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    Pimozide

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    Shruti
    The document discusses the synthesis of the antipsychotic drug Pimozide. It describes the classical synthesis method using methylisobutylketone and a new more efficient method using glycerol formal. The new process has advantages of higher yield, shorter reaction time, and simpler product isolation and purification.

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    © All Rights Reserved
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    Pimozide

    Uploaded by

    Shruti
    245 views24 pages
    The document discusses the synthesis of the antipsychotic drug Pimozide. It describes the classical synthesis method using methylisobutylketone and a new more efficient method using glycerol formal. The new process has advantages of higher yield, shorter reaction time, and simpler product isolation and purification.

    Original Description:

    Anti-psychotic drug based on Benzimidazole

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    The document discusses the synthesis of the antipsychotic drug Pimozide. It describes the classical synthesis method using methylisobutylketone and a new more efficient method using glycerol formal. The new process has advantages of higher yield, shorter reaction time, and simpler product isolation and purification.

    Copyright:

    © All Rights Reserved
    Download as PPTX, PDF, TXT or read online from Scribd
    Download as pptx, pdf, or txt
    245 views24 pages

    Pimozide

    Uploaded by

    Shruti
    The document discusses the synthesis of the antipsychotic drug Pimozide. It describes the classical synthesis method using methylisobutylketone and a new more efficient method using glycerol formal. The new process has advantages of higher yield, shorter reaction time, and simpler product isolation and purification.

    Copyright:

    © All Rights Reserved
    Download as PPTX, PDF, TXT or read online from Scribd
    Download as pptx, pdf, or txt
    of 24

    ORAP- PIMOZIDE

    Antipsychotic Drug Synthesized from Benzimidazole

    What are Antipsychotic


    drugs?
    Antipsychotics are a class of psychiatric medication primarily used to manage

    psychosis, in particular in schizophrenia and bipolar disorder, and are


    increasingly being used in the management of non-psychotic disorders.
    Benperidol (Anguil, Benguil, Frenactil, Glianimon)
    Bromperidol (Bromodol, Impromen)
    Droperidol (Droleptan, Inapsine)
    Haloperidol (Haldol, Serenace)
    Timiperone (Celmanil, Tolopelon)

    Antipsychotics based on

    Benzimidazole
    A class of benzimidazole derivatives, substituted at the 1-position by a
    substituted piperidine or piperazinylethyl moiety, are antagonists of
    dopamine receptor subtypes within the brain, having a selective affinity
    for the dopamine D4 receptor subtype over other dopamine receptor
    subtypes, and are accordingly of benefit in the treatment and/or
    prevention of psychotic disorders such as schizophrenia whilst
    manifesting fewer side-effects than those associated with classical
    neuroleptic drugs.

    Pimozide

    Pimozide (Orap) is an antipsychotic drug of the diphenylbutylpiperidine class.


    It was discovered at Janssen Pharmaceutics in 1963. It has a high potency
    compared to chlorpromazine.

    Pimozide is used in its oral preparation in schizophrenia and chronic psychosis,


    Tourette syndrome and resistant tics.

    Pimozide has been used in the treatment of delusional disorder and paranoid
    personality disorder.

    It has also been used for delusions of parasitosis.

    The side effects include akathisia, tardive dyskinesia, and, more rarely, neuroleptic
    malignant syndrome and prolongation of the QT interval.

    Structure

    Classical
    Procedure
    6

    1-chloro-4,4-di(4-fluorophenyl)butane

    + KI + Na2CO3
    4-(2-oxo-1-benzi
    midazolinyl)piperidine

    Stir and Reflux


    for 65 hrs

    Cool and
    add water

    Filter and Evaporate

    Residue is triturated
    in diisopropyl-ether

    Dry over K2CO3

    Filter and Recrystallize from a


    mixture of 120 parts acetone
    and 80 parts 4-methyl-2pentanone
    7

    Separate O/L

    Pimozide

    New Procedure

    Synthesis of 1-chloro-4,4-di(4-fluorophenyl)-butane
    Reflux. Evaporate.
    Distil the residue
    under vacuum

