MONTELUKAST (OLD)

Stage I:
S.No

Raw materials

Quantity

01.
02.
03.
04.
05.
06.
07.

7-Chloro Quinaldine
Iso Phthaldehyde
Mix Xylene
Acetic Anhydride
Ethyl Acetate
Methanol
N-Hexane

36.48 kgs
41.32 kgs
197 lts
61.32 kgs
560 lts
090 lts
197 + 36 lts

(9.12 Kg x 4 Lots)
(15.33 Kg x 4 Lots)

Manufacturing Process:
01.
02.
03.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.

Clean & dry the reactor

Charge mix Xylene 197 lts at R.T
Charge Iso Phthaldehyde 41.32 kgs at R.T
Charge 7-Chloro Quinaldine lot-I 9.12 kg
Addition of Acetic Anhydride lot-I 15.33 kg
Raise to Reflux
Maintain for 4Hrs at 128-1300C
Cool to 110-1200C
Charge 7-Chloro Quinaldine lot-II 9.12 kg & Addition of Acetic Anhydride lot-II
15.33 kg
Raise to reflux
Maintain for 4Hrs at 128-1300C
Cool to 110-1200C
Charge 7-Chloro Quinaldine lot-III 9.12 kg & Addition of Acetic Anhydride lotIII 15.33 kg
Raise to reflux
Maintain for 4Hrs at 128-1300C
Cool to 110-1200C
Charge 7-Chloro Quinaldine lot-IV 9.12 kg & Addition of Acetic Anhydride lotIV 15.33 kg
Raise to reflux
Maintain for 4Hrs at 128-1300C
Check T.L.C absence of 7-Chloro Quinaldine
If complies cool to R.T
Charge N-Hexane 197 lts
Maintain for 1hr at R.T
Centrifuge the Material & wash with 36 lts of N-Hexane
Spin dry the Material & unload the material in Poly bags
Dry the Material at 70-800C
OUTPUT:
Dry Wt: 36 Kgs
Description: Pale Yellow to Yellowish Crystalline Powder
M.R : 145-1500C

PRINCE LABORATORIES P.LTD

IDA, JEEDIMETLA, HYDERABAD.
MONTELUKAST
Stage I: [PURIFICATION]
Manufacturing Process:
01.Clean & dry the reactor
02.Charge Ethyl Acetate 540 lts
03.Charge Stage-I Crude 36 Kgs
04. Heat to reflux
4. Maintain at reflux for 1hr
5. Filter the Ethyl Acetate Solution through leaf filter
6. Collect the filterate into another reactor
7. Wash the leaf with 20 lts of Ethyl Acetate
8. Collect total Filterate into the reactor
9. Distill out Ethyl Acetate Under Vacuum below 700C
10. After Complete distillation of Ethyl Acetate
11. Charge Methanol 75 lts at 700C
12. Raise the temperature up to Reflux
13. Maintain for 30 min
14. Cool to 0-50C
15. Maintain for 2 Hrs at 0-50C
16. Centrifuge the Material & wash with Chilled Methanol 15 lts
17. Spin dry & unload the material
18. Dry the material at 700C
OUTPUT:
Dry Wt: 31.6 Kgs

PRINCE LABORATORIES P.LTD

IDA, JEEDIMETLA, HYDERABAD.
MONTELUKAST
Stage II:
01.
02.
03.
04.
05.
06.
07.
08.

Stage-I
Toluene
T.H.F
Vinyl Magnesium Bromide
Ammonium Acetate
Sodium Chloride
Iso Propyl Ether
N-Hexane

38 kgs
380 + 144 + 114 + 76 lts
114 lts
267.9 kgs
045.6 Kgs
15.2 Kgs
076 lts
038 lts

Manufacturing Process:
01.
Clean & dry the reactor
Charge Toluene 380 lts
Charge Stage-I 38 Kg at R.T
Charge T.H.F 114 lts
Cool to 5 to 00C under N2 gas
Add the Vinyl Magnesium Bromide ( The reaction is exotheramic )
Maintain at 0-30C for 1Hr under N2 gas
Check T.L.C
If T.L.C complies
Quench the reaction mass with 10% of Ammonium Acetate solution below 100C
Raise the mass to R.T
Stirr for 1Hr
Settle for 30min
Separate the bottom aqueous layer
Collect the top Toluene layer into another reactor
Extract the aqueous layer with Toluene
Wash the both Toluene layers with 76 lts X 2 times
Finally wash with 5% sodium bi carbonate solution
Distill out the Toluene under Vacuum at below 700C
Cool to 500C
Charge 76 lts of Iso Propyl Ether
Stirr for 3-4 Hrs
Centrifuge the material at R.T
Spin dry & unload the wet material
Charge wet solid material into Toluene 114 lts into another reactor
Raise the temperature to 60-700C
Check the clear solution & charge Activated Carbon 3 Kg
Stirr for 30 min at 800C
Filter the mass through leaf filter into another reactor
wash the carbon bed with

Cool to RT and charge n-Hexane 38 Lt.

