FIELD OF THE INVENTION
This present invention relates to an improved process for the preparation of
polyaminocarboxylate, 4-carboxy-5,8, 11-tris(carboxymethyl)-1-phenyl-2-oxa-5,8, 11-
triazatridecan-13-oic acid (BOPTA), the chelating agent used in the synthesis of
Gadobenate dimeglumine. The process involves use of novel intermediate and is simple,
efficient and environment friendly.
BACKGROUND OF THE INVENTION
Gadobenate dimeglumine, also known as GdBOPTA Dimeg (Multihance) belongs to the
class of magnetic resonance imaging contrast agents, which are complex paramagnetic
salts and which, when administered in the body tissue help in improving the diagnostic
information obtained from the imaging technique. Gadeobenic acid, which is
administered as its dimeglumine salt, is a complex of the transition metal gadolinium
with the ligand, 4-carboxy-5,8, 11-tris(carboxymethyl)-1-phenyl-2-oxa-5,8, 11-
triazatridecan-13-oic acid (BOPTA), structurally represented as Formula I. The active
ingredient functions as a gadolinium based MRI contrast agent, and is employed for the
detection of focal liver lesions in liver cancer patients as well as MRI of central nervous
system.
0 OH
BnOYOH ~0
N-..../' ~N'J
ojoH ty.o oAoH
OH
Formula I
US 4,916,246 discloses a process for the preparation of polyaminocarboxylate BOPTA
which comprises the reaction of excess of diethylentriamine with 3-phenylmethoxy-2-
chloropropanoic acid to give a serine derivative which is subjected to basic anion resin
treatment for purification. The serine derivative is then reacted with bromoacetic acid in
presence of base to obtain BOPTAwhich was subjected to acidic cation resin treatment
for purification. The reaction of diethylenetriamine with 3-phenylmethoxy-2-
chloropropanoic acid leads to the formation of ketopiperazine impurity (structurally
IP:O D.ELHI 20-0 l- 2016 1. 7 :8:22
represented as ketopiperazine) in serine derivative, which needs to be removed usmg
additional purification operations, making process lengthier and costlier. Further, the use
of resins for purification of intermediates and final product needs use of large column
establishments for application for industrial scale up, which in turn increases the cost of
manufacturing and makes process cumbersome, thereby the disclosed process is rendered
infeasible for industrial use.
US 6,162,947 discloses a process for the preparation of BOPTA wherein
diethylenetriamine is treated with potassium salt of 2-chloro-3-
(phenylmethoxy)propanoic acid, upon further carboxymethylation with sodium
bromoacetate yields BOPT A. The process disclosed involves use of methyl acrylate for
the preparation of potassium salt of 2-chloro-3-(phenylmethoxy)propanoic acid. The
methyl acrylate is toxic and the use of toxic reagents makes the process unsafe. Further,
the use of sodium bromoacetate yields a sodium salt as product, which when neutralized
leads to the formation of inorganic salts which reduces the assay of product and is
difficult to remove completely, which makes the process tedious and expensive. Thus,
overall. limitations of the disclosed process make it unsuitable for commercial use.
US 7,592,482 discloses synthesis of BOPTA, wherein monoalkylation of
diethylentriamine is carried out using potassium salt of 2-chloro-3-
methylphenoxypropionic acid. However, further reaction of the benzyloxy substituted
polyamine is effected using large excess of the alkylation agent, bromoacetic acid (molar
ratio of acid:amine is between 7:1 and 9:1 ). Also, the procedure involves stage-wise,
sequential and alternate dosing of aliquots of aqueous solutions of bromoacetic acid and
sodium hydroxide at different temperatures. Although the process disclosed does not
involve any critical pH monitoring but use of such cumbersome mode of addition of
various reagents having specific concentrations in alternate manner at different
temperatures, makes the utility of process infeasible to be applicable for large-scale
productions, as varying temperatures frequently at commercial scale involves very high
energy inputs and any minor change in mode of addition, temperature, concentrations of
reagents will lead to the formation of undesired side products. The formation of undesired
products will eventually lead to purification steps that will make the process lengthy.
Thus, it is believed that the process disclosed is unsuitable for industrial application.
