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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:
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02.
03.
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3.
4.
5.
6.
7.
8.
9.
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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

Maintain at reflux for 1hr 5. JEEDIMETLA. 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. Filter the Ethyl Acetate Solution through leaf filter 6.Clean & dry the reactor 02. Wash the leaf with 20 lts of Ethyl Acetate 8. After Complete distillation of Ethyl Acetate 11.Charge Ethyl Acetate 540 lts 03. Distill out Ethyl Acetate Under Vacuum below 700C 10.Charge Stage-I Crude 36 Kgs 04.6 Kgs . Heat to reflux 4.LTD IDA. Collect the filterate into another reactor 7. Raise the temperature up to Reflux 13.PRINCE LABORATORIES P. MONTELUKAST Stage – I: [PURIFICATION] Manufacturing Process: 01. Collect total Filterate into the reactor 9. Cool to 0-50C 15. Charge Methanol 75 lts at 700C 12. HYDERABAD. Maintain for 2 Hrs at 0-50C 16. Maintain for 30 min 14.

05. HYDERABAD. 07.H. 02.L. 06.T Charge T.9 kgs 045. Clean & dry the reactor Charge Toluene 380 lts Charge Stage-I 38 Kg at R.C If T.F Vinyl Magnesium Bromide Ammonium Acetate Sodium Chloride Iso Propyl Ether N-Hexane 38 kgs 380 + 144 + 114 + 76 lts 114 lts 267.C complies Quench the reaction mass with 10% of Ammonium Acetate solution below 100C Raise the mass to 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 . Stage-I Toluene T.PRINCE LABORATORIES P. 03.2 Kgs 076 lts 038 lts Manufacturing Process: 01.LTD IDA.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. 08.H.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. 04. JEEDIMETLA. MONTELUKAST Stage – II: 01.L.6 Kgs 15.

Hexane Spin dry the material Dry the material at 45 – 50 0C Check the LOD .5 Kg – 27.5 % Out Put : Dry : 26. It should be Not More than 0.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 n0.5 Kg MR : 105 – 110 0C .

Hexane Dry the material 50 – 55 0C Unload the material in to polythene bags Out put Dry wt : 19. Maintain for 6. 07. 03. 05. . Stage-II Methyl-2-Iodo Benzoate Tri Ethyl Amine Palladium Acetate Acetonitrile n-Hexane Toluene 26.5 Kg at RT under Nitrogen Atm.5 Kg – 22.3 Kg Slowly raise the temp to mild reflux under Nitrogen atm.300 18.0 hour extra.5 Lt of n. 06.400 0.265 132.500 23. charge Acetonitrile 106 Lt Maintain for 30 min under reflux with Nitrogen atm.000 26. 04.MONTELUKAST Stage – III: 01. Charge methyl –2.5+106 160.000 kg Kg Kg Kg Lt Lts Lt Manufacturing Process: 01.0 hours at mild reflux under Nitrogen atm Check the reaction mass by TLC If not complies add TEA and maintain for 1.Iodo Benzoate 23.5 Kg Description : Dark yellow to pale yellow colured powder MR : 123 – 128 0C . Clean & dry the reactor Charge Acetonitrile 132. 02. Filter the mass at reflux temp Wash the salts with 7.0 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. If complies .5 Lt and stage –II –26.5 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 –20.

00 395.00 1320.D.T Charge above salts & Stirr for 1 Hr Charge 880 Lt of M.0 325 + 90 + 25 kg Kg Kg Kg Lt Lt Lt Lt Lt Manufacturing Process: 01. 03.D.C Mix the both extracted M.C If T.L. 05.D. 10. 15. 21.92 Kg of Di Iso Propyl Ethyl Amine 7. 06.92 355.80 07. 8. 04. 18.D. 17. 19. 27. Stage-III Dip Chloride Di Iso Propyl Ethyl Amine T.F and 7. 24. 28. 12. 26.L.C layer & wash with 5.D. 07.F 155 lt 03. Cool to – 50C under N2 gas 4. Slowly add Dip Chloride at – 5 to –80C under N2 gas 5. Charge T. 9.F Di Ethanol Amine n-Hexane Acetone M. 22. Stirr for 20min at – 5 to –80C under N2 gas 6. 20. 11. 14. 23.0% of sodium Chloride solution (450 Lt) Distill out M.H.MONTELUKAST Stage – IV: 01. 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.C Stirr for 30 min & settle for 30 min Separate the bottom M. 02. 09. 13. 08.C layer into another reactor Extract the aqueous layer with 450 Lt of M. 25.C Methanol 44.00 140.00 46.H.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. Stirr for 3-4 Hrs at – 0 to – 50C under N2 gas Check T.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 . 16.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. Clean & dry the reactor 02.00 36.D.

34. 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. 30. 33. 31.29. 38.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. 32.5 Kg – 30 Kg Description : Pale Yellow colored powder .T & Stirr for 2 Hrs at R. 36. 35. 37.