Stir for 3 to 4 hours at RT
Centrifuge the material at 20 0C
Wash the material with 20 lt of n0- Hexane
Spin dry the material
Dry the material at 45 50 0C
Check the LOD , It should be Not More than 0.5 %

Out Put : Dry : 26.5 Kg 27.5 Kg

MR : 105 110 0C

MONTELUKAST
Stage III:
01.
02.
03.
04.
05.
06.
07.

Stage-II
Methyl-2-Iodo Benzoate
Tri Ethyl Amine
Palladium Acetate
Acetonitrile
n-Hexane
Toluene

26.500
23.300
18.400
0.265
132.5+106
160.000
26.000

kg
Kg
Kg
Kg
Lt
Lts
Lt

Manufacturing Process:
01.
Clean & dry the reactor
Charge Acetonitrile 132.5 Lt and stage II 26.5 Kg at RT under Nitrogen Atm.
Charge methyl 2- Iodo Benzoate 23.3 Kg
Slowly raise the temp to mild reflux under Nitrogen atm.
Maintain for 6.0 hours at mild reflux under Nitrogen atm
Check the reaction mass by TLC
If not complies add TEA and maintain for 1.0 hour extra.
If complies , charge Acetonitrile 106 Lt
Maintain for 30 min under reflux with Nitrogen atm.
Filter the mass at reflux temp
Wash the salts with 7.5 lt of hot Acetonitrile
Take the filtrate back in to the clean reactor
Cool the mass to 20 25 0Cand maintain for 4 hours
Filter the material
Wash the cake with 65 lt of Acetonitrile
Wsah the cake with 50 lt of Acetonitrile
Take the wet cake in to another reactor and chargwe 160 lt of n-hexane
Stir for 20 min
Filter the material and wash the cake with 25 lt of n_Hexane
Spin dry and unload the material
Dry the material at 45 50 0C
Out Put :
Crude Wt : 21.5 Kg 22.0 Kg

Purification
Take the above crude material in 25 lt of Toluene at RT
Raise the temp till the material get dissolves
Cool to 50 55 0C
Stir for 1 hour at same temp
Filter the material and wash the material with 12.5 Lt of n- Hexane
Dry the material 50 55 0C
Unload the material in to polythene bags

Out put
Dry wt : 19.5 20.5 Kg
Description : Dark yellow to pale yellow colured powder
MR
: 123 128 0C

MONTELUKAST
Stage IV:
01.
02.
03.
04.
05.
06.
07.
08.
09.

Stage-III
Dip Chloride
Di Iso Propyl Ethyl Amine
T.H.F
Di Ethanol Amine
n-Hexane
Acetone
M.D.C
Methanol

44.00
140.80
07.92
355.00
46.00
395.00
36.00
1320.0
325 + 90 + 25

kg
Kg
Kg
Kg
Lt
Lt
Lt
Lt
Lt

Manufacturing Process:
01. Clean & dry the reactor
02. Charge T.H.F 155 lt
03. Cool to 50C under N2 gas
4.
Slowly add Dip Chloride at 5 to 80C under N2 gas
5.
Stirr for 20min at 5 to 80C under N2 gas
6.
Slowly add Stage-III solution in about 1-2 Hrs under N2 gas
NOTE :
Preparation of Stage-III Solution
Take 44 Kg of Stage-III into 200 lt of T.H.F and 7.92 Kg of Di Iso Propyl Ethyl Amine
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.

