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
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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
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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
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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%.
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Main Reaction
1-chloro-4,4-di-(4fluorophenyl)-butane
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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.
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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
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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
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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
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Economy
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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
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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
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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
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Hazards
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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.
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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.
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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
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