360 130. 04.6000 35. 09.0 Molar solution) Check TLC If TLC complies Quench the mass in tio 2.6 Lt + 312 Lts of Water (2. 03.60 312.000 494.000 26.000 06.Butanol Di iso propyl Ether n-Hexane 26.0% Sodium Carbonate solution at 30 0C .000 41. 11.60 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..000 104.0 Kg at RT Charge Toluene 312 Lts at RT Slowly raise the temp to reflux for 1. 08.500 65. 05. 06.0 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. MONTELUKAST Stage – V: Raw Materials:01. 02.000 kg Lt Kg Lt Kg Kg Lts Kg Lt Lt Lt Manufacturing Process: 01.0 hour Distill off Toluene 104 Lts azeotropically Cool to RT Transfer the mass in to addition receiver Take the Cerrium Chloride 15.00 15. Stage-IV Toluene Cerrium (III) Chloride THF Acetic Acid Sodium Carbonate Methyl Magnesium Chloride Sodium Chloride t. 07. Clean & dry the reactor Charge stage –IV 26. 10.

Dry the material at 400C only air drying. Add into 7. Out Put Dry wt Description M. 30. 41. 36. 37. Decant the n-Hexane layer. 33. 28.R : : : : 15.Note : Preparation of solution :35. 24. 38. Stir for 1 to 2 Hrs at RT. Settle for 30 min at RT. Spin dry and unload the material.6 Kg Cream colour 115 – 1210C .T Wash the organic layer with 5% sodium chloride solution at R. Again charge into it n-Hexane 52 ltrs at RT. 31. Stirr for 30 min at RT Settle for 30 min at 300C Separate the organic layer at R. 27. 34. Separation of organic layer at RT. Take back the organic layer and dry the organic layer with sodium sulphate. Cool to 20 – 250C and add 52 ltrs of di-iso propyl ether. Crystallization : 29. 25. 26. 39.T Note : Sodium Chloride Solution : 26 kgs of Sodium Chloride + 520 ltrs of Stir for 15 min. at RT. 35.8 ltrs of t-Butanol then warm into it 350C to 400C to get a clear solution. 32. 26. Decant the n-Hexane layer. water. Maintain for 2 Hrs at 20 – 250C. Distill off solvent U/Vaccum at below 500C. 40. Stir for 30 min. Then stir for 30 min. 25.36 Kg of Sodium Carbonate + 707 Lt of water 24. Take the crude and charge into it 52 ltrs of N-Hexane. Filter the material and wash with 5 ltrs di-iso propyl ether.

Raise the temp to reflux. 13. Slowly addition of Methyl Magnesium chloride 1. . 10. Cool to RT. 08. 14. 06. 15. 03. MONTELUKAST Stage – VI: Raw Materials:Stage V Toluene Acetonitrile Di iso propyl ethylamine Methyl sulfonyl chloride N – Hexane : : : : : : 10. 11.00 ltrs Manufacturing Process: 01. Wash the material with 20 ltrs of Acetonitrile and 20 ltrs of n-Hexane. 02. 07. 12. Maintain for 2 Hrs at–30 to –350C U/N2 (Crystals follows observed at the time of maintenance). Store in deefreeze. Add into it 74 ltrs of Acetonitrile. 04. Then filter the material U/N2. Out Put Weight Description : : : 8 – 10 kg Light yellowish Note : This unstable compound please kept it cool. Preserve the material in freeze U/N2 . Distill off Toluene 21 kgs by azeotropically.00 ltrs 94. .00 ltrs 5. Charge Toluene 50 ltrs at RT. Then slowly cool to –30 to –350C U/N2.623ltrs of diethyl amine U/N2 slowly . Clean and dry the reactor.98 ltrs 20. Charge Stage–V 10 kgs at RT. 16.98 ltrs in about 3 – 4 hours at –20 to –250C U/N2.. Cool to –20 to –250C U/N2. 09.65 ltrs 1. 05.00 kg 50. Add into it 5.

