Field of the Invention
The present invention provides a process for the preparation of substituted and un-substituted
benzylamines of Formula I.
Background of the Invention
The substituted and un-substituted benzylamines are both a valuable intermediate for various
applications and a building block for chemical synthesis like for the production of Active Pharma
Ingredients (APIs) in pharmaceuticals and crop protection agents in agrochemicals arena.
Additionally, benzylamines also have vast applications within the coatings industry.
The U.S. Patent No. 6,476,268 provides a process for the preparation of N-benzylamines by
iminization of benzaldehyde with a primary amine in water-miscible solvent. The water of the
reaction, formed while iminization, is not removed. The subsequent hydrogenation is performed
in water miscible solvent without removing water of the reaction.
The Huckabee et al., Organic Process Research & Development, 4, 2000, 594-595 provides a
process for the preparation of N-benzylamines by iminization of benzaldehyde with a primary
amine in toluene. The water of the reaction is azeotropically removed followed by the
hydrogenation of the imine formed in toluene in the presence of palladiudcarbon at elevated 50
psig pressures.
The present inventors have realized that although the prior art states that the reaction of imines
with palladiudcarbon results in hydrogenation along with minor debenzylation, there is no
disclosure in the art specifically for the formation of debenzylated products preferably andlor
exclusively.
The present inventors have realized that there are challenges in the art, which need to be
addressed. While performing the due experimentation, the present inventors found that the use
of water- miscible solvent at imine formation stage results in quantum yield loss since the water
of the reaction becomes miscible with the solvent and hence could not be removed prior to
debenzylation. Further, when debenzylation of imine was tried in toluene, a competitive
hydrogenation reaction of imine resulted in longer reaction times for debenzylation. Thus,
debenzylation of imine in toluene required drastic reaction conditions like high
pressureltemperature to overcome the competitive undesired hydrogenation reaction.
Despite the teaching of these entire prior art documents, the research of new preparation
processes of substituted and un-substituted benzylamine is still an active field. Since, the
industrial exploitation of known processes is new to preferably yield debenzylated products in
high purity, as it has been pointed out in the above-cited documents; the provision of new
preparation processes of substituted and un-substituted benzylamine via debenzylation is
desirable.
Summary of the Invention
The present invention provides a simple, cost effective and industrially scalable process for the
preparation of substituted and un-substituted benzylamines in high yield and purity.
An aspect of the present invention provides a process for the preparation of benzylamine of
Formula I comprising;
Formula I
R is selected from groups RI, R2, R3, R4 and R5. The RI, R2, R3, R4 and R5, independently of one
another, are selected from hydrogen, halogen, CI-C4 alkyl or CI-C4 alkoxy, each of which is unsubstituted
or mono- or poly-substituted by halogen, -OH, CI-C4 alkyl or C1-C4 alkoxy;
n stands for an integer of the value 1 to 4;
% is hydrogen or CI -C4 alkyl;
a) reacting compound of Formula I1 with the compound of Formula I11 to give an imine of
Formula IV in the presence of water-immiscible solvent,
Formula I1
Formula I11
Formula IV
R is selected from groups RI, R2? R3, & and RI. The RI, R2, R3, & and RS, independently of one
another, are selected from hydrogen, halogen7 CI-C4 alkyl or CI-C4 alkoxy, each of which is unsubstituted
or mono- or poly-substituted by halogen, -OH, C1-c4 alkyl or CI-C4 alkoxy;
n stands for an integer of the value 1 to 4;
% is hydrogen or CI -C4 alkyl;
R7 is Cg aryl, which may be un-substituted or mono- or poly-substituted by halogen, -OH, C,-C4
alkyl or CI -Cq alkoxy;
b) optionally isolating imine of Formula IV of step a),
c) debenzylating the imine of Formula IV of step a) or step b) in the presence of
debenzylating catalyst and water-miscible solvent to obtain benzylamine of Formula I,
and
d) isolating benzylamine of Formula I.
