Trouble shooting issues Some case studies

DIPPT – Di iso propyl phenoxy thiourea

NH

O

C

S

NH2

1-(2,6-diisopropyl-4-phenoxyphenyl)thiourea

Stage III

Reaction scheme

NH2

Br2,Conc.HCl

Chloro benzene

NH2

2,6 DIPA 2,6 DIPBA.HBr

(Bromination)

HBr

OH KOH,CuCO3

Br

( Bromo compound + Phenol Ether)

NH2

O

+ KBr + H20

2,6 DIPPA

NaSCN

Conc.HCl

NH

O

C

S

NH2

(Aniline to Thiourea)

2,6 DIPPT

+

NaCl

92%

76%

63%

Raw MaterialsStage IRaw materials Equ

2,6 DIPA 1.00 Conc.HCl 1.25 Bromine 1.10

Stage II

Raw materials Equ

Stage I 1.00 48% Caustic lye 1.20 Phenol 1.50 KOH(88%) 1.45 CuCO3 0.027

Stage III

Raw materials Equ

Stage II 1.00Conc.HCl 1.15NaSCN 1.20

Brief processStage I

Azetropic distillation of water Temperature - 100 - 1050 c

Addition of Conc. HCl (1. 25 equ) Temp - 30-400c

RM charging2,6 DIPA + Chloro benzene

Addition of Bromine (1.10 equ) Temp -600 c , Maintenance - 3 hrs

IPC Check complies

Cool to 50c and filtered, HPLC purity > 99 %, Yield – 92 %

N2 purging to remove excess bromine at 600 c

Stage II

Distillation of water Toluene layer + 88% KOH (1.45 equ) + Phenol (1.50 equ) Temp - 1100c

Neutralisation of HBr2,6 DIPA. HBr (Stage I) + 48% caustic lye (1.20 equ) Temp - RT

Distillation of toluene and DMF charging Temperature- 150-1550c

Toluene extraction

CUCO3 (0.027 equ) charging Temp - 150-1550c Maintenance – until IPC complies

Vacuum distillation of DMF Temp - 700c

Workup

Addition of Water , Dil. KOH solution Temp - 700c , pH > 12

Xylene charging at 700c

Hyflow Filtration & Layer separation Temp - 700c

Stage II in xylene HPLC purity – Stage II – 93%, Stage I – 1% , 2,6 DIPA – 3% Yield – 76%

Stage III RM charging

(Stage II in xylene) + NaSCN (1.20 equ)

Addition of Conc. HCl (1.15 equ) Temp – 95-100 0c

Distillation of water and maintenance Temp – 100-105 0c

IPC Check complies

Vacuum Distillation of water traces Temp - 70 0c

Cool to 200c and filtered, HPLC purity >98% Yield – 63%

Issue formed

Ist batch

Operational issues like raw material handling, utility issues observed

Stage I, II, III material isolated with expected yield and purity

II nd batch

Operational issues rectified

Stage II material isolated with unknown impurities ( ~ 3 - 4%) and not able to eliminate

Stage III material also failed in purity due to unknown impurities ( ~ 3 - 4%) and purification trials failured

Way Forward – Operational issues to be rectified

Impurity Identified

The LCMS analysis confirms the impurity was N-haloamine of Stage I (DIPBA) and stage II (DIPPA).

NHBr

Br

N ,4-dibromo-2,6-diisopropylaniline

NHBr

O

N -bromo-2,6-diisopropyl-4-phenoxyaniline

Route cause

The free bromine (Br2) present in the stage I was the major source for the impurities formation.

