Download - Desired product - the way achieved -updated
Reaction schemeProject – Critical aspects
Various schemes tried and each have its own problems and the routes are failured at various stages
Finally the successful route was identified and based on that the commercially scalable process was developed
The aim was achieved after several issues
Proposed scheme Route A – Ref :- JOC patent
OH
COOH
NO2
NH4OH
NH2
COOH
NO2
NaBF4
NaNO2
F
COOH
NO2
SOCl2 MeOH
NH2
COOCH3
NO2
SOCl2 MeOH
F
COOCH3
NO2
NaBF4 NaNO2
F
COOCH3
NO2
I
II
Pd/C
F
COOCH3
NH2
Pd/C
F
COOCH3
NH2
2-hydroxy-3-nitrobenzoic acid
Stage failure
OH
COOH
NO2
NH4OH
NH2
COOH
NO2
NaBF4
NaNO2
F
COOH
NO2
SOCl2 MeOH
NH2
COOCH3
NO2
SOCl2 MeOH
F
COOCH3
NO2
NaBF4 NaNO2
F
COOCH3
NO2
I
II
Pd/C
F
COOCH3
NH2
Pd/C
F
COOCH3
NH2
X
X
2-hydroxy-3-nitrobenzoic acid
Route cause for failureScheme I failure
NO2
NH2
COOH
NaNO2
HCl,NaBF4
NO2
N2BF4
COOH
NO2
F
COOH
Heating
X
2-amino-3-nitrobenzoic acid
Diazotization not proceeding and starting material only obtained. This may be due to zwitter ion structure
Scheme II failureNO2
NH2
COOCH3
NaNO2
HCl,NaBF4
NO2
N2BF4
COOCH3
NO2
F
COOCH3
Heating
X
methyl 2-amino-3-nitrobenzoate
NO2
COOCH3
methyl 3-nitrobenzoate
During fluorination , des fluoro compound only obtained
Stage I
Proposed scheme Route B – In house procedure
OH
COOH
NO2POCl3
Cl
COOH
NO2
KFF
COOH
NO2
SOCl2 MeOH
F
COOCH3
NO2
Pd/C
F
COOCH3
NH2
POCl3Toluene,TEA
POCl3Toluene,N,N DEA
2-hydroxy-3-nitrobenzoic acid
Stage failure
OH
COOH
NO2
POCl3Cl
COOH
NO2
KFF
COOH
NO2
SOCl2 MeOH
F
COOCH3
NO2
Pd/C
F
COOCH3
NH2
POCl3Toluene,TEA
POCl3Toluene,N,N DEA
X
2-hydroxy-3-nitrobenzoic acid
WorkupRoute cause for failure
All the chlorination reactions with POCl3 (i) without solvent (ii) with toluene and base such as TEA , N,N DEA not proceeding and impurities only formed in major content.
So the scheme was dropped.
Proposed scheme Route C – In house procedureBr COOH
NH2
SOCl2
MeOH
Br COOCH3
NH2
NaNO2 HCl, NaBF4
Br COOCH3
F
HNO3 H2SO4
Br COOCH3
F
NO2
Pd/c
COOCH3
F
NH2
2-amino-5-bromobenzoic acid
Stage failureBr COOH
NH2
SOCl2
MeOH
Br COOCH3
NH2
NaNO2 HCl, NaBF4
Br COOCH3
F
HNO3 H2SO4
Br COOCH3
F
NO2
Pd/c
COOCH3
F
NH2
X
2-amino-5-bromobenzoic acid
Route cause for failureIn Nitration reaction we are getting mainly nitro substitution at ortho position to bromine and methyl ester group instead of meta position due to dominance of Bromine in E+ substitution since – Br is mainly ortho director
Br COOCH3
F
HNO3
H2SO4
X
Desired product
Actual product
Br COOCH3
F
NO2
methyl 5-bromo-2-fluoro-3-nitrobenzoate
Br COOCH3
F
NO2
methyl 3-bromo-6-fluoro-2-nitrobenzoate
methyl 5-bromo-2-fluorobenzoate
Proposed scheme Route D – In house procedure
Br COOCH3
F
NaOH
H2O
Br COOH
F
HNO3 H2SO4
Br COOH
F
NO2
Pd/c
COOH
F
NH2
methyl 5-bromo-2-fluorobenzoate
Stage failure
Br COOCH3
F
NaOH
H2O
Br COOH
F
HNO3 H2SO4
Br COOH
F
NO2
Pd/c
COOH
F
NH2
Xmethyl 5-bromo-2-
fluorobenzoate
Route cause for failure
In nitration reaction mainly impurities only formed
Proposed scheme Route E – In house procedure
F
COOH
SOCl2
MeOH
F
COOCH3
HNO3 H2SO4
F
COOCH3
Pd/c
NO2
F
COOCH3
NH2
2-fluorobenzoic acid
F
COOH
SOCl2
MeOH
F
COOCH3
HNO3 H2SO4
F
COOCH3
Pd/c
NO2
F
COOCH3
NH2
X2-fluorobenzoic acid
Stage failure
Route cause for failureIn Nitration reaction we are getting mainly nitro substitution at para position to fluorine group instead of ortho position due to dominance of Fluorine in E+ substitution since – F is mainly para director
F
COOCH3
HNO3
H2SO4
F
COOCH3
NO2
methyl 2-fluoro-3-nitrobenzoate
Desired product
F
COOCH3
methyl 2-fluoro-5-nitrobenzoate
Actual product
O2N
Xmethyl 2-fluorobenzoate
F
COOCH3
HNO3
X(CH3CO)2O
No reaction
HNO3
CH3COOHNo reaction
X
methyl 2-fluorobenzoate
When Nitration reaction carried out with other reagents reaction not takes place.