Detailed description of the Invention
In an embodiment, the present invention provides a process for the preparation of benzylarnine
of Formula I comprising;
Formula I
R is selected from groups RI, R2, R3, R4 and Rj. The Rl, R2, R3, & and Rj, independently of one
another, are selected from hydrogen, halogen, CI-C4 alkyl or C1-C4 alkoxy, each of which is unsubstituted
or mono- or poly-substituted by halogen, -OH, CI-C4 alkyl or CI-C4 alkoxy;
n stands for an integer of the value 1 to 4;
Rg is hydrogen or CI-C4 alkyl;
a) reacting compound of Formula I1 with the compound of Formula I11 to give an imine of
Formula IV in the presence of water-immiscible solvent,
Formula I1
Formula 111
Formula IV
R is selected from groups R1, R2, R3, Rq and Rg. The RI, R2, R3, Rq and R5, independently of one
another, are selected from hydrogen, halogen, C1-C4 alkyl or C1-C4 alkoxy, each of which is unsubstituted
or mono- or poly-substituted by halogen, -OH, CI-C4 alkyl or CI-C4 alkoxy;
n stands for an integer of the value 1 to 4;
R6 is hydrogen or CI-C4 alkyl;
R7 is C6 aryl, which may be un-substituted or mono- or poly-substituted by halogen, -OH, CI-C4
alkyl or C1-C4 alkoxy;
b) optionally isolating imine of Formula IV of step a),
c) debenzylating the imine of Formula IV of step a) or step b) in the presence of
debenzylating catalyst and water-miscible solvent to obtain benzylamine of Formula I,
and
d) isolating benzylamine of Formula I.
The compounds of Formula I1 and Formula 111 may be prepared by any methods known in the
art. The compound of Formula I1 may be selected from benzaldehyde, 2-methoxy benzaldehyde,
4-methoxy benzaldehyde, 3-methoxy benzaldehyde, 2, 3-dimethoxy benzaldehyde, 2, 4-
dimethoxy benzaldehyde, 3, 4-dimethoxy benzaldehyde, 2, 5-dimethoxy benzaldehyde, 2, 6-
dimethoxy benzaldehyde, 2, 3, 4-trimethoxy benzaldehyde, 3, 4, 5-trimethoxy benzaldehyde, 2,
4, 6-trimethoxy benzaldehyde, 2-tertiary butyl benzaldehyde, 4-tertiary butyl benzaldehyde, 3-
tertiary butyl benzaldehyde, 2, 4-ditertiary butyl benzaldehyde, 4-methyl benzaldehyde, 4-ethyl
benzaldehyde, 4-tert-butyl benzaldehyde, 4-methoxy benzaldehyde, 4-chloro benzaldehyde, 4-
bromo benzaldehyde, 2, 4-difluoro benzaldehyde, 2, 3-difluoro benzaldehyde, 2, 5-difluoro
benzaldehyde, 3, 6-difluoro benzaldehyde, 2, 4-dichloro benzaldehyde, 2, 3-dichloro
benzaldehyde, 2, 5-dichloro benzaldehyde, 3, 6-dichloro benzaldehyde and 3, 5-difluoro
benzaldehyde.
The compound of Formula 111 may be 1 -phenylmethanamine and a-methyl phenylmethanamine,
a-ethyl phenylmethanamine and a-propyl phenylmethanamine.
The imine formation of step a) may take place at a temperature of about 20°C to about 150°C, for
example, at about 70°C to about 120°C for about 5 minutes to about 20 hours, for example, about
30 minutes to 4 hours. The water-immiscible solvent of step a) is selected from aromatic solvent,
chlorinated solvent and ether solvent or mixture thereof. The aromatic solvent is selected from
benzene, toluene and xylene or mixture thereof. The chlorinated solvent is selected from
dichloromethane, dichloroethane, chloroform and carbon tetrachloride or mixture thereof. The
ether solvent may be selected from diethyl ether and di-isopropyl ether or mixture thereof.
The water of the reaction, formed in step a), may be removed from the reaction mixture prior to
debenzylation. The imine of Formula 1V may be optionally isolated prior to debenzylation of
imine.
The catalyst in step c) may contain metal selected from nickel, palladium and platinum. The
catalyst may be, for example, 5% palladium on carbon. The debenzylation of step c) may take
place at a temperature in the range of about 20°C to about 100°C, for example, at about 45OC to
about 80°C for a time period in the range of about 30 minutes to about 40 hours. The
debenzylation of step c) may take place at a hydrogen pressure in the range of about 2 bar to
about 30 bar, for example, 10 bar to about 25 bar. The water-miscible solvent of step c) is
selected from alcohol solvent, ether solvent and amide solvent or mixture thereof. The alcohol
solvent is selected from the group consisting of methanol, ethanol, I-propanol, 2-propanol and
mixtures thereof. The ether solvent is selected from the group consisting of tetrahydrohran and
dioxane and mixtures thereof. The amide solvent is selected from the group consisting of N, Ndimethyl
formamide, dimethyl acetamide N-methyl pyrrolidone and mixtures thereof.
The benzylamine of Formula I is isolated by any of the methods in the art, for example,
evaporation, distillation, filtration and layer separation or mixture thereof.
While the present invention has been described in terms of its specific embodiments, certain
modifications and equivalents will be apparent to those skilled in the art and are intended to be
included within the scope of the present invention.
