Product: -2-Nitro benzene sulfanyl chloride (NSC)
Route of synthesis
N+
O-
O
Cl
N+
O-
O
S
N+O
-
O
S
Sodium sullfideSulfur Trichloro ethylene
IodineN
+O-
O
SCl
2-Nitro benzene sulfanyl chloride1-chloro-2-nitrobenzene bis(2-nitrophenyl) disulfide
Cl2 Gas
Material Balance
Step-1
Input Kg Out put Kg
ONCB 2.85 Stage-1 1.40
Sodium sulfide 2.14 Recovered methanol 18.95
Sulfur 0.43 Vacuum loss of methanol 1.00
Methanol 19.95 aq, layer contain
Water 6.84 1) Water 6.68
2) Sodium chloride 1.60
3) Sodium sulfide 0.73
Residue after mL distillation 1.39
Hydrogen sulfide 0.46
Total 32.21 32.21
Step-2
Trihloro
ethylene 25.60 Finished product 1.00
Stage-I 1.40 Recovered trichloro ethylene 25.34
Iodine 0.75 Vapour loss to trichloroethylene 0.26
Chlorine gas 0.32 Recovered hexane 2.34
Hexane 2.46 Vapour loss of hexane 0.12
Residue after Hexane recovery 0.72
Iodine recovered 0.75
Total 30.53 30.53
Process flow diagram
Product: NSC Stage-01
Aqueous high TDS-10.86L. Recovered Methanol 98% Solid waste
Residue after mL distillation -1.39kg.
Reaction
ONCB-2.85kg. Sodium sulfide-2.14kg. Sulfur-0.43kg. Methanol – 19.95kg. Water-6.84kg.
Extraction and solvent distillation
Material isolation
Output- 1.40 kg.
Product: NSC Stage-II
Aqueous -NA. Recovered trichloro ethylene 98% Recovered hexane 98% Recovered Iodine 98% Solid waste
Residue after Hexane recovery-0.72kg.
Reaction
Trihloro ethylene-25.60kg. Stage-I-1.40kg. Iodine-0.75kg. Chlorine gas – 032kg. Hexane-2.46kg.
Extraction and solvent distillation
Material isolation
Output- 1.0 kg.
Product: -Chlorothymol
Route of synthesis
OH OH
ClSO2Cl
2
CCl3
Material Balance
Input Kg Out put Kg
Thymol 1.39 Chlorothymol 1.00
Sulfuryl chloride 1.50 Recovered CTC 3.13
Carbon tetra chloride 3.19 CTC Loss in vacuum 0.06
Sodiumcarbonate 0.24 Pet ether recovery 0.42
Pet ether 0.47 Pet ether loss 0.05
DM water 1.03 Sulfor diaoxide 0.59
Hydrochloric acid 0.34
Carbon dioxide 0.10
Aq. Layer contains
1) Water 1.01
2) Sodium sulfate 0.27
3) Sodium chloride 0.02
4) HCl 0.05
Residues after HVD & Solvent recovery 0.79
Total 7.83 7.83
Process flow diagram
Product: Chlorothymol
CO2 + SO2 +HCl gas (Scrubber)
Aqueous high TDS-2.14L. Recovered CTC 98% Recovered pet ether 98% Solid waste
Residues after HVD & Solvent recovery-0.79kg.
Reaction
Thymol-1.39kg. Sulfuryl chloridel-1.50kg. Carbon tetra chloride-3.19kg. Sodiumcarbonate-0.24kg. Pet ether-0.47kg. DM water- 1.03kg.
Extraction and solvent distillation
Material isolation
Output- 1.0 kg.
Product: -Sharpless catalyst
Route of synthesis
N
N
Cl
Cl
+N
NN
H
HH
O
O
N
H
H
H
O
O
ClH2N
H
H
H
OH
O
2
N
H
H
H
OH
O
Dichloro phthalylhydrazine
MDC
Ammonia Toluene
KOH; K2CO3
(S)-(6-methoxyquinolin-4-yl) (2R,4S,5R)-5-ethyl-1-azabiclo 2.2.2 oct-2-yl methanol. HCl
(S)-(6-methoxyquinolin-4-yl) (2R,4S,5R)-5-ethyl-1-azabiclo 2.2.2 oct-2-yl methanol
Sharpless catalyst
Material Balance
Step-1
Input Kg Out put Kg
Dihydroquinidine HCl 1.75 Dihydroquinidine Base 1.40
Ammonium hydroxide(25%) 11.29 Aq. Layer contain
MDC 10.83 1) Water 8.56
2) Ammonium chloride 0.26
3) Dissolved ammonia 2.65
4) Dihydroquinidine Base 0.17
MDC Recovered 10.29
MDC Loss in vacuum 0.54
Total 23.88 23.88
Step-2
Dihydroquinidine Base 1.40 Product 1.00
Dichloro phthalazine 0.44 Recovered Toluene 12.02
Toluene 12.14 Recovered Acetone 44.20
Potassium carbonate 0.89 Recovered IPA 9.06
Potassium hydroxide 0.36 Toluene loss 0.12
HCl Gas 0.08 IPA Loss 0.18
IPA 9.25 Acetone Loss 2.33
Acetone 46.53 Aq. Layer contain
Sodium bicarbonate 1.18 1) water 12.13
Water 11.76 2) Sodium chloride 0.49
3) potassium chloride 1.36
4) ureacted dichloro phthalazine 0.01
5) Sodium bicarbonate 0.45
CO2 evolved 0.65
84.01 84.01
Process flow diagram
Product: Sharpless catalyst Stage-01
Aqueous high TDS-11.64L. Recovered DCM 98%
Solid waste-NA
Reaction
Dihydroquinidine HCl-1.75kg. Ammonium hydroxide (25%)-11.29kg. MDC-10.83kg.
Extraction and solvent distillation
Material isolation
Output- 1.40 kg.
Product: Sharpless catalyst Stage-II
CO2 (Scrubber)
Aqueous high TDS-14.44L. Recovered Toluene 98% Recovered Acetone 98% Recovered IPA 98%
Solid waste-NA
Reaction
Dihydroquinidine Base-1.40kg. Dichloro phthalazine-0.44kg. Toluene-12.14kg. Potassium carbonate-0.89kg. Potassium hydroxide-0.36kg. HCl Gas-0.08kg. IPA-9.25kg.
Acetone-46.53kg.
Sodium bicarbonate-1.18kg. Water-11.76kg.
Extraction and solvent distillation
Material isolation
Output- 1.0 kg.
Product: - DOTA for Gadoteric acid
Route of synthesis:-
N
N
N
NO
OH
O
OH
O
OH
O
OH
NH
NH
NH
NH
O
OH
Cl
1) Chloro acetic acid; NaOH
1,4,7,10-Tetra azacyclo dodecane -1,4,7,10-Tetra acetic acid (DOTA)
ClH
ClH
2) HCl
Material Balance
Material Input in Kg Material Out-out in
Kg
Cyclane 0.66 DOTA HCl 1.00
Chloroacetic acid 1.45 Aq. Layer contain
Sodium hydroxide 0.99 Water 9.07
Hydrochloric acid 30% 2.27 Sodium chloride 1.44
Water 7.04 DOTA HCl 0.82
HCl 0.06
Total 12.40 Total 12.40
Process flow diagram
Cyclane 0.66 kg
Chloroacetic acid 1.45 kg
Sodium hydroxide 0.99 kg
Hydrochloric acid 30% 2.27 kg
Water 7.04 kg
Water 9.07 kg
MLR Sodium chloride 1.44 kg
DOTA HCl 0.82 kg
HCl 0.06 kg
out put
1.0 kg
Reaction
workup and
purification
Filter
Product:-Iopamidol
Route of synthesis:-
NH2
COOHHOOC
NH2
COOHHOOC
I I
I
KCl / ICl
Water
NH2
I I
I O
Cl
O
ClTEA/SOCl 2
MDC
O
O
ONH
I I
I O
Cl
O
Cl
DMA
Cl
O
O
O
+
+
DMA/TEAO
O
O
NH
I I
I OOOH
OHNH
OH
OHNH
OH OH
NH2
NH4OH
O
OH
NH
I I
I OOOH
OHNH
OH
OHNH
Stage II
Stage III
Stage I
Stage IV
Stage V
Cl
O
O
O
OH
O
O
O
OH
O
OH
O
Cl
- HCl
- HCl
-SO2
Acetoxy lactic acid chloride
Material Balance
O-Acetyl. Lactic acid chloride Stage-I
Input Kg Out put Kg
Lactic acid (90%) 1.12 Stage-I intermediate 0.82
Acetyl chloride 1.44 HCl gas 0.67
Acetic acid 0.37
Residue after HVD 0.68
Total 2.56 2.54
O-Acetyl. Lactic acid chloride Stage-II
Stage-I intermediate 0.82 Product 0.78
Thionyl chloride 1.37 SO2 gas 0.73
Dichloro methane 7.62 HCl Gas 0.61
DMF 0.02 MDC Vacuum loss 0.76
Water consumed by Th.Chloride 0.09 Recovered MDC 6.86
Residue after HVD 0.18
Total 9.91 9.91
Iopamidol Stage-I
Input Quantity
in Kg Out put
Quantity
in Kg
5-Amino isophthalic acid 0.54 Stage-I intermediate 1.37
Water 24.78 Aq. Effluent contains
Sodium chloride 0.92 1) Water 25.63
Sodium chlorate 0.17 2) NaCl 1.05
Sodium bisulfite 0.08 3) HCl 0.27
Iodine 1.14 4) Sodium chorate 0.08
30% HCl 1.09 5) Dissolved Sulfordioxide 0.05
6) Mono & Di iodo products 0.26
Total 28.71 28.71
Iopamidol Stage-II
Input Quantity
in Kg Out put
Quantity
in Kg
Stage-I intermediate 1.37 Stage-II intermediate 1.23
MDC 4.54 Recovered toluene 2.35
Triethyl amine 0.48 Recovered MDC 4.31
Thionyl chloride 1.69 Recovered Ethyl acetate 14.43
Ethyl acetate 14.73 Solvents/Gases to scrubber
Toluene 2.37 Solvents 0.55
Sodium bicarbonate 0.51 SO2 gas to scrubber 0.91
Sodium chloride 0.75 HCl Gas to scrubber 0.52
Sodium sulfate 0.27 CO2 Gas 0.27
Hyflo 0.07 Solid waste
Activated carbon 0.07 1) Activated carbon 0.07
Water 9.62 2) Sodium Sulfate 0.27
3) Hyflo 0.07
4) Residues after solvent recovery 0.00
Aq. Effluent contains
1) Water 9.73
2) Sodium chloride 1.11
3) Triethyl amine HCl 0.65
Total 36.46 36.46
Iopamidol Stage-III
Input Quantity
in Kg Out put
Quantity
in Kg
Stage-II intermediate 1.23 Stage-III intermediate 1.27
Acetoxy propionyl
chloride 0.78 Recovered Ethyl acetate 12.07
Dimethyl acetamide 1.23 Recovered toluene 1.22
Toluene 1.23 Recovered MDC 6.86
Water 24.62 Recovered acetic acid 0.37
Ethyl Acetate 12.31 Solvents/Gases to scrubber
Sodium sulphate 0.25 1) Ethyl acetate 0.25
Activated Charcoal 0.06 2) MDC 0.76
Sodium bicarbonate 0.49 3) Toluene 0.01
Hyflo 0.06 4) Carbon dioxide 0.26
Sodium chloride 1.02 Solid waste
Lactic acid 1.12 1) Sodiun sulfate 0.25
Acetyl chloride 1.44 2) Hyflo 0.06
thionyl chloride 1.37 3) Activated charcoal 0.06
MDC 7.62 Residues aftersolvent recovery/HVD 0.85
DMF 0.02 Aq. Effluent contains
Scrubber water for
acetoxy 11.28 1) Water 36.55
Caustic for scrubber 1.13 2) sodium bisulfite 1.19
3) Stage-I 0.17
4) O-Acetyl lactic acid 0.44
5) Dimethyl acetamide 1.23
6) Sodium chloride 3.37
7)DMF 0.02
Total 67.25 Total 67.25
Iopamidol Stage-IV
Input Quantity
in Kg Out put
Quantity
in Kg
Stage-III 1.27 Stage-IV 1.34
Serinol 0.41 Recovered methanol 5.25
DMA 9.58 Recovered Isopropanol 11.37
Triethyl amine 0.66 Recovered DMA 9.49
Methanol 5.53 Solvents/Gases to scrubber
Isopropanol 11.97 Methanol 0.28
Activated Charcoal 0.06 Isopropanol 0.60
Hyflo 0.19 Triethyl amine 0.30
DMA 0.10
Solid waste
Activated carbon 0.06
Hyflo 0.19
Triethyl amine hydrochloride 0.49
Residues aftersolvent recovery/HVD 0.21
Total 29.67 29.67
Iopamidol Stage-V
Input Quantity
in Kg Out put
Quantity
in Kg
Stage-IV 1.34 Iopamidol 1.00
25% Ammonia 2.01 Distilled water 16.21
Water 14.87 Recovered methanol 2.52
Methanol 2.65 Recovered Isopropanol 3.66
Isopropanol 3.70 Solvents/Gases to scrubber
Hyflo 0.20 Methanol 0.13
Isopropanol 0.04
Ammonia 0.47
Water 0.16
Solid waste
Hyflo 0.20
Residues aftersolvent recovery/HVD 0.18
Second crop 0.19
Total 24.77 24.77
Process flow diagram
Stage-1
Purified water 24.78 kg
Sodium chloride 0.92 kg
Iodine crystals 1.14 kg
Conc. Hydrochloric acid 1.09 kg
Sodium chlorate 0.17 kg
Purified water
Purified water
5-Amino isophthalic acid 0.54 kg Reaction
Water Water 25.62 kg
Filter NaCl 1.05 kg
sodium bisulphite 0.08kg HCl 0.27 kg
Sodium chorate 0.08 kg
Dissolved Sulfordioxide 0.046 kg
Mono & Di iodo products 0.25 kg
OUT PUT
1.37 kg
Filter
Reaction
Stage-2
MDC 4.54 kg
Triethyl amine 0.48 kg
Distilled water 9.62 kg
Thionyl chloride 1.69 kg
Stages-I 1.37 kg
Reaction
Solvents 0.54kg
SO2 gas to scrubber 0.90 kg
HCl Gas to scrubber 0.52 kg
Ethyl acetate 14.73 kg CO2 Gas 0.27 kg
Sodium bicarbonate 0.51 kg
Sodium chloride 0.75 kg Workup and
distillation