Stirr for 3-4 Hrs at 0 to 50C under N2 gas

Check T.L.C
If T.L.C Complies Charge 40 Lt of Acetone at 50C
Stirr for 1Hr at below 50C
Slowly raise the temperature to 10-150C
Distill out the solvent at 10-150C under vacuum
Add 265 Lt of n-Hexane at 10-150C
Stirr for 2Hr at R.T
Filter the salts and wash with 45 Lt of n-Hexane
Unload the cake into poly bags
Charge water 725 Lt
Charge 46 Lt Di Ethanol Amine at R.T
Charge above salts & Stirr for 1 Hr
Charge 880 Lt of M.D.C
Stirr for 30 min & settle for 30 min
Separate the bottom M.D.C layer into another reactor
Extract the aqueous layer with 450 Lt of M.D.C
Mix the both extracted M.D.C layer & wash with 5.0% of sodium Chloride
solution (450 Lt)
Distill out M.D.C under atmosphere and finnaly apply vacuum and distill
below 200C
Charge Methanol & water ( 352 Lt Methanol + 45 Lt Water )
Reflux for 30 min to get clear solution
Charge 1 Kg Carbon & maintain for 1Hr at reflux

29.
30.
31.
32.
33.
34.
35.
36.
37.
38.

Filter the carbon through leaf filter

Wash the bed with 90 Lt Hot Methanol
Take back filterate into another reactor
Distill out Methanol under atmosphere
Cool to R.T & Stirr for 2 Hrs at R.T
Cool to 0-50C And stir for 5 Hr
Centrifuge the material at 0 5 0C
Wash the material with chilled methanol (25 Lt +Water 25 Lts)
Spin dry the material and unload the material in to Poly Bags
Dry the material at 50 55 0C

Out Put : Dry : 28.5 Kg 30 Kg

Description : Pale Yellow colored powder

.
MONTELUKAST
Stage V:
Raw Materials:01.
02.
03.
04.
05.
06.
07.
08.
09.
10.
11.

Stage-IV
Toluene
Cerrium (III) Chloride
THF
Acetic Acid
Sodium Carbonate
Methyl Magnesium Chloride
Sodium Chloride
t- Butanol
Di iso propyl Ether
n-Hexane

26.000
494.00
15.60
312.000
41.6000
35.360
130.000
26.000
06.500
65.000
104.000

kg
Lt
Kg
Lt
Kg
Kg
Lts
Kg
Lt
Lt
Lt

Manufacturing Process:
01.
Clean & dry the reactor
Charge stage IV 26.0 Kg at RT
Charge Toluene 312 Lts at RT
Slowly raise the temp to reflux for 1.0 hour
Distill off Toluene 104 Lts azeotropically
Cool to RT
Transfer the mass in to addition receiver
Take the Cerrium Chloride 15.60 Kg in to dry reactor and charge Toluene 156 Lts
Slowly distill off Toluene completely azeotropically and cool to 40 0C
then add THF 312 Lts at 40 0C
Distill off THF 104 Lts under Atmospheric distillation
Cool to RT
Cool to 0 0C
Slowly add Methyl Magnesium Chloeride 130 Lts in about 2 3 Hours under Nitrogen
atm at 0 0C
After completion of MMC addition start slowly addition of stage IV solution at 0 0C in
about 2 3
hours
Note: Mean while prepare the 2 Molar Acetic acid solution in to another reactor and cool
to 0 0C
Preparation : Acetic Acid 41.6 Lt + 312 Lts of Water (2.0 Molar solution)
Check TLC
If TLC complies Quench the mass in tio 2.0 Molar Acetic acid solution at below 20 0C
under
stirring
Stirr for 15 min at 20 0C
Settle for 30 min at 20 0C
Separate the organic layer in to another reactor at 30 0C
Wash the organic layer with 5.0% Sodium Carbonate solution at 30 0C

Note : Preparation of solution :35.36 Kg of Sodium Carbonate + 707 Lt of water

24.
25.
26.
water.
24.
25.
26.
27.
28.

Stirr for 30 min at RT

Settle for 30 min at 300C
Separate the organic layer at R.T
Wash the organic layer with 5% sodium chloride solution at R.T
Note : Sodium Chloride Solution : 26 kgs of Sodium Chloride + 520 ltrs of
Stir for 15 min. at RT.
Settle for 30 min at RT.
Separation of organic layer at RT.
Take back the organic layer and dry the organic layer with sodium sulphate.
Distill off solvent U/Vaccum at below 500C.

Crystallization :
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.

Take the crude and charge into it 52 ltrs of N-Hexane.