EXAMPLES
Preparation of 2.4-difluoro benzylamine
2,4-Difluorobenzaldehyde (10 g), benzylamine and toluene were taken together in a reaction
vessel. The reaction mixture was refluxed. The solvent of the mixture was removed to obtain a
residue. The residue was dissolved in methanol and reduced with palladium/carbon. The mixture
was filtered and concentrated to obtain the title compound.Yield: 8.9 g
3'. c-.

We Claim:
1. A process for the preparation of benzylamine of Formula I comprising;
Formula I
R is selected from groups R1, R2, R3, R4 and Rs. The RI, R2, R3, Rq and R5, independently of one
another, are selected from hydrogen, halogen, CI-C4 alkyl or C1-C4 alkoxy, each of which is unsubstituted
or mono- or poly-substituted by halogen, -OH, CI-C4 alkyl or CI-C4 alkoxy.
n stands for an integer of the value 1 to 4;
& is hydrogen or CI -C4 alkyl;
a) reacting compound of Formula I1 with the compound of Formula I11 to give an imine of
Formula IV in the presence of water-immiscible solvent,
RpJcHo
Formula I1
Formula 111
Formula IV
R is selected from groups RI, R2, R3, k and R5. The RI , R2, R3, & and R5,in dependently of one
another, are selected from hydrogen, halogen, CI-C4 alkyl or CI-C4 alkoxy, each of which is unsubstituted
or mono- or poly-substituted by halogen, -OH, CI-Cq alkyl or Cl-C4 alkoxy;
n stands for an integer of the value 1 to 4;
% is hydrogen or Cl-C4 alkyl;
R7 is C6 aryl, which may be un-substituted or mono- or poly-substituted by halogen, -OH, C1-C4
alkyl or CI-C4 alkoxy;
b) optionally isolating imine of Formula IV of step a),
c) debenzylating the imine of Formula IV of step a) or step b) in the presence of
debenzylating catalyst and water-miscible solvent to obtain benzylamine of Formula I,
and
d) isolating benzylamine of Formula I.
2. The process of claim 1, wherein step a) is carried out at a temperature in the range of
70°C to 120°C.
3. The process of claim 1, wherein Formula I1 is selected from benzaldehyde, 2-methoxy
benzaldehyde, 4-methoxy benzaldehyde, 3-methoxy benzaldehyde, 2, 3-dimethoxy
benzaldehyde, 2, 4-dimethoxy benzaldehyde, 3, 4-dimethoxy benzaldehyde, 2, 5-
dimethoxy benzaldehyde, 2, 6-dimethoxy benzaldehyde, 2, 3, 4-trimethoxy
benzaldehyde, 3, 4, 5-trimethoxy benzaldehyde, 2, 4, 6-trimethoxy benzaldehyde, 2-
tertiary butyl benzaldehyde, 4-tertiary butyl benzaldehyde, 3-tertiary butyl benzaldehyde,
2, 4-ditertiary butyl benzaldehyde, 4-methyl benzaldehyde, 4-ethyl benzaldehyde, 4-tertbutyl
benzaldehyde, 4-methoxy benzaldehyde, 4-chloro benzaldehyde, 4-bromo
benzaldehyde, 2, 4-difluoro benzaldehyde, 2, 3-difluoro benzaldehyde, 2, 5-difluoro
benzaldehyde, 3, 6-difluoro benzaldehyde, 2, 4-dichloro benzaldehyde, 2, 3-dichloro
benzaldehyde, 2, 5-dichloro benzaldehyde, 3, 6-dichloro benzaldehyde and 3, 5-difluoro
benzaldehyde.
4. The process of claim 1, wherein the water-immiscible solvent of step a) is selected from
the group consisting of aromatic solvent, chlorinated solvent ether solvent and mixtures
thereof.
5. The process of claim 1, wherein the water-miscible solvent of step c) is selected from the
group consisting of alcohol solvent, ether solvent amide solvent and mixtures thereof.
6. The process of claim 5, wherein the alcohol solvent is selected from the group consisting
of methanol, ethanol, 1 -propano1 2-propanol and mixtures thereof.
7. The process of claim 5, wherein the ether solvent is selected from the group consisting of
tetrahydrofuran dioxane and mixtures thereof.
8. The process of claim 5, wherein the arnide solvent is selected from the group consisting
of N, N-dimethyl formamide, dimethyl acetamide N-methyl pyrrolidone and mixtures
thereof.
9. The process of claim 1, wherein benzylamine of Formula I is isolated by evaporation,
distillation, filtration and layer separation or mixture thereof.