Water 9.62 kg
Recovered MDC 4.31 kg
Water 9.73 kg
Sodium chloride 1.11 kg
Sodium sulfate 0.27 kg Triethyl amine HCl 0.65 kg
Hyflo 0.07 kg Filter
Activated carbon 0.07 kg Activated carbon 0.07 kg
Sodium Sulfate 0.27 kg
Hyflo 0.07 kg
Residues after solvent recovery 0.004 kg
Toluene 2.37 kg
Recovered toluene 2.35 kg
Recovered Ethyl acetate 14.43 kg
OUT PUT
1.23 kg
Distillation and
workup
Stage-3
Dimethyl acetamide 1.23 kg
Stage-II intermediate 1.23 kg
Acetoxy propionyl chloride 0.775 kg
Reaction
Ethyl Acetate 12.31 kg
Sodium bicarbonate 0.49 kg
Sodium chloride 1.01 kg
Sodium sulphate 0.25 kg Workup
Activated Charcoal 0.06 kg
Ethyl acetate 0.25 kg
MDC 0.76 kg
Toluene 0.01 kg
Carbon dioxide 0.26 kg
Toluene 1.23 kg Distillation
Recovered Ethyl acetate 12.06 KG
Recovered toluene 1.22 kg
Toluene Filter
Toluene
Out put
1.27 kg
Stage-4
DMA 9.58 kg
Stage-III 1.27 kg Reaction
Triethyl amine 0.66 kg
Serinol 0.40 kg
Filter
Triethyl amine hydrochloride 0.49 kg
DMA 0.095 kg
Methanol 5.53 kg Distillation
Recovered DMA 9.48 kg
Activated Charcoal 0.06kg
Hyflo 0.19 kg Filter
Methanol
Activated carbon 0.06 kg
Hyflo 0.19 kg
Methanol 0.28 kg
Methanol Distillation
Isopropanol 11.97 kg
Recovered methanol 5.25 kg
Isopropanol Filter
Dryer
Methanol
Isoprpanol Reactor
Isoprpanol Filter
Dryer
out put
1.34 kg
Stage-5
Ammonia 0.47 kg
Water 0.16 kg
25% Ammonia 2.0 kg
Water 14.87 kg Reaction
Stage-IV 1.34 kg
Distilled water 16.21 kg
pass 2 time through IPDA 522
IPDA522
pass 2 time through IPDB068
IPDB068
pass 5 time through IPDPA008
IPDPA008
Water
Hyflo 0.2 kg Filter
Hyflo 0.2 kg
Water 0.16 kg
Distillation
Distilled water 16.21 kg
Isopropanol 0.037 kg scrubber loss
Water
Methanol Work up
Isoprpanol
Isoprpanol Filter Recovered Isopropanol from ML 3.6 KG
Out put
Dryer
1.0 kg
PFD for Acetoxy propionyl chloride
Stage-1
HCl gas 0.67 kg
Lactic acid (90%) 1.11kg
390 g Acetyl chloride 1.44 kg Reaction
Acetic acid 0.37 kg
Residue after HVD 0.68 kg
High vacuum
distillation
Residue after HVD 0.68 kg
OUTPUT
0.82 KG
Stage-2
SO2 gas 0.73 kg
HCl Gas 0.61 kg
MDC loss 0.76 kg
Methylene dichloride 7.62 kg
Stage-I 0.82 kg Reaction
Dimethyl formamide 0.015 kg
Thionyl chloride 1.36 kg
Recovered MDC 6.85 kg
High vacuum
distillation
Residue after HVD 0.18 kg
OUTPUT
0.78 KG
Product:-Iohexol
Route of synthesis:-
NH2
Cl
OO
Cl
I
I I
NH
Cl
O
O
Cl
I
I I
O
NH2 OH
OH
DMA
AcCl
DMA/LiOH
Iohexol
NH
NH
OO
NH
OHOH
OH
OH
I
I I
O
N
NH
OO
NH
OHOH
OH
OH
I
I I
O
OH
OH
Cl
OH
OHMeOH/LiOH
N
NH
O O
NH
O
O
O
O
I
II
OO
O
crude
Triketal
N
NH
O O
NH
OH
OH
OH
OH
I
II
OOH
OHIohexol
Pure
2,4,6-triiodo-5-amino isophthalicacid dichloride
Stage-2
Stage-1
Stage-3a
Stage-6
NH2
Cl
OO
Cl
I
I I
NH2
OH
OO
OH
I
I I
NH2
OH
OO
OH I2-NaOCl
3-HCl
2,4,6-triiodo-5-amino isophthalicacid dichloride
SOCl2
MDC
Stage-3b
Stage-4
Stage-5
triethyl amine
Material Balance
Stage-1
Input Quantity
in Kg Out put
Quantity
in Kg
5-Amino isophthalic acid 0.55 Stage-I intermediate 1.40
Water 25.33 Aq. Effluent contains
Sodium chloride 0.94 1) Water 26.20
Sodium chlorate 0.18 2) NaCl 1.07
Sodium bisulfite 0.08 3) HCl 0.28
Iodine 1.16 4) Sodium chorate 0.09
30% HCl 1.11 5) Dissolved Sulfordioxide 0.05
6) Mono & Di iodo products 0.26
Total 29.35 29.35
Stage-2
Input Quantity
in Kg Out put
Quantity
in Kg
Stage-I intermediate 1.40 Stage-II intermediate 1.26
MDC 4.64 Recovered toluene 2.40
Triethyl amine 0.49 Recovered MDC 4.41
Thionyl chloride 1.73 Recovered Ethyl acetate 14.75
Ethyl acetate 15.05 Solvents/Gases to scrubber
Toluene 2.42 Solvents 0.56
Sodium bicarbonate 0.52 SO2 gas to scrubber 0.93
Sodium chloride 0.77 HCl Gas to scrubber 0.53
Sodium sulfate 0.28 CO2 Gas 0.27
Hyflo 0.07 Solid waste
Activated carbon 0.07 1) Activated carbon 0.07
Water 9.83 2) Sodium Sulfate 0.28
3) Hyflo 0.07
4) Residues after solvent recovery 0.00
Aq. Effluent contains
1) Water 9.95
2) Sodium chloride 1.13
3) Triethyl amine HCl 0.66
Total 37.27 37.27
Stage-3
Input Quantity
in Kg Out put
Quantity
in Kg
2,4,6-triiodo-5-amino isophthalic acid dichloride
1.26 Stage-III intermediate 1.28
Acetyl chloride 0.27 Recovered dimethyl acetamide 9.35
Dimethyl acetamide (DMA) 9.45 Recivered methanol 9.84
3-Amino propane Diol 0.52 Solid waste
Triethyl amine 0.90 TEA hydrochloride 1.31
Methanol 10.93 Residues after distillation of Methanol ML 0.48
Water 0.13 Solvents/Gases to scrubber
Methanol 1.09
Dimethyl acetamide 0.09
Total 23.45 23.45
Stage-4
Stage-III intermediate 1.28 Crude Iohexol 1.33
3-chloro-1,2-propane diol 0.38 Recovered methoxy ethoxy ethanol 3.80
Lithium hydroxide (Anhydrous) 0.08 Recovered Butanol 3.08
Methoxy ethoxy ethanol 3.84 Recovered water 10.04
Butanol 3.12 Solid waste
Conc. HCl 0.29 Activated carbon 0.03
Water 10.26 Hyflo 0.05
Activated carbon 0.03 Residues after distillation of Butanol ML 0.07
Hyflo 0.05 Solvents/Gases to scrubber
Water for resin wash 2.56 Methoxy ethoxy ethanol 0.04
Butanol 0.03
Water 0.51
Aq. Effluents containing
Water 2.56
Lithium chloride 0.15
3-chloro-1,2-propane diol 0.19
Total 21.90 Total 21.90
Stage-5
Crude iohexol 1.33 1.33
Dimethoxy propane 6.67 Recovered dimethoxy propane 6.10
PTSA 0.04 Recovered Methanol 0.25
sodium bicarbonate 0.03 Solvents/Gases to scrubber
Water 8.00 Dimethoxy Propane 0.06
Methanol 0.00
Water 0.80
Aq. Effluents containing
Water 7.20
Sodium p-toluene sulfonate 0.05
Sodium bicarbonate 0.01
Iohexol & O-Alkyl iohexol 0.27
Total 16.07 16.07
Stage-6
Ketal 1.33 Product 1.00
Water 12.97 Distilled water 12.32
Sulfuric acid 0.05 Recovered IPA 7.92
Sodium hydroxide 0.03 Solvents/Gases to scrubber
Activated carbon 0.03 Water 0.65
Hyflo 0.07 IPA 0.08
Isopropanol 8.00 Acetone 0.25
Water for resin wash 2.67 Solid waste
Activated carbon 0.03
Hyflo 0.07
Residue after IPA mL distillation 0.10
Aq. Effluents containing
Water 2.67
Sodium sulfate 0.08
Total 25.15 Total 25.15
Process flow diagram
Stage-1
Purified water 24.78 kg
Sodium chloride 0.92 kg
Iodine crystals 1.14 kg
Conc. Hydrochloric acid 1.09 kg
Sodium chlorate 0.17 kg
Purified water
Purified water
5-Amino isophthalic acid 0.54 kg Reaction
Water Water 25.62 kg
Filter NaCl 1.05 kg
sodium bisulphite 0.08kg HCl 0.27 kg
Sodium chorate 0.08 kg
Dissolved Sulfordioxide 0.046 kg
Mono & Di iodo products 0.25 kg
OUT PUT
1.37 kg
Reaction
Filter
Stage-2
MDC 4.54 kg
Triethyl amine 0.48 kg
Distilled water 9.62 kg
Thionyl chloride 1.69 kg
Stages-I 1.37 kg
Reaction
Solvents 0.54kg
SO2 gas to scrubber 0.90 kg
HCl Gas to scrubber 0.52 kg
Ethyl acetate 14.73 kg CO2 Gas 0.27 kg
Sodium bicarbonate 0.51 kg
Sodium chloride 0.75 kg Workup and
distillation Water 9.62 kg
Recovered MDC 4.31 kg
Water 9.73 kg
Sodium chloride 1.11 kg
Sodium sulfate 0.27 kg Triethyl amine HCl 0.65 kg
Hyflo 0.07 kg Filter
Activated carbon 0.07 kg Activated carbon 0.07 kg
Sodium Sulfate 0.27 kg
Hyflo 0.07 kg
Residues after solvent recovery 0.004 kg
Toluene 2.37 kg
Recovered toluene 2.35 kg
Recovered Ethyl acetate 14.43 kg
OUT PUT
1.256 kg
Distillation and
workup
Stage-3
Stage-II 1.256 kg
Acetyl chloride 0.27 kg
Dimethyl acetamide 9.45 kg
3-Amino propane Diol 0.52 kg
Triethyl amine 0.897 kg Reaction
Methanol 10.93 kg
Water 0.125 kg
DMA Filter TEA hydrochloride 1.3 kg
Dimethyl acetamide 0.09 kg
Methanol 1.09 kg
METHANOL distillation
WATER
Recovered methanol 9.8 kg
Recovered dimethyl acetamide 9.35 kg
Residues after distillation of Methanol ML 0.48 kg
METHANOL Filter Methanol
out put
1.28 kg
Stage-4
Methoxy ethoxy ethanol 0.038 kg
Stage-III 1.28 kg
3-chloro-1,2-propane diol 0.38 kg
Lithium hydroxide (Anhydrous) 0.08 kg Reaction
Methoxy ethoxy ethanol 3.84 kg
Recovered methoxy ethoxy ethanol 3.8 kg
225H
Reaction mass pass through column two time
860
Reaction mass pass through column two time
Activated carbon 0.026 kg Activated carbon 0.026 kg
Hyflo 0.051 kg Filter Hyflo 0.051 kg
Water
Butanol 0.031 kg
Water 0.512 kg
Butanol 3.115 kg Distillation
Recovered Butanol 3.08 kg
Recovered water 10.03 kg
Residues after distillation of Butanol ML 0.075 kg
Under nitrogen Filter
Water 2.56 kg
Lithium chloride 0.15 kg
3-chloro-1,2-propane diol 0.19 kg
out put
1.33 kg
Stage-5
Dimethoxy propane 0.06 kg
Methanol 0.003 kg
Crude iohexol 1.33 kg
Dimethoxy propane 6.67 kg
PTSA 0.039 kg Reaction and distil lation
sodium bicarbonate 0.03 kg
Water 7.99 kg
Recovered dimethoxy propane 6.10 kg
Recovered Methanol 0.25 kg
Water Filter
Water 7.19 kg
Sodium p-toluene sulfonate 0.045 kg
Sodium bicarbonate 0.0138 kg
Iohexol & O-Alkyl iohexol 0.27 kg
Water 0.799 kg
Out put
1.33 kg
Stage-6
Ketal 1.33 kg
water 12.97 kg
Sulfuric acid 0.052 kg Reaction
Sodium hydroxide 0.033 kg
Water for resin wash 2.66 kg
225H
Reaction mass pass through column two time
860
Reaction mass pass through column two time
Activated carbon 0.033 kg Activated carbon 0.03 kg
Hyflo 0.06 kg Filter Hyflo 0.06 kg
Water
Water 0.65 kg
butanol 0.079 kg
Acetone 0.25 kg
Butanol 8.0 kg Distillation
Distilled water 12.32 kg
Recovered butanol 7.91 kg
Under nitrogen Filter
Water 2.66 kg
Sodium sulfate 0.076 kg
Out put
1.0 kg
Product:-Iodixanol
Route of synthesis:-
NH2
Cl
OO
Cl
I
I I
NH
Cl
O
O
Cl
I
I I
O
NH2 OH
OH
DMA
AcCl
DMA/LiOH
TEA (Optional)
NH
NH
OO
NH
OHOH
OH
OH
I
I I
O
Cl
O
2,4,6-triiodo-5-amino isophthalicacid dichloride
Stage-2
Stage-1
Stage-3a
NH2
Cl
OO
Cl
I
I I
NH2
OH
OO
OH
I
I I
NH2
OH
OO
OH I2-NaOCl
3-HCl
2,4,6-triiodo-5-amino isophthalicacid dichloride
SOCl2
MDC
Stage-3b
Stage-4
MeOH/NaOH
Cl
NH O
O
NHOH
OH
OH
OH
I
I
I
OOH
NNH
O
O NH
OH
OH
OH
OHII
IO
Iodixanol
Material Balance
Stage-I
Input Quantity
in Kg Out put
Quantity
in Kg
5-Amino isophthalic acid 0.61 Stage-I intermediate 1.53
Water 27.76 Aq. Effluent contains
Sodium chloride 1.03 1) Water 28.71
Sodium chlorate 0.20 2) NaCl 1.18
Sodium bisulfite 0.08 3) HCl 0.31
Iodine 1.27 4) Sodium chorate 0.10