I.PO DELHI 2.8- Ol- 2:01.6 1 7· :. 13.32
CN1 02603550 discloses the process for the preparation of BOPTA, wherein the
intermediate 6,9, 12-tris[2-(1, 1-dimethylethoxy)-2-oxoethyl]-2,2-dimethyl-5-
[(phenylmethoxy)methyl]-4-oxo-3-oxa-6,9, 12-triazatetradecan-14-oic acid .1, 1-
dimethylethyl ester is hydrolyzed using trifluoroacetic acid to obtain BOPTA. The use of
trifluoroacetic acid is highly discouraged for industrial application because of its
corrosive nature and also, the hydrolysis reaction using trifluoroacetic acid yields
additional by-products which then require purification steps. The disadvantage associated
with use of trifluoroacetic acid renders the disclosed process inapplicable for industrial
use.
CN 102408348 discloses method of synthesizing BOPTA, wherein the 3-benzyloxy-2-
halo-propionic acid is esterified using t-butanoi/DCC/DMAP or alternatively using
magnesium sulfate/sulfuric acid/t-butanol. During the esterification reaction, first
conditions involve DCC (N,N'-Dicyclohexylcarbodiimide), which was converted to a
genotoxic compound DCU (dicyclohexylurea) and the second condition for esterification
require special condition of a closed system autoclave. Thus, both reaction conditions for
esterification do not feasibly support its application on industrial scale and render the
process unsuitable for commercial use.
Hence, there is a· need for an efficient and economical process for the preparation of 4-
carboxy-5,8, 11-tris( carboxymethyl)-1-phenyl-2-oxa-5,8, 11-triazatridecan-13-oic acid
(BOPTA), which not only overcomes the problems in the prior art processes as
mentioned above, but also is simple, environment friendly, capable of restricting
undesired side products, avoid~ use of cumbersome operations and industrially feasible
for the preparation ofBOPTA.
OBJECT AND SUMMARY OF THE INVENTION
The principal object of the present invention is to overcome or alleviate at least one of the
deficiencies of prior art and provide a useful alternative for the preparation of BOPTA
and pharmaceutically acceptable salts thereof.
Another object of the present invention is to provide a simple, economic and efficient
process for the preparation of BOPTA which is devoid of formation of inorganic waste,
rPfr DELHI 28-01-2&16 17:0~
have very short cycle time as compared to prior art processes, uses environment friendly
reagents/solvents and avoids the formation of undesired by-products.
Another object of the present invention is to provide a process for the preparation of
BOPTA, wherein BOPTA is obtained in highly pure form free from 2,2'-((2-(3-
((benzyloxy)methyl)-4-( carboxymethyl)-2-oxopiperazin-1-yl)ethyl)azanediyl)diacetic
acid impurity, dimer impurity, trimer impurity, quaternary impurity of BOPTA and is
substantially free of metal content preferably iron and sodium metals.
A yet another object of the present invention is to provide a novel intermediate, 3-
benzyloxy-2-bromo propionic acid amine addition salt of formula IliA.
0
BnOYOH .amine salt
Br
Formula IliA
A yet another object of the present invention is to provide a process for the preparation of
BOPTA involving use of novel intermediate 3-benzyloxy-2-bromo propanoic acid amine
salt of formula IliA.
A yet another object ofthe present invention is to provide a novel polymorph ofBOPTA
hydrochloride salt.