Stir for 1 to 2 Hrs at RT.
Decant the n-Hexane layer.
Again charge into it n-Hexane 52 ltrs at RT.
Stir for 30 min.
Decant the n-Hexane layer.
Add into 7.8 ltrs of t-Butanol then warm into it 350C to 400C to get a clear
solution.
Then stir for 30 min.
Cool to 20 250C and add 52 ltrs of di-iso propyl ether.
Maintain for 2 Hrs at 20 250C.
Filter the material and wash with 5 ltrs di-iso propyl ether.
Spin dry and unload the material.
Dry the material at 400C only air drying.

Out Put
Dry wt
Description
M.R

:
:
:
:

15.6 Kg
Cream colour
115 1210C

.
MONTELUKAST
Stage VI:
Raw Materials:Stage V
Toluene
Acetonitrile
Di iso propyl ethylamine
Methyl sulfonyl chloride
N Hexane

:
:
:
:
:
:

10.00 kg
50.00 ltrs
94.00 ltrs
5.65 ltrs
1.98 ltrs
20.00 ltrs

Manufacturing Process:
01. Clean and dry the reactor.
02. Charge Toluene 50 ltrs at RT.
03. Charge StageV 10 kgs at RT.
04. Raise the temp to reflux.
05. Distill off Toluene 21 kgs by azeotropically.
06. Cool to RT.
07. Add into it 74 ltrs of Acetonitrile.
08. Add into it 5.623ltrs of diethyl amine U/N2 slowly .
09. Cool to 20 to 250C U/N2.
10. Slowly addition of Methyl Magnesium chloride 1.98 ltrs in about 3 4 hours at 20
to 250C U/N2.
11. Then slowly cool to 30 to 350C U/N2.
12. Maintain for 2 Hrs at30 to 350C U/N2 (Crystals follows observed at the time of
maintenance).
13. Then filter the material U/N2.
14. Wash the material with 20 ltrs of Acetonitrile and 20 ltrs of n-Hexane.
15.
Preserve the material in freeze U/N2 .
16.
Store in deefreeze.
Out Put
Weight
Description

:
:
:

8 10 kg
Light yellowish

Note : This unstable compound please kept it cool.

MONTELUKAST
Stage VII:
Raw Materials:Stage VI
1-(thiomethyl) cyclopropane Acetic Acid
N Hexane
THF
n-Butyl Lithium (3 molar)
Sodium Chloride
Ethyl Acetate
L+ Tartaric acid
Di cyclo hexyl amine

:
:
:
:
:
:
:
:
:

9.000 kg
3.175 kg
216.000 ltrs
67.500 ltrs + 45 ltrs
15.185 ltrs
1.000 kg
108 + 72 + 24 ltrs
7.500 kg
3.600 ltrs

Manufacturing Process:
01.
02.
03.
04.
05.
Hrs.

Clean and dry the reactor.

Charge 67.5 ltrs THF U/N2.
Charge 3.175 kgs of 1-(thiomethyl) cyclopropane Acetic Acid U/N2.
Cool to 10 to 150C U/N2.
Then addition of 15.185 ltrs of n-Butyl Lithium at 10 to 150C U/N2 in about 2

Note : Preparation of stage VI solution : Stage-VI 9.0 kg + 45 ltrs of THF.

06.
Stir for another 15 hours at 50C U/N2.
07. Check the TLC.
08.
If TLC complies quinch the reaction mass with 50 ltrs of 10% Sodium Chloride
solution at RT.
09.
Stir for 30 min.
10.
Settle for 30 min.
11.
Separation of organic layer.
12.
Wash the aq.layer with 108 ltrs of Ethyl acetate at RT.
13.
Stir for 30 min.
14.
Settle for 30 min.
15.
Separation of organic layer.
16.
Wash the aq.layer with 72 ltrs of Ethyl acetate at RT.
17.
Take total extracted organic layer into reactor at RT.
18.
Charge 72 ltrs of 0.5 molar L+Tartaric acid solution.
Note : Preparation of solution : 7.5 kg of L+Tartaric acid + 100 ltrs of water.
19.
Finally wash the organic layer with water 80 ltrs x 3 times .
20.
Check the pH 6.5 to 7.0.
21.
If not complies then give water washings upto neutral pH.
22.
Dry the organic layer with Sodium Sulphate.
23.
Concentrate the organic layer U/Vaccum.
24.
Charge fresh Ethyl acetate 24 ltrs.
25.
Charge into it Di cyclo hexyl amine 3.6 ltrs at RT.
26.
Stir for 15 min at RT.
27.
Seed with DCHA salt and maintain for 20 Hrs at RT.
28.
Add n- Hexane 48 Ltrs in about 2 Hrs at 20 250C.
29.
Maintain for 8 hours at 20 250C.
30.
Filter the material and wash with Ethyl acetate (5.5 ltrs) + n- Hexane (11.0 ltrs).
Montelukast DCHA salt Out Put : 6 to 6.5 kgs