30% HCl 1.22 5) Dissolved Sulfordioxide 0.05
6) Mono & Di iodo products 0.29
Total 32.17 32.17
Stage-II
Input Quantity
in Kg Out put
Quantity
in Kg
Stage-I intermediate 1.53 Stage-II intermediate 1.38
MDC 5.08 Recovered toluene 2.63
Triethyl amine 0.53 Recovered MDC 4.83
Thionyl chloride 1.89 Recovered Ethyl acetate 16.17
Ethyl acetate 16.50 Solvents/Gases to scrubber
Toluene 2.66 Solvents 0.61
Sodium bicarbonate 0.57 SO2 gas to scrubber 1.02
Sodium chloride 0.84 HCl Gas to scrubber 0.58
Sodium sulfate 0.31 CO2 Gas 0.30
Hyflo 0.08 Solid waste
Activated carbon 0.08 1) Activated carbon 0.08
Water 10.78 2) Sodium Sulfate 0.31
3) Hyflo 0.08
4) Residues after solvent
recovery 0.00
Aq. Effluent contains
1) Water 10.90
2) Sodium chloride 1.24
3) Triethyl amine HCl 0.73
Total 40.85 40.85
Stage-III
Input Quantity
in Kg Out put
Quantity
in Kg
Stage-II intermediate 1.38 Stage-III 1.41
Acetyl chloride 0.30 Recovered dimethyl acetamide 10.27
Dimethyl acetamide (DMA) 10.37 Recivered methanol 10.80
3-Amino propane Diol 0.57 Solid waste
Triethyl amine 0.99 TEA hydrochloride 1.43
Methanol 12.00
Residues after distillation of Methanol ML 0.53
Water 0.14 Solvents/Gases to scrubber
Methanol 1.20
Dimethyl acetamide 0.10
Total 25.75 25.75
Stage-IV
Input Quantity
in Kg Out put
Quantity
in Kg
Stage-III intermediate 1.41 Iodixanol 1.00
2-methoxy ethanol 1.38
Recovered 2-methoxy ethanol+ water 3.56
Epichlorohydrin 0.05 Scrubber loss 0.04
Sodium hydroxide 0.09 Aq. Effluent containing
30% HCl 0.11 Water 0.60
Water 2.21 Sodium chloride 0.05
Total 5.25 Total 5.25
Stage-1
Water 27.76 kg
Sodium chloride 1.03 kg
Iodine1.27 kg
Conc. Hydrochloric acid 0.86 kg
Sodium chlorate 0.2 kg
Purified water
Purified water
5-Amino isophthalic acid 0.61 kg Reaction
Water Water 28.71 kg
Filter NaCl 1.18 kg
Sodium bisulfite 0.08 kg HCl 0.31 kg
Sodium chorate 0.1 kg
Dissolved Sulfordioxide 0.05 kg
Mono & Di iodo products 0.29 kg
OUT PUT
1.53 kg
Reaction
Filter
Stage-2
MDC 5.08 kg
Triethyl amine 0.53 kg
Distilled water 7.58 kg
Thionyl chloride 1.89 kg
Stage-I intermediate 1.53 kg
Reaction
Solvents 0.61 kg
SO2 gas to scrubber 1.02 kg
HCl Gas to scrubber 0.58 kg
Ethyl acetate 16.5 kg CO2 Gas 0.3 kg
Sodium bicarbonate 0.57 kg
Sodium chloride 0.84 kg Workup and
distillation Water 10.78 kg
Recovered MDC 4.83 kg
Water 10.9 kg
Sodium chloride 1.24 kg
Sodium sulfate 0.31 kg Triethyl amine HCl 0.73 kg
Hyflo 0.08 kg Filter
Activated carbon 0.08 kg Activated carbon 0.08 kg
Sodium Sulfate 0.31 kg
Hyflo 0.08 kg
Residues after solvent recovery
Toluene 1.87 kg
Recovered toluene 2.63 kg
Recovered Ethyl acetate 16.17 kg
OUT PUT
1.38 kg
Distillation and
workup
Stage-3
Stage-II intermediate 1.38 kg
Acetyl chloride 0.3 kg
Dimethyl acetamide (DMA) 10.37 kg
3-Amino propane Diol 0.57 kg
Triethyl amine 0.99 kg
Methanol 12 kg
Water 0.14 kg
Reaction
DMA Filter TEA hydrochloride 1.43 kg
Dimethyl acetamide 0.1 kg
Methanol 1.2 kg
METHANOL distillation
WATER
Recivered methanol 10.8 kg
Recovered dimethyl acetamide 10.27 kg
Residues after distillation of Methanol ML 0.53 kg
METHANOL Filter Methanol
out put
1.41 kg
Stage-4
Stage-III intermediate 1.41 kg
2-methoxy ethanol 1.38 kg
Sodium hydroxide0.09 kg
Epichlorohydrin 0.05 kg
30% HCl 0.11 kg
Water 2.21 kg Scrubber loss 0.04 kg
Reaction
Recovered 2-methoxy ethanol+ water 3.56 kg
Water 0.6 kg
Filter Sodium chloride 0.05 kg
out put
1.0 kg
Product:-Iopromide
Route of synthesis:-
+
O
ClO
Methoxy acetyl chloride
O
O
O
Cl
O Cl
NH
I
I
I
O
O
OCl
O
NHNH
II
I
OH
OH
OH
OH
NH2
DMA
N1,N3-bis(2,3-dihydroxypropyl)-5-
(2-hydroxyacetamido)-2,4,6-triiodobenzene-1,3-dicarboxamide
1-amino-2,3-propanediol
O
O
O
Cl
O
NH
NH
I
I IO
O
O
O
1) AcOH; H2SO
4
2) NaOAc
DMA
3-[3-(chlorocarbonyl)-2,4,6-triiodo-5-(2-methoxyacetamido)benzamido]propane-1,2-diyl diacetate
Stage-2Stage-1
NH2
Cl
OO
Cl
I
I I
NH2
OH
OO
OH
I
I I
NH2
OH
OO
OH I2-NaOCl
3-HCl SOCl
2
MDC
5-amino-2,4,6-triiodobenzene-1,3-dicarbonyl dichloride
+
3-[(2,3-dihydroxypropyl)carbamoyl]-2,4,6-triiodo-5-[(methoxyacetyl)amino]benzoyl chloride
OH
OH
NH1)
TEA
3-(methylamino)propane-1,2-diol
2) Aq. NaOH
Iopromide
O
O
O
O
NHNH
II
I
OH
OH
OH
OH
N
Stage-3a
Stage-3b
Stage-4
Stage-5
Material Balance
Stage-1
Input Quantity
in Kg Out put
Quantity in
Kg
5-Amino isophthalic acid 0.65 5-amino-2,4,6-
triiodoisophthalic acid 1.65
Water 29.96 Aq. Effluent contains
Sodium chloride 1.11 1) Water 30.99
Sodium chlorate 0.21 2) NaCl 1.27
Sodium bisulfite 0.09 3) HCl 0.33
Iodine 1.37 4) Sodium chorate 0.10
30% HCl 1.31 5) Dissolved Sulfordioxide 0.06
6) Mono & Di iodo products 0.31
Total 34.72 34.72
Stage-2
Input Quantity
in Kg Out put
Quantity
in Kg
5-amino-2,4,6-triiodoisophthalic acid 1.65 5-amino-2,4,6-triiodoisophthalic
acid dichloride 1.49
MDC 5.49 Recovered toluene 2.84
Triethyl amine 0.58 Recovered MDC 5.21
Thionyl chloride 2.04 Recovered Ethyl acetate 17.45
Ethyl acetate 17.81 Solvents/Gases to scrubber
Toluene 2.87 Solvents 0.66
Sodium bicarbonate 0.62 SO2 gas to scrubber 1.10
Sodium chloride 0.91 HCl Gas to scrubber 0.63
Sodium sulfate 0.33 CO2 Gas 0.32
Hyflo 0.08 Solid waste
Activated carbon 0.08 1) Activated carbon 0.08
Water 11.63 2) Sodium Sulfate 0.33
3) Hyflo 0.08
4) Residues after solvent
recovery 0.00
Aq. Effluent contains
1) Water 11.77
2) Sodium chloride 1.34
3) Triethyl amine HCl 0.78
Total 44.09 44.09
Stage-3
Material Input in
Kg Material Output
in Kg
5-amino-2,4,6-triiodoisophthalic acid dichloride 1.49 Stage-3 intermediate 1.19
Dimethyl acetamide for stage-3a 1.87 Revovered MDC 26.74
Methoxy acetyl chloride 0.41 Recovered dimethyl acetamide 5.80
MDC 28.15 Scrubber loss
Water 2.34 Dimethyl acetamide 0.06
Sodium bicarbonate 0.11 MDC 1.41
Dimethyl acetamide 5.86 CO2 generated 0.06
Triethyl amine 0.21 Aq. Layer contain
Aminopropane diol 0.16 Water 2.36
Hydrochloric acid 0.04
Methoxy acetic acid 0.11
trithyl amine hydrochloride 0.29
Sodium chloride 0.08
DMA 1.87
Residues after Solvent recovery 0.59
Total 40.59 40.59
Stage-4
Material Input in
Kg Material Output
in Kg
Stage-3 intermediate 1.19 Stage-4 intermediate 1.20
Acetic acid 0.89 Aq. Layer contain
Sulfuric acid 0.02 water 11.64
Sodium acetate trihydrate 0.05 Sulfuric acid 0.02
Water 11.56 Acetic acid 0.71
Product 0.14
Total 13.71 Total 13.71
Stage-5
Material Input in
Kg Material Output in
Kg
Stage-4 intermediate 1.20 Iopramide 1.00
Dimethyl acetamide 2.01 Water recovered 1.48
Trethyl amine 0.32 Recovered DMA 1.99
Dihydroxy-n-methyl propyl amine 0.16 Scrubber loss
Sodium hydroxide 0.15 DMA 0.02
Water for hydrolysis 1.49 Water 0.01
Water for resin wash 2.98 Aq. Layer of resin wash contain
30% HCl for resin wash 0.45 water 3.42
Caustic for resin wash 0.13 Sodium chloride 0.52
triethyl amine 0.32
Product 0.12
Total 8.90 Total 8.90
Process flow diagram
Stage-1
Purified water 29.96 kg
Sodium chloride 1.11 kg
Iodine crystals 1.37 kg
Conc. Hydrochloric acid 1.31 kg
Sodium chlorate 0.21 kg
Purified water
Purified water
5-Amino isophthalic acid 0.65 kg Reaction
Water Water 30.99 kg
Filter NaCl 1.27 kg
sodium bisulphite 0.09kg HCl 0.33 kg
Sodium chorate 0.10 kg
Dissolved Sulfordioxide 0.06 kg
Mono & Di iodo products 0.31 kg
OUT PUT
1.65 kg
Reaction
Filter
Stage-2
MDC 5.49 kg kg
Triethyl amine 0.58 kg
Distilled water 9.62 kg
Thionyl chloride 2.04 kg
Stages-I 1.65 kg
Reaction
Solvents 0.66kg
SO2 gas to scrubber 1.10 kg
HCl Gas to scrubber 0.63 kg
Ethyl acetate 17.81 kg CO2 Gas 0.32 kg
Sodium bicarbonate 0.62 kg
Sodium chloride 0.91 kg Workup and
distillation
Water 11.63 kg
Recovered MDC 5.21 kg
Water 11.77 kg
Sodium chloride 1.34 kg
Sodium sulfate 0.33 kg Triethyl amine HCl 0.78 kg
Hyflo 0.08 kg Filter
Activated carbon 0.08 kg Activated carbon 0.08 kg
Sodium Sulfate 0.33 kg
Hyflo 0.08 kg
Residues after solvent recovery 0.004 kg
Toluene 2.37 kg
Recovered toluene 2.84 kg
Recovered Ethyl acetate 17.45 kg
OUT PUT
1.49 kg
Distillation and
workup
Stage-3
5-amino-2,4,6-triiodoisophthalic acid dichloride 1.49 kg
Dimethyl acetamide for stage-3a 1.87 kg
Methoxy acetyl chloride 0.41 kg
MDC 28.15 kg
Water 2.34 kg Dimethyl acetamide 0.06 kg
Sodium bicarbonate 0.11 kg CO2 generated
Dimethyl acetamide 5.86 kg
Triethyl amine 0.21 kg
Aminopropane diol 0.16 kg
Reaction
Recovered dimethyl acetamide 5.8 kg
Water 2.34 kg
Hydrochloric acid 0.04 kg
Methoxy acetic acid 0.11 kg
trithyl amine hydrochloride 0.29 kg
Sodium chloride 0.08 kg
DMA 1.87 kg
MDC 1.41 kg
Filter MLR
Revovered MDC 26.74 kg
Residues after Solvent recovery 0.59 kg
out put
1.19 kg
Stage-4
Stage-3 intermediate 1.19 kg
Acetic acid 0.89 kg
Sulfuric acid 0.02 kg
Sodium acetate trihydrate 0.05 kg
Water 11.56 kg
Reaction
Filter
water 11.64 kg
Sulfuric acid 0.02 kg
Acetic acid 0.71 kg
Product 0.14
out put
1.2 kg
Iopramide Stage-V
Stage-4 intermediate 1.20 kg
Dimethyl acetamide 2.01 kg
Trethyl amine 0.32 kg DMA vapours 0.02 kg
Dihydroxy-n-methyl propyl amine 0.16 kg
Sodium hydroxide 0.15 kg
Reaction
and workup
Recovered DMA 1.99 kg
Water for hydrolysis 1.49 kg cation exchange
Water for resin wash 2.98 kg column
30% HCl for resin wash 0.45 kg
anion exchange
Caustic for resin wash 0.13 kg column
Water vapous 0.01 kg
workup
and distillation
Water recovered 1.48 kg
Filter
water 3.42 kg
Sodium chloride 0.52 kg
triethyl amine 0.32 kg
Product 0.12 kg
out put
1.0 kg
Product:-Ioversol
Route of synthesis:-
2
I
II
O
NH
O
NH
NH2
OH
OH
OH
OH
5-amino-N1,N3-bis(2,3-dihydroxy
propyl)-2,4,6-triiodobenzene-1,3-dicarboxamide
3-aminopropane-1,2-diol
I
II
O
NH
O
NH
NH2
O
OO
O
OOO
O
Ac2O
Pyridine
DMF
Na2CO3
I
II
O
NH
O
NH
NH
O
OO
O
OOO
O
O
O
O
DMA
1) MeOH-NaOH
2) Chloroethanolaq. NaOH
+Stage-2
Stage-1
NH2
Cl
OO
Cl
I
I I
NH2
OH
OO
OH
I
I I
NH2
OH
OO
OH I2-NaOCl
3-HCl SOCl
2
MDC
5-amino-2,4,6-triiodobenzene-1,3-dicarbonyl dichloride
Stage-3