In accordance with an object of the present invention, there is provided a process for the
preparation ofBOPTA, comprising the steps of:
(a) brominating 0-benzyl serine of Formula II by diazotization to obtain 3-
benzyloxy-2-bromo propanoic acid of formula III;
Formula II
0
BnOYOH
Br
Formula III
(b) reacting 3-benzyloxy-2-bromo propanoic acid of formula III with an amine in
solvent to obtain amine salt of formula IliA;
IPQ DELHT 2Q-B1-201S 11:02
0
BnOYOH .amine salt
Br
Formula IliA
(c) converting amine salt of formula IliA to 3-benzyloxy-2-bromo propanoic acid of
formula III;
(d) esterifying 3-benzyloxy-2-bromo propanoic acid of formula III to t-butyl-3-
benzyloxy-2-b.romo propanoate of formula IV
0
BnOYOBu1
Br
Formula IV
(e) reacting t-butyl-3-benzyloxy-2-bromo propanoate of formula IV with
diethylenetriamine in presence of a catalyst and solvent to obtain N-[2-[(2-
aminoethyl)amino ]ethyl-0-(phenylmethyl) serine 1, 1-dimethylethyl ester of
formula V;
H2N-...../'N~NH2
H
Diethylenetriamine
0
BnOYOBu1
HN-......../"'-N~NH2
H
Formula V
(f) alkylating N-[2-[(2-aminoethyl)amino ]ethyl-0-(phenylmethyl) senne 1,1-
dimethylethyl ester of formula V with halo-t-butylacetate in solvent in presence of
base to obtain 6,9, 12-tris[2-( 1, 1-dimethylethoxy)-2-oxoethyl]-2,2-dimethyl-5-
[(phenylmethoxy)methyl]-4-oxo-3-oxa-6,9, 12-triazatetradecan-14-oic acid 1,1-
dimethylethyl ester of formula VI;
Formula VI
(g) hydrolysis of 6,9, 12-tris[2-(1, 1-dimethylethoxy)-2-oxoethyl]-2,2-dimethyl-5-
[(phenylmethoxy)methyl]-4-oxo-3-oxa-6,9, 12-triazatetradecan-14-oic acid 1,1-
dimethylethyl ester of formula VI using a hydrolyzing agent in solvent to obtain
4-carboxy-5,8, 11-tris( carboxymethyl)-1-phenyl-2-oxa-5,8, 11-triaza~ridecan-13-
oic acid (BOPTA) salt of formula VII, optionally, treating BOPTA salt with a
solvent
.X
Formula VII
wherein X is hydrochloride, hydroiodide, hydrobromide, sulphate, trifluroacetate
or phosphate and
(h) isolating pure BOPTA from BOPTA salt.
BRIEF DESCRIPTION OF THE DR W AINGS
Figure I: X-ray diffractogram of BOPTA hydrochloride as obtained by process of present
invention
Figure 2: X-ray diffractogram ofBOPTA as obtained by process of present invention
DESCRIPTION OF THE INVENTION
While this specification concludes with claims particularly pointing out and distinctly
claiming that, which is regarded as the invention, it is anticipated that the invention can
be more readily understood through reading the following detailed description of the
invention and study ofthe included examples.
The prior art processes for the preparation of BOPTA, suffer a number of disadvantages
in terms of use of corrosive reagent like trifluoroacetic acid, choice of highly toxic
reagents like methyl acrylate, preparation of intermediates involving use of reaction
conditions having DCC which is converted to DCU during reaction and is genotoxic. The
IPO DELHI 2Q-01-201S 11:0~
prior arts not only face the challenge of above mentioned drawbacks but also struggle
with various impurities formation, such as keto piperazine formed on account of selection
of methyl or ethyl ester intermediates or potassium salt of alkylating agents. Further,
prior arts also suffer the disadvantage of formation of inorganic by-products, which are
very difficult to remove and invite extra purification steps for their removal to make
BOPTA to meet pharmacopeial standards, wherein the required purifications leads to
very low yield, makes process tedious, lengthy and expensive. Understanding, the
limitations of prior arts and for the need of an advantageous process for the preparation of
BOPTA, the present invention is directed to an improved process of preparing BOPT A
with very careful selection of starting materials/substrates, reagents, reaction conditions,
and solvents, wherein the said reaction conditions/reagents/solvent(s) are not only devoid
of environmentally and health hazardous conditions but also results in controlled
formation of undesired impurities, which eventually produces BOPTA almost at par with
pharmacopeial standards and thus require very fewer purification, which results in a
process that reduces the economic inputs in terms of lesser requirement of solvent and
much better yield of BOPT A along with improving the quality of BOPTA and the
process is industrially compatible and environmentally efficient.