Wash the aq. 08. 25. Charge fresh Ethyl acetate 24 ltrs. Then addition of 15. 15.Hexane (11.500 ltrs + 45 ltrs 15. 30. Stir for another 15 hours at –50C U/N2.Hexane 48 Ltrs in about 2 Hrs at 20 – 250C. 16. Settle for 30 min.0 kg + 45 ltrs of THF. Maintain for 8 hours at 20 – 250C. 03.185 ltrs of n-Butyl Lithium at –10 to –150C U/N2 in about 2 Note : Preparation of stage –VI solution : Stage-VI 9. 12. 18.0. Take total extracted organic layer into reactor at RT. Filter the material and wash with Ethyl acetate (5. Clean and dry the reactor.5 to 7. 11. 24. 14. 27.600 ltrs Manufacturing Process: 01. 09. Charge into it Di cyclo hexyl amine 3.5 ltrs) + n. 13.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. 21. Stir for 15 min at RT.500 kg 3. 23. 28. 20. Separation of organic layer. Charge 3.000 kg 3.layer with 72 ltrs of Ethyl acetate at RT. Wash the aq. Seed with DCHA salt and maintain for 20 Hrs at RT. Hrs. Charge 67. Check the pH 6. Stir for 30 min. Cool to –10 to –150C U/N2. 05. 26.5 kg of L+Tartaric acid + 100 ltrs of water.layer with 108 ltrs of Ethyl acetate at RT. Finally wash the organic layer with water 80 ltrs x 3 times . 29.5 molar L+Tartaric acid solution.175 kg 216. 22. Stir for 30 min. Montelukast DCHA salt Out Put : 6 to 6. Concentrate the organic layer U/Vaccum.5 kgs . 19.6 ltrs at RT. Separation of organic layer.5 ltrs THF U/N2. Add n.000 ltrs 67. Check the TLC. If not complies then give water washings upto neutral pH. Dry the organic layer with Sodium Sulphate. 07. 04. 02. 06. 17.0 ltrs).175 kgs of 1-(thiomethyl) cyclopropane Acetic Acid U/N2. Note : Preparation of solution : 7. Charge 72 ltrs of 0. 10.185 ltrs 1. Settle for 30 min. If TLC complies quinch the reaction mass with 50 ltrs of 10% Sodium Chloride solution at RT.000 kg 108 + 72 + 24 ltrs 7.

MONTELUKAST Preparation of Montelukast free acid: Raw Materials:Stage VII MDC Water Acetic Acid : : : : 1. 08. 13. Clean and dry the reactor.. Stir for 30 min. 07. 09. Charge 2. Settle for 30 min. This weighed mass is Montelukast free acid. Wash the organic layer with water 4 x 5 ltrs. . Stir for 30 min.0 kg 10 + 2.0 ltrs of MDC at RT. Note: Preparation of Acetic Acid Solution : 0. Residual mass collect and weigh. Slowly add Acetic Acid solution at RT. Charge MDC 10 ltrs at RT. 05.112 ltr Acetic Acid + 5 ltrs water. 02. Separate MDC layer and collect separately. Distill out MDC U/Vaccum at below 500C. 16. Then dry total organic layer with Sodium Sulphate. 10. Separate MDC layer and collect separately. 04. Charge Stage-VII 1. 14. 12. 15. 03. Settle for 30 min.0 kg. 17. Give one more MDC extraction 0.5 ltrs 5 + 20 ltrs 0. Collect total MDC layer into another reactor.5 ltrs. 06.112 ltrs Manufacturing Process: 01. 11.

5 ltrs of n-Hexane at RT U/N2. 17. 02. 05.0 kg Montelukast free acid U/N2 at RT. Clean and dry the RBF. 16. 13.55 ltrs 2.5 + 2 ltrs Manufacturing Process: 01. Filter the product U/V at 200C and U/N2. 11.0 ltrs U/N2 at RT.0 ltrs of Toluene.7) 1. 10. After Toluene distillation to be obtained residue add 2.9 ltrs of Toluene at RT U/N2. Distillout Toluene completely U/Vaccum < 500C. 08.5 M Methanolic Sodium Hydroxid solution 2. 04. 06.40% HPLC : Column Buffer Flow rate UV detention : : : : symmetry 18 sodium phosphate (pH adjusted 3. Stir for 2-3 Hrs at 200C. After coplete distill the solvent and add 2. 14. Out Put : 650 – 700 gm Purity by HPLC: 99. 09.0 ltrs of n-Hexane. Charge Toluene 2. Slowly start the solvent distillation U/V at below 500C.0 kg 2 + 2. Add 0.5 M Methanolic Sodium Hydroxid n-Hexane : : : : 1. Stir for 30 min at RT U/N2. Dry the material 70-800C U/V for 6-7 Hrs. Charge 1.9 + 2 ltrs 2. 03.55 Ltrs U/N2. Spin dry U/N2 atmosphere. Concentrate reaction mixture and add slowly 2. 12.MONTELUKAST Preparation of Montelukast Sodium: Raw Materials:Montelukast free acid Toluene 0.0ml/min at 225 nm Montelucast Stage wise analytical data: Stage-I TLC Mobile phase Benzene : Ethyl Acetate 9 : 1 . 07. 15. Wash the cake with 2. Check for dissolution. Distill of Toluene 650 ml U/V < 500C.

A + Water Starting material : stage VI + MDC .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.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 Stage-IV TLC Mobile phase LU : Ethyl Acetate 8 : 2 Sample : Reaction Mass + Acetone + diethanol amine solution + E.A then spot Toluene layer Stage-III TLC Mobile phase Sample : LU : Ethyl Acetate 9 : 1 Reaction Mass + water + E.A Starting material: + E.