OH
OH
NH2
OHO
OH
Glycolic acid
1) acetyl chloride
OO
Cl
O 2) acetyl chloride
Stage-4
Stage-5
Stage-6II
I
O NH
O
NHN
OH
OH
OH
OH
OH
O
OH
Ioversol
Stage-1
Input Quantity
in Kg Out put
Quantity in
Kg
5-Amino isophthalic acid 0.83 5-amino-2,4,6-triiodoisophthalic acid 2.11
Water 38.17 Aq. Effluent contains
Sodium chloride 1.42 1) Water 39.49
Sodium chlorate 0.27 2) NaCl 1.62
Sodium bisulfite 0.12 3) HCl 0.42
Iodine 1.75 4) Sodium chorate 0.13
30% HCl 1.68 5) Dissolved Sulfordioxide 0.07
6) Mono & Di iodo products 0.39
Total 44.23 44.23
Stage-2
5-amino-2,4,6-
triiodoisophthalic acid 2.11
5-amino-2,4,6-triiodoisophthalic acid
dichloride 1.90
MDC 6.99 Recovered toluene 3.62
Triethyl amine 0.73 Recovered MDC 6.64
Thionyl chloride 2.60 Recovered Ethyl acetate 22.23
Ethyl acetate 22.69 Solvents/Gases to scrubber
Toluene 3.65 Solvents 0.84
Sodium bicarbonate 0.79 SO2 gas to scrubber 1.40
Sodium chloride 1.16 HCl Gas to scrubber 0.80
Sodium sulfate 0.42 CO2 Gas 0.41
Hyflo 0.11 Solid waste
Activated carbon 0.11 1) Activated carbon 0.11
Water 14.82 2) Sodium Sulfate 0.42
3) Hyflo 0.11
4) Residues after solvent recovery 0.01
Aq. Effluent contains
1) Water 14.99
2) Sodium chloride 1.71
3) Triethyl amine HCl 1.00
Total 56.18 56.18
Stage-3
Material Input in
Kg Material Output in
Kg
Stage-2 intermediate 1.90 Stage-3 intermediate 1.13
Dimethyl formamide 3.55 Solid contains
Sodium carbonate 1.02 Sodium carbonate 0.17
3-amino-1,2-propane diol 0.73 Sodium chloride 0.93
Water 19.62 Recovered DMF 3.51
Conc. HCl 1.74 Recovered methanol 10.26
Ethyl acetate 7.85 Recovered Ethyl acetate 7.77
Methanol 10.47 Scrubber loss
Carbon dioxide 0.35
DMF 0.04
Methanol 0.21
Ethyl acetate 0.08
Aq. Layer contains
Water 20.84
Dissolved HCl 0.52
Stage-3 intermediate 0.91
3-amino-1,2-propane diol 0.15
Total 46.87 Total 46.87
Stage-4
Material Input in
Kg Material Output in
Kg
Stage-3 1.13 Stage-4 intermediate 1.39
Pyridine 1.13 Recovered Ethyl acetate 4.32
Acetic anhydride 0.74 Scrubber loss
Ethyl acetate 4.36 Ethyl acetate 0.04
Water 6.55 Aq. Layer contains
30% HCl 0.65 water 7.00
Pyridine 1.13
hydrochloric acid 0.18
acetic acid 0.49
Total 14.56 14.56
Stage-5
Material Input in
Kg Material Output in
Kg
Stage-4 intermediate 1.39 Stage-5 intermediate 1.28
Acetoxy acetyl chloride 0.65 Aq. Layer contains
Dimethyl acetamide 4.18 Water 19.93
Ethyl acetate 15.94 Acetoxy acetic acid 0.38
Water 19.93 Dimethyl acetamide 4.18
Recovered Ethyl acetate 15.78
hydrochloric acid 0.17
Stage-5 intermediate 0.21
Scrubber loss
Ethyl acetate 0.16
Total 42.10 Total 42.10
Stage-6
Material Input in
Kg Material Output in
Kg
Stage-5 intermediate 1.28 Ioversol 1.00
Methanol 6.97 Recovered methanol 6.83
Water 10.13 Recovered water 10.03
Chloroethanol 0.35 Scrubber loss
Sodium hydroxide 0.44 Ethylene oxide 0.19
Methanol 0.14
Water 0.10
Solid residue after mL recovery 0.88
19.18 19.18
Stage-1
Purified water 38.17 kg kg
Sodium chloride 1.42 kg
Iodine crystals 1.75kg
Conc. Hydrochloric acid 1.68 kg
Sodium chlorate 0.27 kg
Purified water
Purified water
5-Amino isophthalic acid 0.83 kg Reaction
Water Water 39.49 kg
Filter NaCl 1.62 kg
sodium bisulphite 0.12kg HCl 0.42 kg
Sodium chorate 0.13 kg
Dissolved Sulfordioxide 0.07 kg
Mono & Di iodo products 0.39 kg
OUT PUT
2.11 kg
Reaction
Filter
Stage-2
MDC 6.99kg kg
Triethyl amine 0.73 kg
Water 14.82 kg
Thionyl chloride 2.6 kg
Stages-I 2.11 kg kg
Reaction
Solvents 0.84 kg
SO2 gas to scrubber 1.4 kg
HCl Gas to scrubber 0.8 kg
Ethyl acetate 22.69 kg CO2 Gas0.41 kg
Sodium bicarbonate 0.79 kg
Sodium chloride 1.16 kg
Workup and
distillation
Water 14.82 kg
Recovered MDC 6.64 kg
Water 14.99 kg
Sodium chloride 1.71 kg
Sodium sulfate 0.42 kg Triethyl amine HCl ,1 kg
Hyflo 0.11 kg Filter
Activated carbon 0.11 kg Activated carbon 0.11 kg
Sodium Sulfate 0.42 kg
Hyflo 0.11
Residues after solvent recovery 0.01 kg
Toluene 3.65 kg
Recovered toluene 3.62 kg
Recovered Ethyl acetate 22.23 kg
OUT PUT
1.9 kg
Distillation and
workup
Stage-3
5-amino-2,4,6-triiodoisophthalic
acid dichloride 1.9 kg
Dimethyl formamide 3.55 kg
Sodium carbonate 1.02 kg
3-amino-1,2-propane diol 0.73 kg
Methanol 10.47 kg
Carbon dioxide 0.35 kg
Sodium carbonate 0.17 kg
Filter Sodium chloride 0.93 kg
Ethyl acetate 0.08 kg
DMF 0.04 kg
Methanol vapours 0.21 kg
Recovered Ethyl acetate 7.77 kg
Water 19.62 kg work up
Conc. HCl 1.74 kg and distillation
Ethyl acetate 7.85 kg
Recovered methanol 10.26 kg
Recovered DMF 3.51 kg
Water 20.84 kg
Dissolved HCl 0.52 kg
Stage-3 intermediate 0.91 kg
out put 3-amino-1,2-propane diol 0.15 kg
1.13 kg
Stage-4
Stage-3, 1.13 kg
Pyridine 1.1 3kg
Acetic anhydride 0.74 kg Ethyl acetate 0.04 kg
Ethyl acetate 4.36 kg
Water 6.55 kg
30% HCl 0.65 kg
Reaction
Recovered Ethyl acetate 4.3 kg
Filter
water 7 kg
Pyridine 1.13 kg
hydrochloric acid 0.18 kg
acetic acid 0.49 kg
out put
1.39 kg
Stage-5
Stage-4 intermediate 1.39 kg
0.65 kgAcetoxy acetyl chloride
Dimethyl acetamide 4.8 kg Ethyl acetate 0.16 kg
Ethyl acetate 15.94 kg
Water 19.93 kg
Reaction
Water 19.93 kg
Acetoxy acetic acid 0.38 kg
Dimethyl acetamide 4.18 kg
Recovered Ethyl acetate 15.78 kg
out put hydrochloric acid 0.17 kg
1.28 kg Stage-5 intermediate 0.21 kg
Stage-6
Stage-5 intermediate 1.28 kg
Methanol 6.97 kg Ethylene oxide vapours 0.19 kg
Water 10.13 kg Methanol vapours 0.14 kg
Chloroethanol 0.35 kg Water vapours 0.1 kg
Sodium hydroxide 0.44 kg
Reaction
Recovered methanol 6.83 kg
Recovered water 10.03 kg
Filter Solid residue after mL recovery 0.88 kg
MLR recovery
out put
1.0 kg
Product:-Iomeprol
Route of synthesis:-
+
O
ClO O
2-chloro-2-oxoethyl acetate
O
O OO
Cl
OCl
NH
I
I
I
O
OH
O
NH
O
NH
NH
I
I I
OH
OH
OH
OH
2) NaOH
1)
O
OH
O
NH
ONH
N
I
I
IOH
OH
OH
OH
DMA/ Methyl bromide
DMA
DMA
Iomeprol
N1,N3-bis(2,3-dihydroxypropyl)-5-
(2-hydroxyacetamido)-2,4,6-triiodobenzene-1,3-dicarboxamide
1-amino-2,3-propanediol
2-[3,5-bis(chlorocarbonyl)-2,4,6- triiodoanilino]-2-oxoethyl acetate
+Stage-2
Stage-1
NH2
Cl
OO
Cl
I
I I
NH2
OH
OO
OH
I
I I
NH2
OH
OO
OH I2-NaOCl
3-HCl SOCl
2
MDC
5-amino-2,4,6-triiodobenzene-1,3-dicarbonyl dichloride
OH
OH
NH2
Stage-3
Stage-4
Stage-5
Material balance
Stage-1
Input Quantity
in Kg Out put
Quantit
y in Kg
5-Amino isophthalic acid 0.43 5-amino-2,4,6-
triiodoisophthalic acid 1.08
Water 19.51 Aq. Effluent contains
Sodium chloride 0.73 1) Water 20.19
Sodium chlorate 0.14 2) NaCl 0.83
Sodium bisulfite 0.06 3) HCl 0.22
Iodine 0.89 4) Sodium chorate 0.07
30% HCl 0.86 5) Dissolved Sulfordioxide 0.04
6) Mono & Di iodo products 0.20
Total 22.61 22.61
Stage-2
Input Quantity
in Kg Out put
Quantity
in Kg
5-amino-2,4,6-
triiodoisophthalic acid 1.08
5-amino-2,4,6-triiodoisophthalic
acid dichloride 0.97
MDC 3.57 Recovered toluene 1.85
Triethyl amine 0.37 Recovered MDC 3.39
Thionyl chloride 1.33 Recovered Ethyl acetate 11.37
Ethyl acetate 11.60 Solvents/Gases to scrubber
Toluene 1.87 Solvents 0.43
Sodium bicarbonate 0.40 SO2 gas to scrubber 0.72
Sodium chloride 0.59 HCl Gas to scrubber 0.41
Sodium sulfate 0.22 CO2 Gas 0.21
Hyflo 0.05 Solid waste
Activated carbon 0.05 1) Activated carbon 0.05
Water 7.58 2) Sodium Sulfate 0.22
3) Hyflo 0.05
4) Residues after solvent
recovery 0.00
Aq. Effluent contains
1) Water 7.66
2) Sodium chloride 0.87
3) Triethyl amine HCl 0.51
Total 28.72 28.72
Stage-3
Material Input in
Kg Material Output
in Kg
Stage-2 intermediate 0.97 Stage-3 intermediate 1.10
Dimethyl acetamide 3.88 Recovered DMA 3.84
Acetoxy acetyl chloride 0.55 Scrubber loss
Water 7.76 DMA scrubber loss 0.02
Water 0.19
HCl Gas to scrubber 0.15
Aq. Effluent contains
Water 7.56
Dimethyl acetamide 0.02
Acetoxy acetic acid 0.29
Total 13.16 Total 13.16
Stage-4
Material Input in
Kg Material Output
in Kg
Stage-3 intermediate 1.10 Stage-4 intermediate 1.06
Dimethyl acetamide 7.20 Recovered DMA:water 20.05
2,3-dihydroxy propyl amine 0.72 Scrubber loss
Water 13.05 DMA:Water 0.20
Sodium hydroxide 0.07 Aq. Resin Column wash effluent contain
Water for resin column wash 11.25 Water 11.35
Sodium acetate 0.15
2,3-dihydroxy propyl amine 0.58
Total 33.39 Total 33.39
Step-5
Material Input in
Kg Material Output
in Kg
Stage-4 intermediate 1.06 Iomeprol 1.00
Dimethyl acetamide 8.21 Recovered DMA, Methanol &
Water 9.33
Sodium hydroxide 0.01 Scrubber loss Methanol 1.58 DMA, Methanol & Water 0.49
Methy bromide 0.22 Methyl bromide 0.09
Water for resin wash 5.28 Aq. Resin Column wash effluent contain
30% Hydrochloric acid for resin wash 0.02 Water 5.30
Sodium chloride -0.07
Sodium bromide 0.14
Iomeprol 0.10
Total 16.37 Total 16.37
Process flow diagram
Stage-1
Purified water 19.51 kg
Sodium chloride 0.73 kg
Iodine crystals 0.89kg
Conc. Hydrochloric acid 0.86 kg
Sodium chlorate 0.14 kg
Purified water
Purified water
5-Amino isophthalic acid 0.43 kg Reaction
Water 1) Water 20.19 kg
Filter 2) NaCl 0.83kg
sodium bisulphite 0.06kg 3) HCl kg
4) Sodium chorate 0.07 kg
5) Dissolved Sulfordioxide 0.04 kg
6) Mono & Di iodo products 0.2 kg
OUT PUT
1.08kg
Reaction
Filter
Stage-2
MDC 3.57 kg
Triethyl amine 0.37 kg
Distilled water 7.58 kg
Thionyl chloride 1.33 kg
Stages-I 1.08 kg
Reaction
Solvents 0.43kg
SO2 gas to scrubber 0.72 kg
HCl Gas to scrubber 0.41kg
Ethyl acetate 11.6 kg CO2 Gas 0.21 kg
Sodium bicarbonate 0.40 kg
Sodium chloride 0.59 kg Workup and
distillation
Water 7.58 kg
Recovered MDC 3.39 kg
Water 7.66 kg
Sodium chloride 0.87 kg
Sodium sulfate 0.05 kg Triethyl amine HCl 0.51 kg
Hyflo 0.05 kg Filter
Activated carbon 0.05 kg Activated carbon 0.05 kg
Sodium Sulfate 0.22 kg
Hyflo 0.05 kg
Residues after solvent recovery 0.003 kg
Toluene 1.87 kg
Recovered toluene 1.85 kg
Recovered Ethyl acetate 11.37 kg
OUT PUT
0.97 kg
Distillation and
workup
Stage-3
stage-II, 0.97 Kkg
Dimethyl acetamide 3.88 kg
Acetoxy acetyl chloride 0.55 kg
water 7.76 kg