In accordance with an object of the present invention, there is provided a process for the
preparation of BOPTA, comprising the steps of:
(a) brominating 0-benzyl serine o( Formula II by diazotization to obtain 3-
benzyloxy-2-bromo propanoic acid of formula III;
Formula II
0
BnOYOH
Br
Formula III
(b) reacting 3-benzyloxy-2-bromo propanoic acid of formula III with an am me m
solvent to obtain amine salt of formula IliA;
0
BnOYOH .amine salt
Br
Formula IliA
TFO DELKI 20-·01-2016 17:Gt
(c) converting amine salt of formula IliA to 3-benzyloxy-2-bromo propanoic acid of
formula Ill;
(d) esterifying 3-benzyloxy-2-bromo propanoic acid of formula III to t-butyl-3-
benzyloxy-2-bromo propanoate of formula IV
0
BnOYOBu'·
Br
Formula IV
(e) reacting t-butyl-3-benzyloxy-2-bromo propanoate of formula IV with
diethylenetriamine in presence of a catalyst and solvent to obtain N-[2-[(2-
aminoethyl)amino ]ethyl-0-(phenylmethyl) senne 1, 1-dimethylethyl ester of
formula V;
H2N-....../'-N~NH2
H
Diethylenetriamine
0
BnOYOBu'
HN-....../'-N~NH2
H
Formula V
(f) alkylating N-[2-[(2-aminoethyl)amino ]ethyl-0-(phenylmethyl) senne 1,1-
dimethylethyl ester of formula V with halo-t-butylacetate in solvent in presence of
base to obtain 6,9, 12-tris[2-(1, 1-dimethylethoxy)-2-oxoethyl]-2,2-dimethyl-5-
[(phenylmethoxy)methyl]-4-oxo-3-oxa-6,9, 12-triazatetradecan-14-oic acid 1,1-
dimethylethyl ester of formula VI;
Formula VI
(g) hydrolysis of 6,9, 12-tris[2-(1, 1-dimethylethoxy)-2-oxoethyl]-2,2-dimethyl-5-
[(phenylmethoxy)methyl]-4-oxo-3-oxa-6,9, 12-triazatetradecan-14-oic acid 1,1-
dimethylethyl ester of formula VI using a hydrolyzing agent in solvent to obtain
4-carboxy-5,8, 11-tris( carboxymethyl)-1-phenyl-2-oxa-5,8, 11-triazatridecan-13-
oic acid (BOPTA) salt of formula VII, optionally, treating BOPTA salt with a
solvent; and
IPa DELHI 2Q-Ol-201S 11:0~
.X
Fonnula VII
wherein X is hydrochloride, hydroiodide, hydrobromide, sulphate, trifluroacetate
or phosphate and
(h) isolating pure BOPTA from BOPTA salt.
According to the present invention, bromination of 0-benzylserine is carried out in step
(a) wherein 0-benzyl serine first underwent diazotization using sodium nitrite in presence
of acid in a solvent, wherein acid is selected from the group comprising of hydrochloric
acid, hydrobromic acid, hydroiodic acid, sulfuric acid, acetic acid, phosphoric acid,.
fluoroboric acid and the like or mixture thereof. The solvent used is selected from the
group comprising of methanol, ethanol, dimethylforrriamide, acetone, water and mixtures
thereof. The in-situ generated diazonium salt then underwent reaction with a brominating
agent, wherein the brominating agent used is selected from the group comprising of
potassium bromide, cuprous bromide, lithium bromide, sodium bromide, ammonium
bromide and the like. The diazotization and bromination reaction is preferably carried out
at temperature below s·c.
According to the present invention, 2-benzyloxy-2-bromo propanoic acid obtained in step
(a) is treated with an amine in solvent to obtain amine salt of fonnula IliA, wherein the
amine is selected from the group comprising of cyclohexylamine, benzylamine,
phenethyl amine, dicyclohexyl amine, glucosamine, diethanolamine, methoxyethylamine
and the like, preferably cyclohexylamine. The. solvent used is selected from the group
comprising of alcohols such as methanol, ethanol, isopropanol and the like; esters such as
ethyl acetate; propyl acetate and the like; nitriles such as acetonitrile, propionitrile and the
like; water and mixtures thereof.
IPO DELHL 2Q-Ol-2BlS 11:~~
According to the present invention, the amine salt of formula IliA is treated with a
acid/potassium bisulfate in step (c) to obtain 2-benzyloxy-2-bromo propanoic acid,
wherein the acid is selected from the group comprising of organic and inorganic, wherein
organic is selected from the group comprising of acetic acid and the like. The inorganic
acid is selected from the group comprising of hydrochloric acid, hydrobromic acid and
the like.