1.Reaction of Sodium hypobromite with amine (in stage II – HBr neutralisation)

2 NaOH + Br2 NaBr + NaOBr1.

2. NaOBr + RNH2 + H2O RNHBr +NaOH + H2O

+ H2O

2. Reaction of Hypobromous acid with amine (in stage II – HBr neutralisation)1. Br2 + H2O HOBr

2. HOBr + RNH2 RNHBr + H2O

+ HBr

Corrective action ( Quenching of free bromine)

1.The free bromine trapped in the stage I wet cake was quenched by treating with Sodium bisulfite solution ( introduced in stage I isolation)Br2 + 3NaHSO3 2NaBr + NaHSO4 + H2O + 2 SO2

2.The Bromine free stage I then treated with 48% caustic lye in stage II process to neutralise the trapped HBr

HBr + NaOH NaBr + H2O

The Impurities formed in 2nd batch and not in first batch – why ?.

In the Ist batch, due to lot of issues in utility operations and raw material (Br2) handling the certain quantity of bromine was liberated and not trapped in the stage I .

Therefore there is no purity issues observed.

In the second batch, the operational issues are rectified. Due to that stage I material was trapped with Bromine and this free bromineleads to the formation of above described impurities.

Preventive actionThe Bromine equivalent was reduced form 1.10 to 1.05 which was sufficient for the reaction completion.

Conclusion

The importance of negative experiments and the exact workup process was clearly evident from the above issue.

Key person

Who identified & corrected the issue

Dr G.V .Raj , Former Director & Board member - NACL

EL2- LSN 2779699

O

O O

tert-butyl 3-methoxy-2-propylbenzoate

HO

O OH

3-hydroxy-2-propylbenzoic acid

Stage II Stage III

Reaction scheme

OO

O O

2,3-Dimethoxy benzoic acid

tertiary butyl ester

O

O O

n-PrMgCl,

HO

O OH

3-hydroxy-2-propylbenzoic acid

48%HBr,CH3COOH

(Methoxy to propyl)

( Methoxy to hydroxy)

THF

95 - 98 %

82 - 87%

tert-butyl 3-methoxy-2-propylbenzoate

( Ester to Acid )

Raw MaterialsStage II

Raw materials Equ

2,3 Dimethoxy benzoic acid tertiary butyl ester (Stage I) 1 .00 n-PrMgCl 1.20THF 4.56VAcetic acid 1.30

Stage IIIRaw materials Equ

Stage II 1 .0048% HBr 7.28Acetic acid 15.93

Brief processStage II

RM chargingStage I + THF

Addition of n-PrMgCl (1. 20 equ) Temp - - 25 to - 300c Time – 2 hrs

Maintenance Temp - - 15 to -200c

Time - 2hrs

IPC Check complies

Addition of Acetic acid (1. 30 equ) Temp - - 15 to - 200c Time – 1 hr

Workup Addition of water

Temp - 25 to 300c Time – 30 mins

Charging of MTBETemp - 25 to 300c Layer

separation Back extraction of Aqu. layer

with MTBETemp - 25 to 300c

Water wash and brine solution wash of org. layerTemp - 25 to 300c Vacuum distn of org.layer

Temp - 45 to 500cHPLC purity – 90 to 95 %

Yield – 95 - 98%

Stage III RM chargingStage II + Acetic acid ( 15.93

equ)

Addition of 48% HBr( 7.28 equ) Temp - - 25 to - 280c Time – 20 mins

Maintenance Temp - 115 to 1200c

Time – 22 – 24 hrs

IPC Check complies

Addition of water and MTBETemp - 25 to 300c

Time – 30 mins

Workup

Layer separation

Back extraction of Aqu. layer

with MTBETemp - 25 to 300c

Water wash and brine solution wash of org. layer Temp - 25 to 300c

Vacuum distn of org.layerTemp - 45 to 500c

Chasing with n-Hexane

Temp - 45 to 500c Charging of n – Hexane at RT

Cool to 50c and filtered, HPLC purity > 98 %,Yield – 82 – 87%

Issue formedLab batch

No issues observed in yield & purity of stage II reaction in lab trails

Plant batchIn stage II reaction the un reactive Stage I - ~ 7% in IPC and isolated product also (Limit – NMT – 0.50 % )

The stage II plant material (which contains ~ 7% of stage I ) converted in to stage II in lab with good yield & purity by adding excess n-PrMgCl in THF