DMA scrubber loss 0.02 kg
Water 0.19 kg
HCl Gas to scrubber 0.15 kg
Reaction
Recovered DMA 3.84 kg
Water 7.56 kg
Filter Dimethyl acetamide 0.02 kg
Acetoxy acetic acid 0.29 kg
out put
1.10 kg
Stage-4
Stage-4 intermediate 1.10 kg
Dimethyl acetamide 7.20 kg
2,3-dihydroxy propyl amine 0.72 kg
water 13.05 kg
Sodium hydroxide 0.07 kg
Reaction
and workup
Water for resin column wash 11.25 kg cation exchange
column
anion exchange
column
DMA:Water vapours 0.20 kg
workup
DMA:Water vapours 20.05 kg
Filter
water 11.35 kg
Sodium acetate 0.15 kg
2,3-dihydroxy propyl amine 0.58 kg
out put
1.06 kg
Stage-5
Stage-4 intermediate 1.06 kg
Dimethyl acetamide 8.21 kg
Sodium hydroxide 0.01 kg DMA, Methanol & Water 0.49 kg
water 13.05 kg
methanol 1.58 kg
Methy bromide 0.22 kg Reaction
and workup
DMA, Methanol & Water 9.33 kg
Water for resin wash 5.28 kg cation exchange
30% Hydrochloric acid for resin wash
0.02 kg column
anion exchange water 5.30 kg
column sodium chloride 0.07 kg
sodium bromide 0.10 kg
Iomeprol 0.10 kg
Water vapours
distillation
Water distilled
Filter
out put
1.00 kg
Product:-Gadoterate meglumine
Route of synthesis:-
N
N
N
NO
OH
O
OH
O
OH
O
OH1,4,7,10-Tetra azacyclo dodecane -1,4,7,10-Tetra acetic acid (DOTA)
ClH
OH
NH
H OH
H OH
OH H
H OH
+
Meglumine
Gd2O
3+N
N
N
NO
OH
O
OH
O
OH
O
OH
Gd3+
OH
NH
H OH
H OH
OH H
H OH
Gadoterate meglumine
Material Balance
Material Input in Kg Material Out-put in Kg
1,4,7,10-Tetra azacyclo dodecane -1,4,7,10-Tetra acetic acid (DOTA)
0.15 Gdotarate meglumine solution 1.00
Meglumine 0.07
Gadolinium oxide 0.07
Water 0.71
Total 1.00 Total 1.00
Process flow diagram
1,4,7,10-Tetra azacyclo dodecane -1,4,7,10-Tetra acetic acid (DOTA) 0.15 Kg
Meglumine 0.07 Kg
Gadolinium oxide 0.07 Kg
Water 0.71 Kg
Gadoterate miglumine
1 Kg
No effluents
Reactor Filter
Product:- Paroxetine Hydrochloride
Route of synthesis:-
N
F
O S
O
O
O
OOH
SesamolNaOH
Tosylate
ClH
Stage-II
S
O
OCl
MDC
TEA
N-methyl paroxetine
Stage-III
Phenyl chloroformate
Toluene
Carbamate
NaOH-Toluene
Paroxetine Hydrochloride hemihydrate
1/2 H2O
IsopropanolParoxetine hydrochloride hemi hydrate(Pure)
+
N
OH
F
Tosyl chloride
Stage-I
HCl
S-Carbinol
N
O
F
O
O
O
O
Cl+
N
O
F
O
O
O
O
Toluene
NH
O
F
O
O
Material Balance
Stage-I
Input Kg Out put Kg
S-Carbinol 1.23 Stage-I intermediate 1.77
Tosyl chloride 1.31 Recovered MDC 15.15
Triethyl amine 0.85 Recovered Hexane 3.37
Dimethylamino pyridine 0.05 Solvent loss to vacuum 0.98
Sodium bicarbonate 0.46 Aq. Layer containing
Sodium sulphate 0.38 1) Water 19.78
Methylene dichloride (MDC) 15.95 2) sodium para toluene sulfonate 0.27
Hexane fraction 3.55 3) Sodium chloride 0.24
Purified water 19.68 4) triethyl amine 0.85
5) Hydrochloric acid 0.05
CO2 gas to atmosphere 0.24
Solid waste
sodium sulfate 0.38
Residue after Hexane recovery 0.37
Total 43.46 43.46
Stage-II
(-)-Tosylate 1.77 Stage-II intermediate 1.31
Sodium hydroxide flakes 2.74 Recovered toluene 5.94
Sesamol 0.71 Recovered Hexane 3.35
Toluene 6.00 Solvent loss to vacuum 0.24
Tetrabutyl ammonium bromide 0.06 Aq. Layer containing
Hexane fraction 3.52 1) Water 21.49
Water 21.49 2) sodium para toluene sulfonate 0.91
3) Sodium hydroxide 2.55
4) Tetrabutyl ammonium bromide 0.06
Solid residue after hexane distillation 0.45
Total 36.29 36.29
Stage-III
Input Kg Out put Kg
(-)-N-methyl Paroxetine 1.31 Stage-III intermediate 1.38
Phenyl chloroformate 0.65 Recovered toluene 9.00
Toluene 9.10 Recovered Hexane 3.45
N,N-Di-isopropyl ethylamine 0.10 Solvent loss to vacuum 0.27
Sulphuric acid 0.38 Methyl chloride to scrubber 0.19
Hexane fraction 3.63 Aq. Layer containing
Sodium sulphate 0.38 1) Water 8.70
Water 8.70 2) Sulfuric acid 0.38
3) N,N-Di-isopropyl ethyl amine 0.10
Solid waste containing
1) Sodium sulfate 0.38
2) Oily residue to insinarator 0.32
3) Residue after hexane ML distillation 0.06
Total 24.25 24.25
Stage-IV Carbamate 1.38 Crude paroxetine 1.08
Sodium Hydroxide flakes 0.581175 Recovered toluene 10.13
Toluene 10.23283 Recovered Hexane 0.58
Activated carbon 0.076875 Solvent loss to vacuum 0.13
Hydrochloric acid (min.33%) 0.572565 Aq. Layer containing
Methanol 0.24354 1) Water 10.62
Hyflo 0.083025 2)Sodium hydroxide 0.58
Hexane 0.60885 3) Phenol 0.29
Water 10.24 Carbondioxide to atmosphere 0.14
Solid reside contains
1) Hyflo 0.08
2) Activated carbon 0.08
3) Residue after hexane ML distillation 0.32
Total 24.02 24.02
Stage-V Crude Paroxetine 1.08 Pure paroxetine 1.00
Isopropanol 5.92 Recovered IPA 5.80
Solvent loss to vacuum 0.12
Residue after IPA recovery 0.08
Total 7.00 7.00
Process flow diagram
Product: Paroxetine Stage-01
CO2 (Scrubber)
Aqueous high TDS 21.19 L Recovered MDC 98% Recovered Hexane 98%
Solid waste
(Sodium sulphate 0.38 Kg.) (Residue of hexane0.37 Kg.)
Reaction
S-Carbinol- 1.20 Kg. Tosyl chloride- 1.31 Kg Triethylamine-0.85 Kg Sodium bicarbonate0.46 Kg. Sodium sulphate-0.38Kg. MDC-15.95 Kg. Hexane fraction-3.55 Kg. Purified water-19.68 kg.
Extraction and solvent distillation
Material isolation
Output-1.77 Kg
Product: Paroxetine Stage-II
Aqueous high TDS 25.01 L Recovered Toluene 98% Recovered Hexane 98%
Solid waste (Solid residue after hexane distil.0.45kg)
Reaction
(-)-Tosylate- 1.77 Kg. Sodium hydroxide flakes-2.74Kg Sesamol-0.71 Kg Toluene-6.0 Kg. Tetrabutyl ammonium bromide-0.06 kg. Hexane fraction-15.95 Kg. Hexane fraction-3.92 Kg. Water-21.19 kg.
Extraction and solvent distillation
Material isolation
Output-1.31 Kg
Product: Paroxetine Stage-III
Aqueous high TDS 9.18 L Recovered Toluene 98% Recovered Hexane 98% Methyl chloride to scrubber 0.19 kg.
Solid waste Sodium sulphate-0.38 kg. Oily residue to incinerator-0.32 kg. Residue after hexane ML distillation0.06kg.
Reaction
(-)-N-methyl Paroxetine- 1.31 Kg. Phenyl chloroformate-0.65 Kg Toluene-9.10 Kg N, N-Di-isopropyl ethylamine-0.10 Kg. Sulphuric acid-0.38 kg. Hexane fraction-3.63 Kg. Sodium sulphate-0.38 Kg. Water-8.70 kg.
Extraction and solvent distillation
Material isolation
Output-1.38 Kg
Product: Paroxetine Stage-IV
CO2 (Scrubber)
Aqueous high TDS 11.49 L Recovered Toluene 98% Recovered Hexane 98% Methyl chloride to scrubber 0.19 kg.
Solid waste Hyflo-0.08 kg. Activated carbon-0.08 kg. Residue after hexane ML distillation 0.32kg.
Reaction
Carbamate - 1.38 Kg. Sodium Hydroxide flakes-0.581175Kg. Toluene- 10.23283Kg Activated carbon-0.076875Kg. Hydrochloric acid (min.33%) 0.572565 kg. Methanol -0.24354Kg. Hyflo-0.083025Kg. Hexane -0.60885kg. Water-10.24kg.
Extraction and solvent distillation
Material isolation
Output-1.08 Kg
Product: Paroxetine Stage-V
CO2 (Scrubber)
Aqueous - NA Recovered IPA 98%
Residue after IPA recovery-0.08kg.
Reaction
Crude Paroxetine - 1.08 Kg. Isopropanol-5.92Kg.
Extraction and solvent distillation
Material isolation
Output-1.0 Kg
Product: - Lithium carbonate
Route of synthesis:-
2 LiCl + Na2CO
3Li
2CO
3 + 2 NaCl
Water
Material Balance
Materials Input in
Kg Materials Out put in
Kg
Lithium chloride 1.54 Lithium carbonate 1.00
Sodium carbonate anhydrous 1.92 Aq. Layer contain
Water 20.38 water 19.46
Sodium chloride 2.12
Lithium chloride 0.34
Vacuum loss of water 0.9228
Total 23.84 Total 23.84
Process flow diagram
Lithium chloride 1.538 kg
Sodium carbonate anhydrous 1.92 kg
Water 20.38 kg
water 19.455 kg
Sodium chloride 2.12 kg
Lithium chloride 0.34 kg
Vacuum loss of water 0.9 kg
out put
1 kg
Reaction
Filter
Product: - Valacyclovir hydrochloride
Route of synthesis:-
N
NH
NH2
O
N
N
O
OH OH
O
NH
O
OO
NH
OO
NNH
O
NH2
NN
O
O
Acyclovir Cbz-L-ValineDMF
Stage-I
Stage-III
Crystall ization
H2/Pd-C
MeOH, HCl
+
Cbz-Valacyclovir
O
NH2
N
NH
O
NH2
N
N
O
O
Valacyclovir HCl (Crude)
HClEtOH-Water
Stage-II
Valacyclovir HCl Hydrate
Dicyclohexylcarbodiimide (DCC)
Dimethyl amino pyridine (DMAP)
Material Balance
Stage-I
Input Kg Out put Kg
Acyclovir 1.3621 Stage-I intermediate 1.81159
Cbz-L-valacyclovir 1.89332 Recovered DMF 11.5295
DCC 2.88765 Di-cyclohexyl urea 2.50626
DMF 11.646 Aq. Layer contains
DMAP 0.10897 1) Water 26.9015
Water 29.217 2) DMAP 0.10897
Acetone 29.7346 3) DMF 0.11646
Methanol 7.54603 4) Dicyclohexyl urea 0.64019
Recovered acetone 28.2479
Recovered methanol 7.16873
Residues after acetone recovery containing
1) Chirally impure Stage-I intermediate 0.85812
2) Dicyclohexyl urea 0.64019
3) Water 2.22022
Residues after methanol recovery containing
1) Stage-I intermediate 0.09535
2) Dicyclohexyl urea -
Solvent loss during recovery and drying 1.55279
Total 84.40
84.40
Stage-II
Stage-I intermediate 1.81159 Crude Valacyclovir 1.08696
Methanol 21.5217 Carbon dioxide 0.16304
Hydrochloric acid 0.41667 Toluene 0.36232
Palladium carbon 0.36232 Recovered methanol 20.4456
ethanol 8.5326 Recovered ethanol 8.10597
Hyflo 0.72464 Solvent loss during recovery and drying 1.91123
Residue after distillation of ethanol ML (2nd
Crop) 0.38768
Hyflow and Pd/C 0.9058
Total 33.37
33.37
Stage-III Input Kg Out put Kg
Stage-II intermediate 1.08696 Valacyclovir hydrate 1
Ethanol 10.1413 Recovered ethanol 9.63423
Water 3 Residue after ethanol-water recovery
Valacyclovir HCl 0.08696
Water 3
Solvent loss during recovery and drying 0.50652
Total 14.23
14.23
Process flow diagram
Product: valcyclovir Stage-01
Aqueous Low TDS 63.18L Di-cyclohexyl urea 98% Recovered DMF 98% Recovered acetone 98% Recovered Methanol 98%
Solid waste-NA
Reaction
Acyclovir - 1.3621kg. Cbz-L-valacyclovir -1.89332Kg. DCC - 2.k2.88765g. DMF -11.646Kg. DMAP -0.10897kg. Water -29.217kg. Acetone -29.7346kg. Methanol -7.54603kg.
Extraction and solvent distillation
Material isolation
Output- 1.81159kg.
Product: valcyclovir Stage-II
CO2 (scrubber)
Aqueous NA Toluene 98% Recovered Methanol 98% Recovered Ethanol 98%
Solid waste-NA Residue after distillation of ethanol ML (2nd Crop)-0.38768kg. Hyflow and Pd/C-0.9058kg.