According to the present invention, esterification of 2-benzyloxy-2-bromo propanoic acid
of formula III obtained in step (c) is carried out in !-butanol in presence of di-t-butyl
dicarbonate/pivolyl chloride · and catalyst to obtain t-butyl-3-benzyloxy-2-bromo
propanote of formula IV. The catalyst used for esterification is selected from the group
comprising of DMAP (dimethylamino pyridine), Hf(OTt)4, Mg(CI04)z, Sc(0Tt)3,
Yb(OTt)3 and the like. The esterification reaction is carried out at temperature between
50-70 OC in about 1-4 hours. According _!:o the present invention, the reaction mixture
involving use of DMAP as catalyst is quenched with potassium bisulfate to isolate tbutyl-
3-benzyloxy-2-bromo propanote of formula IV free from 1-[3-(benzyloxy)-1-(tbutoxy)-
1-oxopropan-2-yl]-4-(dimethylamino)pyridinium bromide (Formula IVA).
Formula IVA
According to the present invention, t-butyl-3-benzyloxy-2-bromo propanoate of formula
IV obtained in step (b) is reacted with diethylenetriamine in presence of a catalyst and
solvent to obtain N-[2-[(2-aminoethyl)amino ]ethyl-0-(phenylmethyl) serine 1,1-
dimethylethyl ester of formula V, wherein the catalyst used is selected from the group
comprising of potassium iodide, sodium iodide and the like. The solvent used is selected
from the group comprising of ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran,
dioxane, t-butyl methyl ether, diisopropyl ether and the like; esters such as ethyl acetate,
propyl acetate and the like; halogenated hydrocarbons such as dichloromethane, ethylene
dichloride, chlorobenzene, and the like; nitrites such as acetonitrile, propionitrile and the
LPO DELKT 2B-Ol-291S 17:02
---- -- --------------------------------------------
like; water and mixtures thereof. The reaction is performed at room temperature for about
16-20 hours. The N-[2-[(2-aminoethyl)amino )ethyl-0-(phenylmethyl) serine 1,1-
dimethylethyl ester of formula V is optionally isolated as an organic acid addition salt,
wherein the organic acid is selected from the group comprising of fumaric acid, tartaric
acid, oxalic acid, succinic acid and the like.
According to the present invention, alkylation of N-[2-[(2-aminoethyl)amino]ethyl-0-
(phertylmethyl) serine 1, 1-dimethylethyl ester of formula V using !-butyl haloacetate in
solvent in presence of base is carried out in step (d), wherein N-[2-[(2-
aminoethyl)amino )ethyl-0-(phenylmethyl) serine I, I-dimethylethyl ester of formula V
obtained as organic acid addition salt is desaltified before exposing the compound of
formula V to alkylating agent. The desaltfication is carried out using a base, wherein the;
base used is selected from organic such as triethylamine, diisopropyl ethyl amine and the
like; and inorganic selected from a group comprising of alkali or alkaline earth metal
carbonates, bicarbonates, hydroxides and ammonia. The alkali and alkaline earth metal is
selected from the group comprising of sodium, potassium, lithium, calcium and the like.
The solvent used is selected from the group comprising of ketones such as acetone, ethyl
methyl ketone and the like; nitriles such as from acetonitrile, propionitrile and the like;
water and mixtures thereof. The in-situ generated N-[2-[(2-aminoethyl)amino]ethyl-0-
(phenylmethyl) serine I, I-dimethylethyl ester of formula V is then reacted with
alkylating agent, wherein the alkylating agent is selected from the group comprising of!butyl
haloacetate, wherein the halo is selected from the group comprising of chloro,
bromo and iodo. The alkylation reaction is carried out at temperature between 50-70 ·c
in about I6-20 hours to result in 6,9,I2-tris[2-(1,1-dimethylethoxy)-2-oxoethyl]-2,2-
dimethyl-5-[ (phenylmethoxy)methyl]-4-oxo-3-oxa-6,9, 12-triazatetradecan-14-oic acid
I, I-dimethylethyl ester of formula VI.
