t Trouble shooting issues

Desired product – The way achieved

Trouble

Targeted Product

F

H2NO

OCH3

methyl 3-amino-2-fluorobenzoate

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

Thank U