Reaction
Stage-I intermediate- 1.81159kg. Methanol-21.5217Kg. Hydrochloric acid- 41667g. DMF -11.646Kg. Palladium carbon -0.36232kg. Ethanol -8.5326kg. Hyflo -0.72464kg.
Extraction and solvent distillation
Material isolation
Output- 1.08696 kg.
Product: valcyclovir Stage-III
Aqueous Low TDS 3.08696L Recovered Methanol 98% Solid waste-NA
Reaction
Stage-II intermediate- 1.81159kg. Ethanol-10.1413Kg. Water- 3.0kg.
Extraction and solvent distillation
Material isolation
Output- 1.0 kg.
Product: -trans Retinoic acid, 1-hydroxy-3,3-dimethyl-2-butanone ester(G-101)
Route of synthesis
OH
O ClO+ O
O
O
All trans retinoic acid
Cs2CO3/DMF
1-Chloro picolone trans Retinoic acid, 1-hydroxy-3,3-dimethyl-2-butanone ester(G-101)
Material Balance
Input Kg Out put Kg
Trans retinoic acid 0.90 G-101 (Product) 1.00
1-Chloro picolone 0.90 Aq. Layer contain
Cesium carbonate 1.06 1) Water 55.99
DMF 4.43 2) Cesium chloride 0.50
DM Water 55.96 3) Cesium carbonate 0.57
Isopropanol 2.56 4) DMF 4.43
5) 1-Chloro picoline 0.50
Recovered IPA 2.51
IPA loss in distillation 0.05
CO2 Gas liberated 0.07
Residue after IPA recovery 0.20
Total 65.81 65.81
Process flow diagram
Product: G-101
CO2 (scrubber)
Aqueous high TDS-61.99L. Recovered IPA 98% Solid waste
Residue after IPA recovery -0.20kg.
Reaction
Trans retinoic acid-0.90kg. 1-Chloro Pico lone -0.90kg. Cesium carbonate -1.06kg. DMF - 4.43kg. DM Water -55.96kg. Isopropanol – 2.56 kg.
Extraction and solvent distillation
Material isolation
Output- 1.0 kg.
Product: - Oxybutynin hydrochloride
Route of synthesis:-
O
OHOH
cyclohexyl(hydroxy)phenylacetic acid
Br+
2) CH2O; Dimethyl amine
1)Toluene
Toluene
O
O
OHN
Oxybutynin base
O
O
OHN
ClH
Acetone-HCl
Oxybutynin hydrochloride
Stage-1
Stage-2
Material Balance
Stage-1
Material Input in
Kg Material
Output in Kg
Cyclohexyl
(hydroxyl) phenyl
acetic acid
0.69 Oxybutynin base 1.03
Propargyl Bromide 0.35 Recovered toluene 3.79
Formaldehyde 0.09 Scrubber loss
Diethyl amine 0.22 toluene 0.04
Sodium carbonate 0.31 Carbon dioxide 0.06
Toluene 3.83 aq. Layer contains
Water 2.21 Water 2.29
Sodium bromide 0.30
Sodium carbonate 0.16
Residues after solvent recovery 0.02
Total 7.70 Total 7.70
Stage-2
Material Input in
Kg Material
Output in Kg
Oxybutanin base 1.03 Oxybutynin hydrochloride 1.00
Dry HCl 0.11 Recovered acetone 1.31
Acetone 1.34 Recovered hexane 1.41
n-Hexane 1.44 Scrubber loss
Acetone 0.03
Hexane 0.03
HCl 0.00
Residue after hexane recovery 0.14
Total 3.92 Total 3.92
Process flow diagram
Stage-1
Cyclohexyl (hydroxyl) phenyl acetic acid 0.69 kg
Sodium carbonate 0.31 kg
Propargyl Bromide 0.35 kg
Toluene 3.83 kg Carbon dioxide 0.1 kg
Toluene vapours 0.04kg
Water 2.21 kg
Water 2.3 kg
Sodium bromide 0.3 kg
Sodium carbonate 0.2kg
Residues after solvent recovery 0.02 kg
Recovered toluene 3.8 kg
Formaldehyde 0.09 kg Reaction
toluene and distillation
Diethyl amine 0.22 kg
OUT PUT
1.03 kg
Reaction
work up and
distillation
Stage-2
Oxybutanin base 1.03 kg
Dry HCl 0.10 kg
Acetone 1.34kg
n-Hexane 1.44 kg acetone vapours 0.027 kg
hcl vapours 0.0003 kg
Recovered acetone 1.31 kg
Hexane vapours 0.028 kg
MLR
Recovered hexane 1.41 kg
Residue after hexane recovery 0.13 kg
out put
1.0 kg
Reaction and
workup
Filter
Product: - Fexofenadine hydrochloride
Route of synthesis:-
MeOH; NaBH 4
Toluene
aq. KHCO 3; KIOH2
O
Cl
O
O
NH
+
O
O
O
NOH
OH
O
O
NOH
1) NaOH;Water:Methanol
2) HCl
OH
O
OH
NOHFexofenadine base
MeOH; HCl
OH
O
OH
NOH
ClH Fexofinadine hydrochloride
Material Balance
Stage-I
Input in Kg Output in Kg
Azacyclonol 0.8965 Stage-I intermediate 1.41
Chloro intermediate 1.420056 Recovered toluene 9.23
Potassium bicarbonate 1.420056 Aq. Layer contain
Potassium iodide 0.04742485 1) Water 4.51
Toluene 9.327186 2) Potassium iodide 0.05
Water 4.4825 3) Potassium chloride 0.25
4) Potassium salt of keto intemediate 0.51
5) Potassium bicarbonate 0.92
Solid waste
Residues after toluene revovery 0.41
Scrubber discharge
Carbon dioxide 0.15
Methanol 0.05
Touene vapour loss 0.09
Total 17.59 Total 17.59
Stage-II
Input in Kg Output in Kg
Stage-I intermediate 1.41 Fexo Base 1.17
Sodium borohydride 0.10 Recovered Methanol 20.92
Sodium Hydroxide 0.32 Aq. Layer contain
Methanol 26.62 Water 8.56
Acetic acid 0.39 Boric acid 0.04
Methyl formate 0.71 Sodium acetate 0.53
Water 8.56 Methanol 4.75
Sodium formate 0.81
Scrubber discharge
Methanol 1.33
Hydrogen 0.0040
Total 38.11 Total 38.11
Stage-III
Input in Kg Output in Kg
Fexo base 1.17 Fexo hydrochloride 1.00
Conc. HCl 0.223949729 Recovered Acetone 9.65
Acetone 10.16120348 Scrubber discharge
Acetone 0.51
Hydrochloric acid 0.0013
Water 0.2156
Residues after Acetone mL revovery 0.1748
Total 11.55 11.55
Process flow diagram
Stage-1
Azacyclonol 0.89 kg
Chloro intermediate 1.42 kg
Potassium bicarbonate 1.42 kg
Potassium iodide 0.047 kg Carbon dioxide 0.15 kg
Toluene 9.32 kg Methanol vapour loss 0.05 kg
Water 4.48 kg Toluene vapour loss 0.09 kg
Water 4.51 kg
MLR Potassium iodide 0.05 kg
Potassium chloride 0.25 kg
Potassium salt of keto intemediate 0.51 kg
Potassium bicarbonate 0.92 kg
Residues after toluene revovery 0.41 kg
Recovered toluene 9.23 kg
out put
1.41 kg
Reaction and
workup
Filter
Stage-2
Stage-I intermediate 1.41 kg
Sodium borohydride 0.1 kg
Sodium Hydroxide 0.32 kg
Methanol 26.32 kg
Acetic acid 0.39 kg Methanol vapours 1.33 kg
Methyl formate 0.71 kg Hydrogen 0.004 kg
Water 8.56 kg
Recovered Methanol 20.92 kg
Water 8.56 kg
MLR Boric acid 0.04 kg
Sodium acetate 0.53 kg
Methanol 4.75 kg
Sodium formate 0.81 kg
out put
1.17 kg
Reaction and
workup
Filter
Stage-3
Fexo base 1.17 kg
Conc. HCl 0.224 kg
Acetone 10.16 kg Acetone to scrubber 0.51 kg
Hydrochloric acid to scrubber 0.0013 kg
Water vapours 0.22 kg
MLR Recovered Acetone 9.65 kg
Residues after Acetone mL revovery 0.175 kg
out put
1.0 kg
Reaction and
workup
Filter
Product: - Meclizine hydrochloride
Route of synthesis:-
+
O
Cl
4-Chloro benzophenone
NaOH, NaBH 4
Methanol-Water
Cl
Cl
CaCl 2-HCl Water N
NH
Cl
Piperazine
Toluene, TBAB
N
NH
Cl
piperazine
1-[(4-chlorophenyl)(phenyl)methyl]
piperazine
(4-chlorophenyl)(phenyl)methanol
(4-chlorophenyl)(phenyl)methanol 1-chloro-4-[chloro(phenyl)methyl]benzene 1-[(4-chlorophenyl)(phenyl)methyl]
OH
Cl
OH
Cl
Cl
Step-1a
Step-1bStep-2
3-methyl benzyl chloride
1) Triethyl amine-Toluene2) HCl N
NCl
ClHMeclizine hydrochloride
Step-3
Material Balance
Step-1a
Material
Input in
Kg Material
Output in
Kg
4-chloro benzophenone 0.91 4-chlorobenzhydrol (Wet) 1.13
Methanol 3.59 Aq. Layer contain
Water 21.79 Water 21.51
Sodium hydroxide 0.02 Methanol 3.59
Sodium borohydride 0.08 Sodium acetate 0.23
Acetic acid 0.15 Sodium hydroxide 0.01
Boric acid 0.00
4-chlorobenzhydrol 0.06
Hydrogen scrubber
discharge 0.0033
Total 26.55 Total 26.55
Step-1b
Material
Input in
Kg Material
Output in
Kg
(4-chlorophenyl) (phenyl) methanol 0.92 Toluene layer with intermediate 6.85
Conc. HCl (C. P. grade) 5.90 Aq. Layer contain
Calcium chloride 1.11 Water 11.01
Toluene 5.86 Calcium chloride 1.11
Purified Water 6.81 Hydrochloric acid 1.62
Total 20.60 Total 20.60
Step-2
Material
Input in
Kg Material
Output in
Kg
1-Chloro-4-[Chloro(phenyl)
methyl]benzene 6.85
1-Chloro-4-[Chloro(phenyl)
methyl]benzene 0.93
Piperazine (anhydrous) 1.30 recovered toluene 8.52
TBAB 0.09 Recovered Hexane 0.71
Toluene 2.74 toluene scrubber loss 0.09
Hexane 0.74 Hexane scrubber loss 0.04
Sodium hydroxide 0.36 Aq. layer containr contain
Purified Water 11.80 Water 11.80
TBAB 0.09
Sodium chloride 0.24
Sodium hydroxide 0.20
Piperazine 0.94
Residues after solvent recovery 0.35
Total 23.89 Total 23.89
Step-3
Material
Input in
Kg Material
Output in
Kg
1-[(4-Chlorophenyl)(phenyl)
methyl] piperazine 0.93
Pure meclizine
dihydrochloride 1.00
Toluene 16.86 Recovered toluene 16.69
Triethylamine 0.48 Recovered Acetone 12.20
3-Methylbenzylchloride 0.48 Scrubber loss
DM-water 18.52 Toluene scrubber loss 0.17
Anhydrous sodium sulfate 0.37 Acetone scrubber loss 0.25
Hydrochloric acid (CP grade) 0.98 HCl Scrubber loss 0.06
Activated charcoal 0.05 Triethyl amine 0.13
Hyflow 0.05 Water 0.64
Acetone 12.45 Aq. Layer contain
Water 18.52
Triethyl amine hydrochloride 0.47
Solid residues
Sodium sulfate 0.37
Activated carbon 0.05
Hyflo 0.05
Residue after sovlent recoveries 0.57
Total 51.16 Total 51.16
Process flow diagram
Stage-1a
Methanol 3.59 kg
4-chloro benzophenone 0.91 kg
Water 21.79 kg
Sodium hydroxide 0.08 kg
Sodium borohydride 0.08 kg Hydrogen scrubber discharge 0.0033 kg
Acetic acid 0.15 kg
Water 21.51 kg
Methanol 3.59 kg
Sodium acetate 0.23 kg
Sodium hydroxide 0.01 kg
Boric acid
4-chlorobenzhydrol 0.06 kg
out put
1.13 kg
Reaction and
workup
Filter
Stage-1b
Conc. HCl (C. P. grade) 5.9 kg
(4-chlorophenyl) (phenyl) methanol 0.92 kg
Calcium chloride 1.11 kg
Toluene 5.86 kg
Purified Water 6.81 kg
Water 11.01 kg
Calcium chloride 1.11 kg
Hydrochloric acid 1.62 kg
out put
6.85 kg
Reaction and
workup
Filter
Stage-2
Stage-2
Piperazine (anhydrous) 1.13 kg
TBAB 0.09 kg
1-Chloro-4-[Chloro(phenyl) methyl]benzene 6.85 kg
Purified Water 11.8 kg
Toluene 2.74 kg
Hexane 0.74 kg
Sodium hydroxide 0.36 kg
Water 11.8 kg
Sodium hydroxide 0.36 kg Work up TBAB 0.09 kg
and isolation Sodium chloride 0.24 kg
Sodium hydroxide 0.2
Piperazine 0.94 kg
Recovered toluene 8.52 kg
Recovered Hexane 0.71 kg
Toluene scrubber loss 0.09 kg
out put Hexane scrubber loss 0.04 kg
0.93 kg Residues after solvent recovery 0.35 kg
Reaction and
workup
Filter
Stage-3
Toluene 16.86 kg
1-[(4-Chlorophenyl)(phenyl) methyl] piperazine 0.93
kg
Triethylamine 0.48 kg
3-Methylbenzylchloride 0.48 kg Triethyl amine 0.13 kg
DM-water 18.52 kg
Anhydrous sodium sulfate 0.37 kg Anhydrous sodium sulfate 0.37 kg
Activated charcoal 0.05 kg Activated charcoal 0.05 kg
Hyflow 0.05 kg Hyflow 0.05 kg
Water 18.52 kg
Triethyl amine hydrochloride 0.47 kg
HCl Scrubber loss 0.06 kg
Hydrochloric acid (CP grade) 0.98 kg
Acetone 12.45 kg workup