According to the present invention, the 6,9,I2-tris[2-(l,I-dimethylethoxy)-2-oxoethyl]-
2,2-dimethyl-5-[ (phenylmethoxy)methyl]-4-oxo-3-oxa-6,9, I2-triazatetradecan-14-oic
acid 1,1-dimethylethyl ester of formula VT obtained in step (d) is hydrolyzed to BOPTA
salt using a hydrolyzing agent in solvent, wherein the hydrolyzing agent is selected from
the group comprising of acidic or basic hydrolyzing agent. Acidic hydrolyzing agent is
selected from the group comprising of trifluoroacetic acid or sulfuric acid,
IP 0.: DELHI. 20- 01- 2~8 16 17 :. Oll
iodine/acetonitrile, TMSX (X=Cl, Br, 1), or hydrogen chloride (g) or hydrochloric acid,
hydrobromic acid, hydroiodic acid, phosphoric acid, silica and the like. Basic
hydrolyzing agent is selected from the group comprising of alkali or alkaline earth metal
hydroxide, carbonate etc. The solvent used is selected from the group comprising of
nitriles such as acetonitrile, propionitrile and the like; esters such as ethyl acetate,
isopropyl acetate, methyl acetate and the like; ethers such as tetrahydrofuran, methyl
tetrahydrofuran, dioxane, t-butyl methyl ether and the like; halogenated hydrocarbons
such as methylene chloride, ethylene dichloride and the like; aromatic hydrocarbons such
as toluene, xylene and the like, alcohols such as ethanol, methanol and the like, ketones
such as acetone, methyl isobutyl ketone and the like, water and mixtures thereof.. The
hydrolysis reaction is carried out 30°C to reflux temperature in about 3-16 hours.
According to the present invention, when silica is used as a hydrolyzing agent in step (e),
it results in the formation ofBOPTA, which is further used in step (f).
According to the present invention, the BOPTA or BOPTA salt as obtained in step (e) is·
optionally treated with a solvent, wherein the solvent is selected from the group
comprising of alcohols such as methanol, ethanol, isopropanol and the like; ketones such
as acetone, propanone and the like; nitriles such as acetonitrile, propionitrile and the like;
water and mixtures thereof.
According to the present invention, the pure BOPTA is isolated in step (f) by processes
such as crystallization, wherein the crystallization is done in water, optionally in presence
of base, or by eluting through weakly basic anion exchange resin such as Indion 860. The
base used is selected from the group comprising of sodium hydroxide, potassium
hydroxide, ammonium hydroxide and the like. The purification ofBOPTA is carried out
at temperature between 30-50°C. The inventors of present invention very successfully
achieved the most feasible conditions for carrying out the purification at optimum pH,
wherein BOPT A is isolated in highly pure form and that too in the shortest time wherein
reaction conditions as reported in prior art takes more than 5 days to achieve the
precipitation of BOPTA from the aqueous medium, which not only provides BOPTA
having pharmaceutical grade purity but also reduces the cycle-time of the process,
making the process highly advantageous for industrial application.
According to the present invention, the BOPTA obtained has purity not less than 99.9%.
LPO DELHI 2G-Ol-2Bl6 17:8~
According to the present invention, the BOPTA obtained is substantially free from any
one or more of 2,2'-((2-(3-((benzyloxy)methyl)-4-(carboxymethyl)-2-oxopiperazin-1-
yl)ethyl)azanediyl)diacetic acid impurity, dimer impurity, trimer impurity or quaternary
salt ofBOPTA and metal impurities preferable iron and sodium.
2,2' -( (2-(3 -( (benzyloxy )methy I )-4-( carboxymethyl )-2-oxopiperazin-1-
yl)ethyl)azanediyl)diacetic acid
0~ 0~
,~~·~.~·~0'"
0 OH y 0 OH
OH
Dimer Impurity ofBOPTA
Trimer Impurity of BOPT A
------------------------
Quaternary Salt ofBOPTA
have the characterization data as
The isolated impurity of 2,2'-((2-(3-((benzyloxy)methyl)-4-( carboxymethyl)-2-
oxopiperazin-1-yl)ethyl)azanediyl)diacetic acid is corroborating to m/z = 437.87, M-1
(436.04) in mass spectral analysis and is further characterized by 1H NMR (8 in ppm,
DMSOd6, 400 MHz): 3.359-3.638(m, N-CH2,6H), 3.782-3.815(m,CH,IH), 4.082-3.993
(m, CH2, 8H), 4.22-4.272 (m, CH2, 2H), 4.494-4.557 (m, CH2 , 2H), 7.302-7.356 (m, CH,
5H)
The isolated dimer impurity of BOPTA is corroborating to m/z: M+ 1 =634.07; M-1 =
632.15 in mass spectral analysis and is further characterized by 1 H NMR (8 in ppm,
CDCb, 400 MHz): 3.112-3.181(m, N-CH2, 4H), 3.347-3.561 (m, N-CH2,6H),3.561-
3.787(m, CH2, 8H), 4.428-4.563 (m, -O-CH2+CH, 4H+2H),7.278-7.351 (m, CH, IOH).