.
MONTELUKAST
Preparation of Montelukast free acid:
Raw Materials:Stage VII
MDC
Water
Acetic Acid

:
:
:
:

1.0 kg
10 + 2.5 ltrs
5 + 20 ltrs
0.112 ltrs

Manufacturing Process:
01.
02.
03.
04.
05.
06.
07.
08.
09.
10.
11.
12.
13.
14.
15.
16.
17.

Clean and dry the reactor.

Charge MDC 10 ltrs at RT.
Charge Stage-VII 1.0 kg.
Slowly add Acetic Acid solution at RT.
Note: Preparation of Acetic Acid Solution : 0.112 ltr Acetic Acid + 5 ltrs water.
Stir for 30 min.
Settle for 30 min.
Separate MDC layer and collect separately.
Charge 2.0 ltrs of MDC at RT.
Stir for 30 min.
Settle for 30 min.
Separate MDC layer and collect separately.
Give one more MDC extraction 0.5 ltrs.
Collect total MDC layer into another reactor.
Wash the organic layer with water 4 x 5 ltrs.
Then dry total organic layer with Sodium Sulphate.
Distill out MDC U/Vaccum at below 500C.
Residual mass collect and weigh.
This weighed mass is Montelukast free acid.

MONTELUKAST
Preparation of Montelukast Sodium:
Raw Materials:Montelukast free acid
Toluene
0.5 M Methanolic Sodium Hydroxid
n-Hexane

:
:
:
:

1.0 kg
2 + 2.9 + 2 ltrs
2.55 ltrs
2.5 + 2 ltrs

Manufacturing Process:
01.
02.
03.
04.
05.
06.
07.
08.
09.
10.
11.
12.
13.
14.
15.
16.
17.

Clean and dry the RBF.

Charge Toluene 2.0 ltrs U/N2 at RT.
Charge 1.0 kg Montelukast free acid U/N2 at RT.
Check for dissolution.
Distillout Toluene completely U/Vaccum < 500C.
After Toluene distillation to be obtained residue add 2.9 ltrs of Toluene at RT U/N2.
Add 0.5 M Methanolic Sodium Hydroxid solution 2.55 Ltrs U/N2.
Stir for 30 min at RT U/N2.
Slowly start the solvent distillation U/V at below 500C.
After coplete distill the solvent and add 2.0 ltrs of Toluene.
Distill of Toluene 650 ml U/V < 500C.
Concentrate reaction mixture and add slowly 2.5 ltrs of n-Hexane at RT U/N2.
Stir for 2-3 Hrs at 200C.
Filter the product U/V at 200C and U/N2.
Wash the cake with 2.0 ltrs of n-Hexane.
Spin dry U/N2 atmosphere.
Dry the material 70-800C U/V for 6-7 Hrs.
Out Put
: 650 700 gm
Purity by HPLC: 99.40%
HPLC :
Column
Buffer
Flow rate
UV detention

:
:
:
:

symmetry 18
sodium phosphate (pH adjusted 3.7)
1.0ml/min
at 225 nm

Montelucast Stage wise analytical data:

Stage-I TLC
Mobile phase

Benzene : Ethyl Acetate

9
:
1

Sample : Reaction Mass in MDC

Starting material : 7-CQ in MeOH

Stage-II TLC
Mobile phase
Sample :

Toluene : Ethyl Acetate

9
:
1
Reaction Mass + Ammonium acetate + E.A then spot Toluene layer

Stage-III TLC
Mobile phase
Sample :

LU : Ethyl Acetate
9
:
1
Reaction Mass + water + E.A

Stage-IV TLC
Mobile phase

LU : Ethyl Acetate
8
:
2
Sample : Reaction Mass + Acetone + diethanol amine solution + E.A
Starting material: + E.A then put spot

Stage-V TLC
Mobile phase

Benzene : Ethyl Acetate

7
:
3

Stage-I TLC
Mobile phase

Benzene : Ethyl Acetate

8
:
2
Sample : Reaction Mass + E.A + Water
Starting material : stage VI + MDC