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

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.

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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
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

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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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