The isolated trimer impurity ofBOPTA is corroborating to m/z: M+1=1034.19; M+23=
1 056.17 in mass spectral analysis and is further characterized by 1 H NMR (8 in ppm,
CDCb, 400 MHz): 1.413-1.453 (m, CH3, 45H), 2.702-2.822 (m, N-CH2, 8H), 3.342-
3.397 (m, CH, 2H), 3.564 -3.679 (m, CH2, 6H) 3.714 -3.748 (m, -CH2,CH, 3H+2H),
4.483-4.497 (m, -O-CH2, 2H+4H), 7.241-7.339 (m, CH, ISH).
The isolated quaternary impurity of BOPTA is corroborating to rn/z: 571.95 in mass
spectral analysis and is further characterized 1H NMR (8 in ppm, CDCb, 400 MHz):
3.763-3.801 (m,-CH2,+CH,6H+ 1H),3.903(s,-CH2,2H),4.039(s,-CH2,,8H), 4.272 (s,CH2,
4H), 4.462(m,-CH2,,2H),7.291-7.357(m,Ar,5H).
IPO DELHI 2Q-91-2BIS 17:0~
-------------
The process of present invention has following advantages over prior art processes:
(a) The process avoids the use of synthesis and isolation of potassium 3-benzyloxy-2-
chloropropanote, wherein the prior art preparation involves the use of methyl
acrylate which is known toxic reagent.
(b) The process avoids the use of potassium 3-benzyloxy-2-chloropropanote or
methyl or ethyl ester of 3-benzyluxy-2-chloropropanoic acid wherein the prior art
involves formation of significant amount of ketopiperazine impurity which
requires a separate step to remove the said impurity.
(c) The process is environment friendly in terms of devoid of use of hazardous
reagents like trifluoroacetic acid.
(d) The alkylation reaction involving use oft-butyl acetate avoids the formation of
inorganic waste like sodium chloride and further esterification reaction is devoid
of use of reagents like DCC (as used in prior art) that leads to the formation of
genotoxic and carcinogen agents like DCU during the reaction.
(e) The careful selection of reagents and reaction conditions has resulted in control of
formation of impurities at various stages, thereby reducing the requirement of
purification steps.
(f) The process reduces the generation of toxic waste, thereby making the process
environment friendly.
EXAMPLES
Example 1: Preparation of "3-benzyloxy-2-bromo propanoic acid cyclohexyl amine
salt
To a suspension of 0-benzyl serine (25 g) in water (125 mL), added 48% aqueous
hydrobromic acid (48.60g) and stirred to obtain a clear solution. The reaction mixture
was then cooled to 0-5°C and added potassium bromide (53.39g). To resulting mixture,
added sodium nitrite (13.26g) portion-wise keeping temperature below 5°C and stirred
the reaction mixture for 30 min. To the reaction mixture was then added diisopropyl ether
(150 mL) and stirred for 30 min. The layers were separated arid aqueous layer was
extracted with diisopropyl ether (150 mL). The combined organic layers were washed
with water (50 mL) and concentrated to obtain an oily mass which was.dissolved in ethyl
IP·O DELHI.. 2:0-01- 2016 17 :Of~
;.,
--~----~----------------------~
acetate (216 mL). To the resulting solution of ethyl acetate slowly added a solution of
cyclohexylamine (1 0.33g) in ethyl acetate (54 mL) at 1 0-15°C. The reaction mass was
stirred at 75-80°C for 30 min and at 25-30°C for 3h. The precipitated solid was filtered,
washed with ethyl acetate (54 mL) and dried under vacuum to afford the title compound
as off-white solid.
Weight: 29g
Yield: 58.52%
Example 2: Preparation of t-butyl3-benzyluxy-2-bromo propanoatc
The biphasic mixture of aqueous solution of cyclohexanamine salt of 3-(benzyloxy)-2-
bromopropanoic acid (29.0g) and ethyl acetate (145 mL) was acidified to pH ~1-2 with
20% aq potassium bisulfate solution at 1 0-15°C and stirred at 25-30°C for 30 min. After
separating the organic layer the aqueous layer was extracted with ethyl acetate (145 mL).