Toluene scrubber loss 0.17 kg
Acetone scrubber loss 0.25 kg
Water 0.64 kg
MLR
Recovered toluene 16.69 kg
Recovered Acetone 12.2 kg
out put
1.0 kg
Reaction and
workup
Filter
Filter
Product: - Hdroxazine hyrochloride
Route of synthesis:-
+
O
Cl
4-Chloro benzophenone
NaOH, NaBH 4
Methanol-Water
Cl
Cl
CaCl 2-HCl Water N
NH
Cl
Piperazine
Toluene, TBAB
N
NH
Cl
piperazine
1-[(4-chlorophenyl)(phenyl)methyl]
piperazine
(4-chlorophenyl)(phenyl)methanol
(4-chlorophenyl)(phenyl)methanol 1-chloro-4-[chloro(phenyl)methyl]benzene 1-[(4-chlorophenyl)(phenyl)methyl]
OH
Cl
OH
Cl
OCl OH
Step-1a
Step-1bStep-2
1) Triethyl amine-Toluene2) HCl-IPA
Step-3
N
N
Cl
O
OHClH
ClH2-(2-chloroethoxy) ethanol
Hydroxazine Dihydrochloride
Material Balance
Step-1a
Material
Input in
Kg Material
Output in
Kg
4-chloro benzophenone 1.46 4-chlorobenzhydrol (Wet) 1.83
Methanol 5.79 Aq. Layer contain
Water 35.12 Water 34.67
Sodium hydroxide 0.04 Methanol 5.79
Sodium borohydride 0.13 Sodium acetate 0.37
Acetic acid 0.25 Sodium hydroxide 0.02
Boric acid 0.01
4-chlorobenzhydrol 0.09
Hydrogen scrubber
discharge 0.01
Total 42.79 Total 42.79
Step-1b
Material
Input in
Kg Material
Output in
Kg
(4-chlorophenyl)
(phenyl) methano 1.48
Toluene layer with
intermediate 11.05
Conc. HCl (C. P. grade) 9.51 Aq. Layer contain
Calcium chloride 1.79 Water 17.75
Toluene 9.45 Calcium chloride 1.79
Purified Water 10.97 Hydrochloric acid 2.61
Total 33.20 Total 33.20
Step-2
Material Input
in Kg Material
Output
in Kg
1-Chloro-4-[Chloro(phenyl)
methyl]benzene 11.05
1-[(4-Chlorophenyl)
(phenyl) methyl] piperazine
hydrochloride
1.49
Piperazine (anhydrous) 2.09 recovered toluene 13.73
TBAB 0.15 Recovered Hexane 1.14
Toluene 4.42 toluene scrubber loss 0.14
Hexane 1.20 Hexane scrubber loss 0.06
Sodium hydroxide 0.59 Aq. layer containr contain
Purified Water 19.02 Water 19.02
TBAB 0.15
Sodium chloride 0.39
Sodium hydroxide 0.32
Piperazine 1.51
Residues after solvent
recovery 0.56
Total 38.51 Total 38.51
Step-3
Material
Input
in Kg Material
Output
in Kg
1-[(4-Chlorophenyl)(phenyl)
methyl]piperazine 1.49 Hydroxazine Di HCl 1.00
Toluene 5.82 Recovered toluene 5.76
Triethylamine 1.21 Recovered IPA 9.75
2-chloroethoxy ethanol 0.91 Scrubber loss
Water 29.10 Toluene scrubber loss 0.06
Anhydrous sodium sulfate 0.37 IPA Scrubber loss 0.10
IPA-HCl 15% 2.61 Triethyl amine 0.47
Activated charcoal 0.07 Aq. Layer contain
Hyflow 0.07 Water 29.10
IPA 7.63 Triethyl amine
hydrochloride 1.00
Sodium chloride 0.60 Sodium chloride 0.60
2-chloro ethoxy ethanol 0.26
Solid residues
Sodium sulfate 0.37
Activated carbon 0.07
Hyflo 0.07
Residue after solvent
recoveries 1.27
Total 49.90 Total 49.90
Process flow diagram
Stage-1a
4-chloro benzophenone 1.46 kg
Methanol 5.79 kg
Water 35.12 kg
Sodium hydroxide 0.04 kg Hydrogen scrubber discharge 0.01 kg
Sodium borohydride 0.13 kg
Acetic acid 0.25 kg
Water 34.67 kg
Methanol 34.67 kg
Sodium acetate 0.37 kg
Sodium hydroxide 0.02 kg
Boric acid 0.01 kg
4-chlorobenzhydrol 0.09 kg
out put
1.48 kg
Filter
Reaction and
workup
Stage-1b
(4-chlorophenyl) (phenyl) methano 1.48 kg
Conc. HCl (C. P. grade) 9.51 kg
Calcium chloride 1.79 kg
Toluene 9.45 kg
Purified Water 10.97 kg
Water 17.75 kg
Calcium chloride 1.79 kg
Hydrochloric acid 2.61 kg
out put
11.05 kg
Reaction and
workup
Filter
Stage-2
1-Chloro-4-[Chloro(phenyl) methyl]benzene 11.05 kg
Piperazine (anhydrous) 2.09 kg
TBAB 0.15 kg
Toluene 4.42 kg
Hexane 1.2 kg
Purified Water 19.02 kg
Water 19.02 kg
Sodium hydroxide 0.59 kg Work up TBAB 0.15 kg
and isolation Sodium chloride 0.39 kg
Sodium hydroxide 0.32 kg
Piperazine 1.51 kg
recovered toluene 13.73 kg
Recovered Hexane 1.14 kg
toluene scrubber loss 0.14 kg
out put Hexane scrubber loss 0.06 kg
1.49 kg Residues after solvent recovery 0.56 kg
Reaction and
workup
Filter
Stage-3
1-[(4-Chlorophenyl)(phenyl) methyl]piperazine 1.49 kg
Toluene 5.82 kg
Triethylamine 1.21 kg
2-chloroethoxy ethanol 0.91 kg
Water 29.1 kg Triethyl amine 0.47 kg
Sodium chloride 0.6 kg
Activated charcoal 0.07 kg Sodium sulfate 0.37 kg
Hyflow 0.07 kg Activated carbon 0.07 kg
Anhydrous sodium sulfate 0.37 kg Hyflo 0.07 kg
Water 29.1 kg
Triethyl amine hydrochloride 1 kg
Sodium chloride 0.6 kg
2-chloro ethoxy ethanol 0.26 kg
IPA-HCl 15% 2.61 kg
IPA 7.63 kg workup
Toluene scrubber loss 0.06 kg
IPA Scrubber loss 0.1 kg
Water 0.64 kg
MLR
Recovered toluene 5.76 kg
Recovered IPA 9.75 kg
Residue after sovlent recoveries 1.27 kg
out put
1.0 kg
Filter
Reaction and
workup
Filter
Product: - Fluconazole
Route of synthesis:-
FF
FF
O
ClF
F
O
N+
NN
NH2
Cl-
FF
O
N
N
NF
F
NN
NO
N
NN
F
FN
+N
N
OH
NH2
N
NN NH2
Methane sulfonicacid; Isopropanol
Stage-II
Stage-IIIStage-IV(a)
NaNO 2-HCl
NaNO 2-HCl
AlCl3-MDC
Acetonitrile
N
NN NH2
MDC/KOH
I-
S+
O
1,3-Difluorobenzene 2-chloro-1-(2,4-difluorophenyl)ethanone4-amino-1-[2-(2,4-difluorophenyl)-2-oxoethyl]-4H-
1,2,4-triazol-1-ium Chloride
1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone
1-{[2-(2,4-difluorophenyl)oxiran-2-yl]methyl}-1H-1,2,4-triazole
4-amino-1-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-1H-1,2,4-triazol-4-ium
methane sulphonate
SO
O
CH3
OH
N
NN
F
FN
N
N
OH
Chloroacetyl chloride
Fluconazole
Material Balance
Stage-I
Name Input in Kg Name
Output in Kg
1,3-Difluorobenzene 0.89 Stage-I intermediate 1.92
Chloro acetyl chloride (98%)
0.90 Recovered dichloromethane 6.77
Aluminium trichloride 1.04 Recovered Acetonitrile 4.19
Dichloromethane 7.13 Scrubber loss
Conc. HCl 2.67 Vacuum loss MDC 0.36
Water 12.14 Vacuum loss Acetonitrile 0.04
5% Brine 0.89 Aq layer containing
4-amino-1,2,4-triazole 0.69 Water 14.44
Acetonitrile 4.23 Sodium choride 0.04
Dissolved HCl 1.66
Scrubber HCl 0.29
Alumniium hydroxide 0.61
Chloriacetic acid 0.25
Residues after Acetonitrile recovery 0.02
Total 30.59 Total 30.59
Stage-II
Name Input in Kg Name
Output in Kg
Stage-I intermediate 1.92 Stage-II intermediate 1.42
Sodium Nitrite 0.50 Scrubber discharge
Hydrochloric acid (30%) 1.44 Nitrogen 0.20
25% Aq. Ammonia 1.18 Aq. Layer containing
Water 13.74 Water 15.90
Ammonium chloride 0.62
Sodium choride 0.42
Ammonia 0.10
Stage-II intermediate taces 0.13
Solid residues -
Total 18.78 Total 18.78
Stage-III
Name Input in Kg Name
Output in Kg
Stage-II intermediate 1.42 Epoxide 1.43
Trimethylsulfoxonium
iodide 1.425213
Recovered MDC 27.37
Potassium hydroxide 1.676613 Recovered Hexane 2.42
Citrimide 0.0053851 Scrubber Loss
Dichoromethane 28.810362 MDC Loss to scrubber 1.44
Hexane 2.5448917 Hexane Loss to scrubber 0.13
Water 23.405691 Dimethyl sulfide 0.40
Aq. Layer containing
Water 23.66
Potassium iodide 1.08
Citrimide 0.01
Potassium hydroxide 1.26
Residues after Hexane ML recovery 0.10
Total 59.29 Total 59.29
Stage-IV
Name Input in Kg Name
Output in Kg
Epoxide 1.43 Crude fluconazole 1.21
4-amino-1,2,4-triazole 0.9875111 Recovered IPA 4.46
Methane sulfonic acid 0.659722 Recovered MDC 43.33
Isopropanol 4.5096008 Recovered toluene 8.86
Sodium Nitrite 1.0788177 Ethyl acetate 2.54
Conc. HCl 3.9437574 Scrubber Discharge
25% ammonium
hydroxide 4.143803
IPA 0.05
Toluene 8.9527579 MDC 2.28
Ethyl acetate 2.5634423 Toluene 0.09
Dichoromethane 45.610411 Ethyl acetate 0.03
Water 30.01 Nitrogen 0.33
Aq. Layer containing
Water 35.88
Sodium chloride 0.91
Ammonium methane sulfonate 0.78
Ammonium chloride 1.02
Dissolved ammonai 1.93
Residues after solvent recoveries 0.19
Total 103.89 Total 103.89
Stage-V
Name Input in Kg Name
Output in Kg
Crude fluconazole 1.21 Pure fluconazole 1.00
Acetone 0.4323844 Scrubber loss
Ethyl acetate 0.3813728 Water 0.22
Activated carbon 0.0607281 Aq. Layer contain
Hyflo 0.1214563 Water 28.92
Water 29.15 Acetone 0.43
Ethyl acetate 0.38
Product 0.21
Solid residues
Hyflo 0.12
Carbon 0.06
Total 31.36 Total 31.36
Process flow diagram
Stage-1
1,3-Difluorobenzene 0.89 kg
Dichloromethane 7.125 kg
Aluminium trichloride 1.043 kg Reaction
Chloro acetyl chloride (98%) 0.90 kg
Conc. HCl 2.67 kg Water 14.44 kg
Water 12.14 kg Workup Sodium choride 0.04 kg
5% Brine 0.89 kg Dissolved HCl 1.66 kg
Scrubber HCl 0.29 kg
Alumniium hydroxide 0.61 kg
Chloroacetic acid 0.25 kg
Distillation
Recovered dichloromethane 6.77 kg
Acetonitrile 4.23 kg
4-amino-1,2,4-triazole 0.69 kg Reaction
Recovered Acetonitrile 4.19 kg
Vacuum loss Acetonitrile 0.04 kg
Residues after Acetonitrile recovery 0.02 kg
Out put
1.92 kg
Stage-2
Nitrogen 0.19 kg
Water 13.7 kg
Stage-I intermediate 1.91 kg
Hydrochloric acid (30%) 1.44 kg Reaction
Sodium Nitrite 0.49 kg
25% Aq. Ammonia 1.175 kg
Filter
Water 15.89 kg
Ammonium chloride 0.622 kg
Sodium choride 0.42 kg
out put Ammonia 0.09 kg
1.42 kg Stage-II intermediate taces 0.13 kg
Stage-3
Potassium hydroxide 1.68 kg
Water 23.4 kg
Dichoromethane 28.81 kg
Trimethylsulfoxonium iodide 1.425 kg reaction
Citrimide 0.005 kg
Stage-II intermediate 1.417 kg
MDC Loss to scrubber 1.44 kg
Hexane Loss to scrubber 0.13 kg
Dimethyl sulfide 0.4 kg
Hexane 2.54 kg distillation
Recovered MDC 27.37 kg
Recovered Hexane 2.42 kg
Filter
Water 23.66 kg
Potassium iodide 1.075 kg
Citrimide 0.005 kg
out put Potassium hydroxide 1.26 kg
1.43 kg Residues after Hexane ML recovery 0.104 kg
Stage-4
Isopropanol 4.509 kg
Epoxide 1.43 kg
4-amino-1,2,4-triazole 0.99 kg Reaction
Methane sulfonic acid 0.66 kg
IPA 0.045 kg
Water 30.0 kg Distillation
Recovered IPA 4.46 kg
Conc. HCl 3.943 kg
Sodium Nitrite 1.08 kg workup
Ethyl acetate 2.56 kg
filter
MDC 2.28 kg
Toluene 0.089 kg
Water 35.87 kg
Dichoromethane 45.61 kg Workup & Sodium chloride 0.91 kg
25% ammonium hydroxide 4.14 kg distillation Ammonium methane sulfonate 0.776 kg
Toluene 8.95 kg Ammonium chloride 1.02 kg
Dissolved ammonai 1.9 kg
Recovered MDC 43.32 kg
Recovered toluene 8.86 kg
filter
out put
1.21 kg
Stage-5
Water 29.14 kg
Acetone 0.43 kg Reaction
Ethyl acetate 0.38 kg
Crude fluconazole 1.21 kg
Filter
Hyflo 0.121 kg
Activated carbon 0.06 kg reactor Carbon 0.06 kg
Hyflo 0.121 kg
filter Water 28.92 kg
Acetone 0.43 kg