Proposed scheme Route F – In house procedure
OH
COOH
NO2
SOCl2, DMF
OH
COOCH3
NO2
CH3SO2ClO
COOCH3
NO2
KF,DMF
F
COOCH3
NO2
Pd/C
F
COOCH3
NH2
CH3OH Toluene,TEA
S
O
OCH3
KI
2-hydroxy-3-nitrobenzoic acid
Stage failure
OH
COOH
NO2
SOCl2, DMF
OH
COOCH3
NO2
CH3SO2ClO
COOCH3
NO2
KF,DMF
F
COOCH3
NO2
Pd/C
F
COOCH3
NH2
CH3OH Toluene,TEA
S
O
OCH3
KI X
2-hydroxy-3-nitrobenzoic acid
WorkupRoute cause for failure
O
COOCH3
NO2
F
COOCH3
NO2
S
O
OCH3
KI,KF
DMF
Desired product
methyl 2-fluoro-3-nitrobenzoate
KI,KF
DMF
OH
COOCH3
NO2
Actual product
methyl 2-hydroxy-3-nitrobenzoate
Xmethyl 2-(methylsulfonyloxy)-3-nitrobenzoate
In reaction with KI,KF instead of fluorination ,hydrolysis only takes place
Proposed scheme Route G – Vogel process
NH2
CH3
NHCOCH3
NO2
CH3
HCl
NH2
NO2
CH3
NaBF4NaNO2
F
NO2
CH3
Pd/C
F
NH2
COOCH3
(CH3CO)2O
HNO3
CH3COOH
SOCl2, DMFCH3OH
F
NO2
COOH
F
NO2
COOCH3
KMnO4
O-Toluidine
Stage failure
NH2
CH3
NHCOCH3
NO2
CH3
HCl
NH2
NO2
CH3
NaBF4NaNO2
F
NO2
CH3
Pd/C
F
NH2
COOCH3
(CH3CO)2O
HNO3
CH3COOH
SOCl2, DMFCH3OH
F
NO2
COOH
F
NO2
COOCH3
KMnO4
X
O-Toluidine
Route cause for failureCH3
NH2
NO2
NaNO2
HCl,NaBF4
CH3
N2BF4
NO2
CH3
F
NO2
Heating
X
2-methyl-6-nitroaniline
During fluorination , des fluro compound only obtained
COOH
NO2
3-nitrobenzoic acid
Learned Facts
1. Amino to Fluoro conversion through diazotization was not effective and mainly end up with either (i) no diazotization reaction or (ii) des fluoro compound.
So it was decided better to avoid this amine to flouro conversion and proceed with fluorine substituent moiety.
2. Chlorination of hydroxy phenol was not effective and it may due to the unsuitable process conditions like (i) high temperature (ii) improper mole equivalence of reagents (iii) usage of non suitable base.
Extensive studies in this route was not done for this moiety.
3. Nitration was not effective and it may due to the reaction was highly selective oriented and orientation mainly decided by other substituents like halogen groups.
The reaction conditions like temperature, rate of addition, mole equivalence of reagents also take major role in deciding the orientation. So the nitration route was held up.
4. Reaction of mesylate group with KF was not fruit full and end up with cleavage of mesyl group only happened. It may be due to improper reaction conditions.
Extensive studies in this route was not done for this moiety.
Conclusion:-
1. Proceed with fluorine substituent moiety.
2. Avoiding of diazotization and nitration reactions for this moiety.
Proposed schemeRoute H – Successful route – Ref :- Japanese patent
F
CH3
CH3
KMnO4
F
COOH
COOH
F
COOCH3
COOCH3
MeOH
F
COOH
COOCH3
H2O
NaOH H2O
SOCl2
DMF
F
COCl
COOCH3
NaN3
DMF,MDC
F
CON3
COOCH3
t-BuOH
F
NH
COOCH3
O
O
TFA
MDC
F
NH3
COOCH3
CF3 COO
SOCl2
HCl
NaHCO3
F
NH2
COOCH3
2-fluoro-1,3-dimethylbenzene
methyl 3-amino-2-fluorobenzoate
Learned Facts
1. Even though reaction proceeding well it was decided to avoid the sodium azide usage due to safety constraints.
2. For that the usage of DPPA as alternative reagent was initialized.
3. Avoiding of TFA due to cost issues and introduction of MeOH.HCl as substitute reagent was motivated.
Commercial route
NH2
CH3
CH3
NaBF4
NaNO2,HCl
F
CH3
CH3
F
COOH
COOCH3
SOCl2 MeOH ,
F
COOCH3
COOCH3
KMnO4
H2O
F
COOH
COOH
DMF
NaOH
MeOH,H2O
t-BuOH P N3
OPh
PhO
O
F
NH
COOCH3
diphenyl phosphorazidate
DPPA
O
O
P OH
OPh
PhO
O
+
methyl 3-(tert-butoxycarbonylamino)-2-fluorobenzoate
MeOH.HCl
MeOH
F
NH2
COOCH3
methyl 3-amino-2-fluorobenzoate
2,6-dimethylaniline