When the same concept repeated in plant the reaction was not proceeding and material failed in purity with ~ 5% of stage I (Limit – NMT – 0.50 % )

The stage II Plant material (5% stage I content) converted in to stage III . Isolated material failured in purity due to ~ 5 % un known impurity content

The failured stage II material converted in to stage III and endup with ~ 5% of un known impurity in the isolated material

Impurity identified

The LCMS analysis confirms the impurity was 2,3 di hydroxy benzoic acid

HO

HO

O OH

2,3-dihydroxybenzoic acid

Route cause

It formed from the ~ 5% stage I (in stage II material) reacted with48% HBr in acetic acid in stage III reaction

O

O

O O

Stage I

tert-butyl 2,3-dimethoxybenzoate

48%HBr

CH3COOH

HO

HO

O OH

2,3-dihydroxybenzoic acid

Corrective action ( pH variation)

The same thing repeated in plant and desired result obtained.

In lab, Stage III of plant material treated with dil.caustic solution up to pH>12 in chilled condition to make it as sodium salt

The clear solution filtered through hyflow bed

The basified aqu.layer treated with dil.HCl at chilled condition up to pH - 5 Extracted with toluene

and stage III material isolated with passing quality

The impurity separated by further dil.HCl addition to aqu.layer up to pH - 2

The issue developed in plant batches only and not in lab trials - why?

For the project, the raw material n-PrMgCl received from the same manufacturer in two different packs (i) ~ 1kg for lab trials (ii) ~ 50 kg for plant batches.

For the lab trials the corresponding 1kg pack material only used. There is no issue in the reactivity of lab material.

The 50 kg pack material never used for lab trials and its reactivity never checked. So when it is used for plant batches , due to its poor reactivity ( poor purity) the reaction not proceeding well.

Preventive actionDue to this problem, commercial n-PrMgCl procured freshly and itsreactivity confirmed by IUT trials in lab. The remaining batches conducted withfresh commercial n-PrMgCl and no issues observed in yield and purity of stage II.

Conclusion

1.The importance of IUT trials for commercial raw materials was evident.

2. In process development ,negative experiments must be done to avoid this kind of issues.

Key person

Who identified & corrected the issue

Mr P. Satya Narayanan – Former GL, PHC, Ennore

Isouron

O

N

NH

C

O

NCH3

CH3

3-(5-tert-butylisoxazol-3-yl)-1,1-dimethylurea

Reaction scheme

O

N

CONH2

NaOCl,(C4H9)4NBr

(C4H9)4NCl,Tolune

O

N

NCO(Amide to isocyanate)

(CH3)2NH

(Isocyanate to urea)

O

N

NH C

O

NCH3H3C

(Isouron)

60 - 65%

5-isopropylisoxazole-3-carboxamide

3-(5-tert-butylisoxazol-3-yl)-1,1-dimethylurea

Raw Materials

Raw materials Equ

Carboxamide - 1.00 NaOCl - 1.00 TBAB - 0.04TBACl - 1.00Dimethyl amine - 1.10

Brief process RM charging

14% Aqu. NaOCl solution (1.00 equ)

Lot wise addition of Carboxamide Temp – 15 0c Time – 1 hr

Maintenance Time – 2 hrs Temp - 15 0c

Addition of TBAB (0.04 Equ) ,TBACl ( 1.00 equ) Temp – 15 0c

Maintenance Time – 30 mins

Temp - 15 0c Toluene charging

Temp – 15 0cAqu. Layer separation

Dimethyl amine gas purging in autoclave Temp - 700c, Time – 3 hrs, Pressure – 2 Kg

Work upN2 purging to remove excess DMA at 700c

Water wash of toluene layer Temp - RT

Dil.HCl (3%) wash at RT

Dil. NaOH (5%) wash @ RT

Water wash of toluene layer Temp - RT

Vacuum distillation of toluene Temp - 45 - 550c

Addition of waterTime – 60 mins

Temp – 45 -55 0c

Cool to 50c and filtered HPLC purity > 97 %, Yield – 60- 65 %

Issue formedLab batch Scale up batch

No issues observed in yield & purity in lab trails

No issues observed in yield

One particular known impurity formed more ( 1 % against the limit of 0.50% ) and material failed in specification

Impurity identified The LCMS analysis confirms the impurity was mono methylated product of Isouron.