Ethyl acetate 0.38 kg
Product 0.21 kg
Water 0.22 kg
out put
1.0 kg
Product: - Colestipol hydrochloride
Route of synthesis:-
NH2
NHNH2
O
Cl
+Diethylene triamine
OHNH
NH
N
NH
NH
N
NH
OH
OH
NH
N
NH
OH
OH
NH
Epichlorohydrine
Sodium dodecylbenzene sulfonate
NaOH/Toluene Colestipol
Material Balance:-
Input Output
Name qty in Kg Name qty in Kg
Diethylenetriamine 0.5 Colestipol 1.00
Epichlorohydrin 0.901333 Recovered toluene 4.29165
Sodium Dodecyl benzene Sulphonate 0.006833 Aq. Layer containing
50% Caustic lye 0.658667 Water 30.57933
Toluene 4.335 Sodium hydroxide 0.329333
Water 33.25 Sodium dodecyl benzene sulfonate 0.006833
Epichlorohydrin 0.14205
Diethylene triamine 0.256069
Vacuum loss
Toluene 0.04335
Water 3
Residues after toluene recovery 0.0032
Total 39.65 Total 39.65
Process flow diagram
Diethylenetriamine 0.5 kg
Epichlorohydrin 0.90 kg
Sodium Dodecyl benzene Sulphonate 0.0068 kg Toluene 0.043 kg
50% Caustic lye 0.67 kg Water 3.0 kg
Toluene 4.33 kg
Water 33.25 kg
Recovered toluene 4.29 kg
Water 30.58 kg
MLR Sodium hydroxide 0.33 kg
Sodium dodecyl benzene sulfonate 0.0068 kg
Epichlorohydrin 0.14 kg
Diethylene triamine 0.26 kg
Residues after toluene recovery 0.03 kg
out put
1.0 kg
Reaction
Filter
Product: - Esomeprazole magnesium
Route of synthesis:-
O
NH
NS N
O
O
NH
NS N
O
O
O
NH
NS
O
O Mg
K+
O
NH
NS
O
O
OH2OH2 OH21) Water / MgSO
4
1) Cumine hydroperoxideTitanium isopropoxideDiethyl-L-TartarateToluene; Di-isopropyl ethyl amine; 2) KOH
2) MeOH-Acetone
Esomeprazole Magnesiumtrihydrate
Material Balance:-
Stage-I
Name Input in
Kg Name O/p in
Kg
Omeprazole sulfide 1.29 Crude esomeprazole 1.17
Cumene hydroperoxide 0.7998 Recovered toluene 28.79
Diethyl tartarate (D) 0.4902 Recovered methanol 0.88
Titanium isopropoxide 0.3354 Aq. Layer containing
Toluene 29.07918 Water 30.63
water 33.54 Potassium sulfate 0.88
Di-isopropyl ethyl amine 0.148608 Titanium hydroxide 0.14
Potassium hydroxide 0.284832 tartaric acid 0.36
Magnesium Sulphate Heptahydrate 0.7224 Ethanol 0.22
Methanol 0.9288 Di-isopropyl ethyl amine 0.15
Isopropanol 0.28
impure esopeprazole 0.21
Scrubber loss
Toluene 0.29
Methanol 0.05
Water 2.94
Residue containing
Cumine 0.63
Total 67.62 Total 67.62
Stage-II
Name Input in
Kg Name O/p in
Kg
Crude esomeprazole 1.17 Pure esomeprazole 1.00
Methanol 8.22 Recovered methanol 7.81
Activated carbon 0.01 recovred acetone 6.69
Acetone 7.04 Solid residues
Hyflo 0.06 Carbon 0.01
Hyflo 0.06
Residues after solvent recovery 0.18
Vacuum loss
Methanol 0.41
Acetone 0.35
Total 16.51 Total 16.51
Process flow diagram
Stage-1
water 33.54 kg
Diethyl tartarate (D) 0.49 kg
Titanium isopropoxide 0.335 kg
Omeprazole sulfide 1.29 kg
Toluene 29.079 kg
Di-isopropyl ethyl amine 0.149 kg
Cumene hydroperoxide 0.7998 kg
Potassium hydroxide 0.28 kg Toluene vapours 0.29 kg
Magnesium Sulphate Heptahydrate 0.72 kg Methanol vapours 0.05 kg
Methanol 0.929 kg Water vapours 2.94 kg
Recovered toluene 28.79 kg
Recovered methanol 0.88 kg
Water 30.63 kg
Potassium sulfate 0.88 kg
MLR Titanium hydroxide 0.14 kg
tartaric acid 0.36 kg
Ethanol 0.22 kg
Di-isopropyl ethyl amine 0.15 kg
Isopropanol 0.28 kg
impure esopeprazole 0.21 kg
residue containing Cumine 0.63 kg
out put
1.17 kg
Reaction and
work up
Filter
Stage-2
Crude esomeprazole 1.17 kg
Methanol 8.217 kg Methanol vapours 0.41 kg
Acetone 7.04 kg Acetone vapours 0.35 kg
Reaction
Recovered methanol 7.81 kg
recovred acetone 6.69 kg
Activated carbon 0.011 kg Carbon 0.01 kg
Hyflo 0.059 kg Filter Hyflo 0.06 kg
Residues after solvent recovery 0.18 kg
Out put
1.0 kg
Product: - Metformin hydrochloride
Route of synthesis:-
NH
NH NH2
NC + NH3C CH3
HClH N
H
NH2
NHNH
NMix xylene
Purified water ClH
Dicyanodiamide Dimethylamine hydrochlorideMetformin hydrochloride
Molecular formula: C2H4N4Molecular formula: C2H8ClN Molecular formula: C4H12ClN5
Molecular weight: 84.08 Molecular weight: 81.54 Molecular weight: 165.62
CharcoalMethanol
Material Balance
Material Input in
Kg Material Output in
Kg
DCDC 0.56 Metformin 1.00
DMA-HCl 0.66 Recovered methanol 0.40
Mixed Xylene 1.07 Recovered Xylene 1.02
Methanol 0.45 Rec. water 1.52
Activated Carbon 0.00 Methanol vacuum loss 0.05
Hyflo 0.00 Xylene vacuum loss 0.04
Water 1.31
Solid waste
Carbon 0.00
Hyflo 0.00
Residues after solvent recovery 0.01
Total 4.05 Total 4.05
Process flow diagram
DCDC 0.56 kg
DMA-HCl 0.66 kg
Mixed Xylene 1.067 kg
Water 1.312 kg
Activated Carbon 0.004 kg Carbon 0.004 kg
Hyflo 0.003 kg Hyflo 0.0032 kg
Methanol vacuum loss 0.048 kg
Xylene vacuum loss 0.0424 kg
Distillation
Recovered methanol 0.4 kg
Recovered Xylene 1.0248 kg
distilled water 1.524 kg
filter
Residues after solvent recovery 0.008 kg
out put
1 kg
Reaction and
workup
Filter
Product: - Sucralfate
Route of synthesis:-
OH
O
OH
OHOH
O
O
OH
OH
OH
OH
Sucrose
1) Chlorosulfoic acid2) Ammonia
2-Picoline
Sucrose Octaammonium sulfonate salt
S
O
O
O
S
O
O
O
SO
O
OS
O
O
O
O
O
O
O
O
O
O
O
O
S
O
O
O
O
S
O
O O
O
SOO
O
S
O
O
O
Al-
O+
O+
Al-
O+ O
+
Al-
O+
O+Al
-
O+
O+
Al-O
+
O+
Al-O
+
O+
Al-
O+
O+
Al-
O+
O+
Al-
OH
OH
Al-
OHOH
Al-
OH
OH
Al-OH
OH
Al-
OHOH
Al-
OH
OH
Al-
OH
OH
Al-
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
AlOH OH
Cl
Sucralfate
S
O
O
OH
SO
O
OH
SO
OOH
SO
O OH
O
O
O
O
O
O
OO
O
S
O
OO
OH
SOO
OOH
SO
OOH
SO
O
OH
8NH3
Material Balance
Stage-1
Input Quantity
in Kg Out put
Quantity
in Kg
Sucrose 0.23 Sucrose octanesulfate ammonium salt 0.67
Chlorosulfonica acid 0.63 Recovered methanol 4.97
2-Picoline 1.97 Recovered picoline 1.95
Aq. Ammonia 25% 0.82 Water recovered 0.61
Methanol 5.07 Scrubber loss
Water 1.89 Methanol 0.10
Hyflo 0.05 Picoline 0.02
Charcoal 0.02 Water recovered 0.01
Ammonia 0.02
Residues contains
Ammonium chloride 0.28
Ammonium sulfate 0.02
Activated crobon 0.02
Hyflo 0.05
Aq. Layer contains
Water 1.89
Sucrose octanesulfate ammonium salt 0.07
Total 10.68 Total 10.68
Stage-2
Sucrose octasulfate ammonium salt 0.67 Sucralfate 1.00
Aluminium chlorohydrate 0.97 Recovered ethanol 5.96
ethanol 6.08 Recovered methanol 6.24
Methanol 6.37 Water 3.74
Water 3.74 Scrubber loss
Ethanol 0.12
Methanol 0.13
Water 0.09
Residues after revovery
Ammonium chloride 0.26
Aluminium chlorohydrate 0.04
Product 0.24
Total 17.83 Total 17.83
Process flow diagram
Stage-1
2-Picoline 1.97 Kg
Chorosulfonic acid 0.63 Kg
Sucrose 0.23 Kg Rec water 0.61 kg
25% Aq. Ammonia 0.82 Kg Recovered methanol 4.97 Kg
Methanol 0.79 Kg Recovered picoline 1.95 Kg
Methanol scrubber loss 0.1 Kg
Picolin scrubbr loss 0.02 Kg
Ammonia scrubber loss 0.02
Recovery of
Mother Liquor
Methanol washing 0.68 Kg
Crude stage-I
Water 1.42 Kg
Activated carbon 0.023 Kg
Hyflo 0.045 Kg
Methanol 2.25 kg
Residues
Ammonium chloride 0.28 Kg
Ammonium sulfate 0.02 Kg
Aq. layer contain
Water wash 0.47 Kg Water 1.89
Stage-I intermediate 0.07
Solid residues Methanol wash 1.35 Kg
Hyflo 0.05 Kg
Chrocoal 0.02 Kg
Reactor
Centrifuge
Reactor
Centrifuge &
Drying
Filtration
Reactor
Filtration
Stage-I intermediate 0.67 Kg
Stage-2
Water 3.74 Kg
Alumnium chlorohydrate 0.97 Kg
Stage-I:- 0.67 Kg
Ethanol 6.08 Kg
Methanol 3.63 Kg
Decanted aq. layer
Methanol wash 2.74 Kg
Sucralfate 1 Kg
Recovered ethanol 5.96 Kg
Recovered methanol 5.2 Kg
Recovered Water 3.74
Ethanol Scruber loss 0.12 Kg
Methanol scruber loss 0.11 Kg
Water scruber loss 0.08 Kg
Residues
Ammonium chloride 0.26 Kg
Aluminium chlorohydrate 0.04 Kg
Product 0.24 kg
Recovery reactor
Reactor
Centrifuge and drying
Product: -Ractopamine hydrochloride
Route of synthesis:-
1) NH3
2) H2,Pd/C Methanol
3) HCl
Raspberry KetoneOctopamine Hydrochloride
ClHNH2
OH
OH O
OH
+
HydrochlorideRactopamine
ClH
NH
OH
OH
OH
Material Balance
Input Kg Out put Kg
Octopamine HCl 0.87 Racto HCl 1.00
Mathanol 8.79 Recovered methanol-1 8.35
Ammonia 0.09 Recovered methanol-2 6.78
Activated carbon 0.04 Recovered Ethyl acetate 9.16
Mathanol 7.14 Vaccum loss of Methanol 0.80
Raspberry ketone 0.90 Vaccum loss of ethyl acetate 0.19
Catalyst 0.08 Solid Waste
water wash 2.78 Activated carbon 0.04
Water 6.72 Residue contain RK 0.17
Ethyl acetate 9.34 Aq. Effluent contains
1) Water 9.62
2) Amminium chloride 0.29
3) Octopamine 0.03
4)Ractopamine 0.33
Total 36.76 36.76
Aqueous high TDS-10.28L. Recovered Methanol 98% Recovered Methanol 98% Recovered Ethyl Acetate-98%
Solid waste Activated carbon-0.04kg. Residue contain RK -0.17kg. .
Reaction
Octopamine HCl – 0.87kg. Methanol-8.89Kg. Ammonia – 0.09g. Activated carbon -0.04Kg. Methanol -7.14kg. Raspberry ketone -0.90kg. Catalyst -0.08kg. Water wash-2.78kg. Water-6.72kg. Ethyl acetate-9.34kg.
Extraction and solvent distillation
Material isolation
Output- 1.0 kg.
Product: - Benzocaine
Route of synthesis:-
N+
O-
O
OHO
H2SO4
Ethanol
N+
O-
O
OO
NH2
OO
H2/Pd - C
Toluene
4-nitrobenzoic acid ethyl 4-nitrobenzoate Benzocaine
Material Balance
Stage-I
Input Kg Out put Kg
PNBA 1.47 Ester 1.50
Ethanol 1.74 Aq. Layer
Sulfuric acid 0.68 1) Water 13.41
Sodium carbonate 0.09 2) SodiumSulfate 0.12
Water 13.24 3) Sulfuric acid 0.59
Hyflo 0.00 4) Ethanol 1.34
5) Ester 0.22
Hyflo 0.00
Carbon dioxide 0.04
Total 17.21 17.21
Stage-II
Stage-I 1.50 Stage-II 1.00
Toluene 3.08 Recovered toluene 3.05
Pd/C 0.00 Vacuum loss toluene 0.03
Sodium bicarbonate 0.00 Pd/C 0.00
Hyflo 0.00 Aq. Layer
Hydrogen consumed 0.05 1) Water 0.28
Solid waste
Hyflo 0.00
Sodium carbonate 0.00
Residue after toluene distillation 0.27
Total 4.63 4.63
Process flow diagram
Product: Benzocaine Stage-01
CO2 (Scrubber)
Aqueous high TDS-15.68L. Ethanol 98% Solid waste -NA
Reaction
PNBA–1.47kg. Ethanol-1.74kg. Sulfuric acid – 0.68kg. Sodium carbonate-0.09Kg. Water -13.24kg.
Extraction and solvent distillation
Material isolation
Output- 1.50 kg.
Product: Benzocaine Stage-II
Aqueous Low TDS-0.28L. Recovered Toluene 98% Solid waste Residue after toluene distillation 0.27kg.
Reaction
Stage-I– 1.50kg. Toluene- 3.08kg. Hydrogen consumed– 0.05kg.
Extraction and solvent distillation
Material isolation
Output- 1.0 kg.