    SOCl2
    In benzene

    4-chloro1,1-di-(4fluorophenyl)-1butene

    cyclopropyl-di-(4fluorophenyl)-carbinol

    Distil
    1-chloro-4,4-di-(4fluorophenyl)-butane

    Evaporate

    Filter

    Hydrogenate
    in the
    presence of
    Pd/C

    Reaction
    F

    F
    F

    Cl

    Cl
    C

    OH

    SO C l 2

    H2/Pd- C

    F
    F

    Cyclopropyl-di-(4-fluoro
    phenyl)-carbinol

    4-chloro-1,1-di-(4
    -fluorophenyl)-1butene

    10

    1-chloro-4,4-di-(4fluorophenyl)-butane

    Main Process
    0.963 g (4.310-3 mole, 1 eq) of 4-(2-oxo-1-benzimidazolinyl)-piperidine, 0.504 g (4.710-3
    mole, 1.09 eq) of sodium carbonate, 0.0245 g (0.8% by weight) of potassium iodide and 3
    mL of glycerol formal were weighed. 1.489 g (4.810-3 mols, 1.10 eq) of 1-chloro-4,4-di-(4fluorophenyl)butane were added.
    The reaction mixture was stirred at 80C. Analysis by thin layer chromatography showed
    that the reaction had been completed within 7 hours.
    3 mL of water were added, then stirred and filtered under vacuum.
    The resulting solid was washed twice with 2 mL of water. The obtained solid was dried at
    40C under reduced pressure. The title compound was obtained as a white solid.
    Yield: 97.5%, purity: 99.5%.

    11

    Main Reaction
    1-chloro-4,4-di-(4fluorophenyl)-butane

    12

    Classical method
    Vs
    New method

    Classical way uses methylisobutylketone (MIBK) which is highly flammable, harmful


    by inhalation, Irritating to eyes and to respiratory system. Isolation of the end
    product is performed by grinding the solid residue with diisopropyl ether and then
    the resulting material is recrystallized firstly from acetone/MIBK and finally from
    acetone. This process takes 65 hours.

    This new process is much more efficient than the classical process because it
    enables to obtain a 98% yield and exhibits the advantages of requiring fewer base
    equivalents, a shorter reaction time and a lower reaction temperature.
    Furthermore, the use of glycerol formal in the process of the present invention
    allows simplifying the isolation and purification of the product.

    13

    Glycerol
    Formal

    4-(2-oxo-1benzimidazolinyl)
    Na2CO3 -piperidine
    KI

    MS

    1-chloro-4,4-di-(4fluorophenyl)butane

    SS

    SS

    HDPE

    Water Tank

    TC

    TT

    MSGL
    Hot waterout

    Hot water in

    Reactor

    Product Wet
    Cake

    SS

    Filtrate

    Vacuum
    Pump

    Filter

    SS

    Product
    Tank

    400C
    Collecting Vessel

    SS

    Dryer

    Effluent
    Treatment

    Transport

    14

    Effluent Treatment
    Glycerol Formal + Water +
    NaCl + KI

    Add MTBE

    2 layers:
    O/L : Glycerol Formal + MTBE
    A/L : Water + NaCl + KI

    Layer Separation

    Waste Stream:
    Water + NaCl + KI

    Recycle Glycerol Formal

    Distillation

    15

    MS
    SS
    Collecting
    Vessel

    MTBE
    CC

    LC

    MSRL

    Glycerol Formal +
    MTBE

    MTBE

    3- way valve

    HDPE
    Water + KI
    + NaCl

    CC

    LC

    Glycerol
    Formal
    (Recycle)

    Effluent
    Stream
    16

    Economy
    17

    Raw Material Cost


    Pimozide (Product)