O

N

NH

C

O

NHCH3

1-(5-tert-butylisoxazol-3-yl)-3-methylurea

Route causeFrom the lab trials over look , it was confirmed that the more quantity of NaOCl used (instead of 1.00 equ , 1.05 equ used) leads to the impurity formation more in that particular scale up batch.

This happens due to some manual error in calculation and weighing.

Relation between excess NaOCl and particular impurity

Possible Mechanism (Hoffman rearrangement)

R C

O

NH2NaOCl R C

ON

H

Cl(i)

N-Chloro amide

(ii) R CO

N

H

Cl

N-Chloro amideR C

ON Cl

NaOH

NaOHH2O Na

(iii) R CO

N Cl N (C4H9)4 Cl R CO

NN (C4H9)4

Cl

R CO

NN (C4H9)4

Cl(iv) R C

O

N N (C4H9)4 Cl

NaCl

R N C O

(v) R N C O NHCH3

CH3R NH

O

N CH3H3C

Preventive actionThe excess NaOCl leads to the formation of impurity (mono methylatedProduct) was confirmed by done some more negative experiments. In all the cases the same result obtained.

Conclusion

Before the scale up batches the negative experiments should be done and data to be generated.

Acetic anhydride

CH3

O

O

O

H3C

Reaction scheme

H3C C

O

OH7000C

Under vacuumH2C C O H2O

Ketene1.

2. H2C C O H3C C

O

OH600c

CH3

O

O

O

H3C

88%

99%

Brief process The crude acetic acid (88%) was cracked under vacuum at 7000c in the furnace to produce ketene gas.

Ketene gas reacted with glacial acetic acid (99%) at 600c to form crude acetic anhydride (88 % of anhydride + 12% of acetic acid)

Continuous process

The crude acetic anhydride (88%) was purified to > 99% by atmospheric distillation

Batch process

Checking controlCrude acetic anhydride purity – online checking

Mixing the 25 ml of fresh sample + 25 ml of calcium chloride solution in stoppered measuring jar and shaked well.

After settling for 2-3 minutes the layers separated with definite values . Based on the values acetic anhydride content in the sample confirmed with standard chart

The pure acetic anhydride was checked by GC

Issue formedThe crude acetic anhydride plant operation was disturbed by heavy vacuum fluctuations

Column flooding i.e. non consistent vapor flow due to choke in the lines was suspected . The problem continued for 5 hours

After 5 hrs , when the crude acetic anhydride content checked by online sample it shows complete absence of acetic anhydride and only acetic acid present

The Dip level in production tank confirms ~ 1500 kgs of acetic anhydride converted in to acetic acid. Production stopped and plant was under shut down

Route causeBy visual inspection it was confirmed that the absorption tower temp ( where ketene gas reacted with acetic acid to form acetic anhydride at 600c ) reached 900c.

By checking the absorption tower it was confirmed that the condenser leak happened. Due to that water entered in to the system.

There by temperature raised from 60 to 900c and also the formed acetic anhydride converted in to acetic acid.

Why the root cause was not immediately identified ?

1. The online sample check for the acetic anhydride content was not done for 5hrs (to be checked for every one hr) due to the concentration focused on suspected column flooding only.

2. The absorption tower temperature scanner in the PLC system panel board not working properly i.e. it indicates the temperature around 600c by constant instead of the actual temperature (900c).

Conclusion1. Doing the basic things on constant basis particularly during the critical times was very important.

2. Doing the physical examination i.e visual checking was much more required especially during trouble shooting. Don’t rely on systems blindly.