clip of the reaction.

Sodium triAcetoxy Borohydrate is a better cut downing agent as comparted to other for Reductive Amination, moreover it has to be stored under inert gas as it can emancipate Hydrogen gas under normal conditions, doing it hard for its application on larger volumes. ( 5 )

Acetic acid used can besides be used to recrystallise the merchandise formed. The acid is besides caustic and flammabel in nature and can do lasting oculus harm and hence proper attention should be taken for managing big measures of acetic acid. ( 2 )

The remotion of Amine protecting group can be achieved by hydrogenation over Palladium accelerator utilizing Methanol as a dissolver. The cardinal factor for this transition is the H force per unit area and the contact of H gas with the reaction mixture, therefore the gas has to be introduced at the underside of the scaremonger to increase the mass transportation rate and thereby reaction output every bit good. ( 5 )

The storage of H gas needs particular control system and the storage and reaction vass needs to be designed good otherwise it can take to ruinous consequences.

Addition of intermediate 2. Is achieved in presence of Sodium Carbonate which can assist in alkylation of Amines and can besides move as a neutralizing agent. The output obtained in this reaction is significantly low and can be improved by anterior commixture of Sodium Carbonate and the reactant in the reaction vass and the add-on of intermediate 2. In DCM can be done easy to accomplish the coveted transition.

An Overview on appraisal of the given Med-Chem Synthesis.

Figure An overview on given Med-Chem Sytnthesis Route

Section 2

Comparison of the modified Synthesis path.

The modified synthesis path is more appropriate for scale-up and fabricating bulk measures of given cost sensitive merchandise. The advantages of utilizing this path over the Med-Chem path are as follows.

The usage of bulk of flammable and moisture sensitive dissolvers such as BH3.THF, CDI is avoided, which can cut down the storage and managing cost of the stuffs to a great extent.

DCM widely used in the earlier synthesis path is really much minimized as the handling of big measures of DCM can take to ruinous consequences and besides it is non allowed by regulative governments.

Lesser figure of reaction stairss reduces the entire sum of clip required to acquire the merchandise.

The add-on of diflourocyclohexane carboxylic acid in the really first measure reduces the usage of NH2 protecting group.

Besides the hydrogenation measure is avoided which otherwise could incur greatly in the production cost of the stuff and its operation on big measures is non considered as safe.

The dissolvers used such as Ethyl Acetate, Toluene and other are lesser toxic, commercially available and can be easy separated.

The demands of reactors and other equipments are non diverse as most of the reactions can be carried out utilizing a Batch or Continious Stirred Tank Reactor ( CSTR ) which gives this procedure a greater flexibleness to run in majority measures.

There is no demand for application of high force per unit area to the system, as it can be cost finding for fabrication merchandises in majority measures.

Higher output is obtained which is really much beneficial and therefore waste coevals and its farther intervention is greatly reduced. ( 10 )

Section 3

Oxidation of Intermediate 3.

Potential Scale-up Problems refering the above shown transition.

Solvent Choice: – DCM used as a dissolver has a really broad scope of solubility, but it has to be noted that it is extremely volatile and its handling can incur higher operational cost as it has to be used in bulk measures.

It is hence advisable to utilize Acetonitrile as it is besides a really good dissolver for organic synthesis as replacing to DCM which is widely available and lesser toxic as compared to DCM. ( 9 )

Chemical reaction Dynamicss: -Sodium hypochlorite ( NaOCl ) used is a really strong oxidizing agent and therefore it generates heat during oxidization reaction. In order to command the heat of reaction an efficient chilling system is required around the reactor system to avoid any thermic dazes. ( 2 )

Likely Side Reactions: – Since NaOCl is really strong oxidising agent it can besides respond with O nearer to Amine group giving unsought side merchandises, this can be controlled by continuously taking the merchandise formed and maintaining its concentration depression in the reactor system. Last the merchandise formed should be separated from the dissolvers to avoid any rearward reaction, this can be taken attention of by the add-on of Sodium thiosulfate which can move as an anionic wetting agent in the spread solution.

Reagent Addition order or equality: – The proposed method of blending reagents and its add-on to the reactor seems to be justified and the exothermicity of the reaction can be controlled by utilizing higher sum of Na2HCO3 and by slower add-on of NaOCl.

Equipment Issues: – Since the coevals of heat is traveling to be significantly higher, the conventional Batch or CSTR reactor system may non be able to function the needed intent.

Alternate attack to transport out the given reaction.

It has to be noted that we need to transport out this reaction on the uninterrupted footing to avoid any side reactions and keep the concentration gradient towards the coveted merchandise formation.

For runing reaction under given conditions it is non advisable to utilize CSTR since the difference in Entire Volume ( M3 ) of the liquid nowadays in the reactor and the Surface Area ( M2 ) for heat transportation to is excessively high doing the control of heat coevals highly hard and can besides take to thermic blowout. ( 11 )

Figure Continious Stirred Tank Reactor

Whereas utilizing a Plug Flow Reactor ( PFR ) can function the given intent as they have higher Volumetric Conversions and heat transportation rate can be expeditiously maintained by cut downing or increasing the thickness of the tubings every bit good as by increasing or diminishing figure of chilling spirals around the tubing. ( 11 )

Figure Plug Flow Reactor


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