    1.935 gm

    1 kg

    4-(2-oxo-1-benzimidazolinyl)piperidine

    0.963 gm

    497.67 gm

    Sodium carbonate

    0.504 gm

    260.465 gm

    Potassium iodide

    0.0245 gm

    0.101 gm

    Glycerol formal

    3.609 gm

    1.865 kg

    1-chloro-4,4-di-(4fluorophenyl)butane

    1.489 gm

    769.51 gm

    18

    Chemical

    Rate
    (Rs/kg)

    Amount used

    Cost
    (Rs)

    4-(2-oxo-1benzimidazolinyl)piperidine

    309600

    497.67 gm

    154078.632

    Sodium carbonate

    32

    260.465 gm

    8.335

    Potassium iodide

    2300

    0.101 gm

    0.2323

    Glycerol formal

    57

    1.865 kg

    106.312

    1-chloro-4,4-di-(4fluorophenyl)butane

    129600

    769.51 gm

    99728.496

    Methyl t-butyl
    ether

    1299.6/ liter

    5 liter

    6498

    Total

    260420.0069
    19

    Manufacturing Cost:
    Considering manufacturing cost to be 30% of the raw material cost:

    RMC: Rs 2,60,500
    Manufacturing cost: Rs 78150
    Glycerol formal recovery:
    Considering 80% recovery, amount of glycerol formal recovered = 1492.09 gm

    Therefore reduction in RMC = Rs 85.049


    RMC: Rs 2,60,415
    Cost Price of the product: Rs 3,38,565
    Market Price of the product: Rs 3,60,000

    20

    Hazards
    21

    Pimozide is harmful by ingestion and a potential carcinogen. May be harmful if inhaled


    or cause respiratory irritation. Harmful if absorbed through the skin. May cause skin or
    eye irritation. Some symptoms of adverse effects can target the central nervous
    system and may include general discomfort, symptoms of giddiness, headache,
    dizziness, nausea, slowed reaction time, slurred speech and may progress to
    unconsciousness. Serious poisonings may result in respiratory depression and may
    be fatal.

    Potential Health Effects:


    Inhalation: May be harmful if inhaled. May cause respiratory tract irritation.
    Skin: May be harmful if absorbed through skin. May cause skin irritation.
    Eyes: May cause eye irritation.
    Ingestion: Harmful if swallowed.
    Signs and Symptoms of Exposure: Exposure to and/or consumption of alcohol may
    increase toxic effects. Parkinson-like symptoms, headache, drowsiness, sedation,
    dizziness, tremors, impairment of voluntary movement, dry mouth, diarrhea, nausea,
    vomiting, gastrointestinal discomfort, nervousness, rash, hypotension, palpitation,
    and/or tightness of muscles.

    22

    Handling and storage:


    Storage: ROOM TEMPERATURE
    Handling: Use only in area provided with appropriate exhaust ventilation.
    Safe handling advice: Wear personal protective equipment. Remove and wash
    contaminated clothing before reuse.
    Technical measures/storage conditions: Keep containers tightly closed in a cool,
    well-ventilated place. Keep container tightly closed in a dry and well-ventilated place.
    Incompatible products: Oxidising and spontaneously flammable products.
    Engineering measures: Ensure adequate ventilation.

    PERSONAL PROTECTIVE EQUIPMENT:


    Respiratory protection: Breathing apparatus only if aerosol or dust is formed.
    Hand protection: PVC or other plastic material gloves.
    Skin and body protection: Usual safety precautions while handling the product will
    provide adequate protection against this potential effect.
    Eye protection: Safety glasses with side-shields.
    Hygiene measures: Handle in accordance with good industrial hygiene and safety
    practice.

    23

    References

    Estvez Company, Carlos. 24.12.2007. Process for the preparation of


    pimozide, European Patent 2 357 172 B1.

    Pharmaceutical Manufacturing Encyclopaedia. Third Edition. William Andrew


    Publishing.

    Sustainable Solutions - Green Solvents for Chemistry, in Sustainable


    Solutions for Modern Economies, edited by Rainer Hfer. RSC Publishing

    Websites:

    www.wikipedia.com
    www.alibaba.com
    www.molbase.com

    24

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