The combined organic layers were washed with water (48 mL) and concentrated under
reduced pressure to afford free bromo acid (22.5g). The obtained oily mass in t-butanol
(158 mL) was warmed to 55-60°C and added dimethylamino pyridine (2.33 g) followed
by a solution of BOC anhydride (34g) in t-butanol (68 mL) at 55-60°C. The mixture was
stirred for 30 min. On completion of reaction, the reaction mass was cooled to 25-30°C,
decomposed with 50% aqueous potassium bisulphate solution and then concentrated
under reduced pressure. The residue thus obtained was dissolved in a mixture oft-butyl
methyl ether (170 mL) and water (35 mL) and stirred for 30 min. The organic layer was
washed with water and concentrated under vacuum to obtain the title compound as an
oily mass.
Weight: 24.27g
Yield: 95.21%
Example 3: Preparation of N-[2-[(2-Aminoethyl)amino]ethyl-0-(phenylmethyl)
serine 1,1-Dimethylethyl Ester
To a mixture of diethylenetriamine (29.24 g) and potassium iodide (0.94 g) in acetonitrile
(356 mL), added a solution of t-butyl 3-(benzyloxy)-2-bromopropanoate (17.8 g) in
acetonitrile (178 mL) slowly at 25-30°C and stirred for about 16-18h. The reaction mass
was concentrated under vacuum to obtain an oily residue which was dissolved in t-butyl
-IPQ DELHr 20-01-2016 11:0~7
methyl ether (180 mL). The resulting solution was washed with water (35 mL) and brine.
The organic layer was filtered through hyflo-bed and distilled out under vacuum to obtain
an oily mass which was dissolved in ethanol (240 mL). To the resulting solution, added
fumaric acid (5.50g) and stirred at 45-50°C for 1h and then at 25-30°C for 4h. The solid
was filtered, washed with ethanol (15 mL) and dried under vacuum to afford the title
compound as off-white solid.
Weight: 14.0g
Yield: 54.69%
Example 4: Preparation of 6,9,12-tris[2-(1,1-dimethylethoxy)-2-oxoethyl]-2,2-
dimethyl-5-[ (phenylmethoxy )methyl]-4-oxo-3-oxa -6,9 ,12-triaza tetradecan -14-oic
Acid 1,1-dimethylethyl ester (t-butyl penta ester)
To a cooled solution of fumaric acid salt of N-[2-[(2-aminoethyl)amino ]ethyl]-0-benzyl
serine t-butyl ester (lOg) in water (30 mL), added potassium carbonate (20.6g). The
temperature of reaction mixture was raised to 25-30°C and then t-butyl bromocetate
(19.43g) was added and stirred at 60-65°C for 16-18h. The reaction mixture was then
cooled to 25-30°C, organic layer was separated, washed with water and concentrated to
dryness under vacuum to afford the title compound as an oily mass.
Weight: 17.0g
Yield: 97.14%
Example 5: Preparation of 4-Carboxy-5,8,11-tris(carboxymethyl)-1-phenyl-2-oxa-
5,8,11-triazatridecan-13-oic Acid (BOPTA)
Method A: Preparation of 4-carboxy-5,8,11-tris( carboxymethyl)-1-phenyl-2-oxa-
5,8,11-triazatridecan-13-oic acid (BOPTA) using silica: To a solution of !-butyl penta
ester (5.0g) in toluene (50g) was added silica (5.67g) and stirred under reflux at 110-
l200C for 16h. The reaction mass wasthen cooled to room temperature and filtered. The
solid so obtained was suspended in water (1 0 mL), stirred for 1 h and filtered. The filtrate
obtained was concentrated to obtain title compound as an oily mass (2.7 g).
Yield: 83.47%
LPQ DELHT 26-81-~016 -1· 7 . 8'·218 ~ ... . .
Method B: Preparation of 4-carboxy-5,8,11-tris( carboxymethyl)-1-phenyl-2-oxa-
5,8,11-triazatridecan-13-oic acid (BOPTA) via preparation of BOPTA
hydrochloride salt:
STEP I: Preparation of of 4-carboxy-5,8,11-tris( carboxymethyl)-1-phenyl-2-oxa-
5,8,11-triazatridecan-13-oic acid hydrochloride salt (BOPTA hydrochloride):
Process (I) A: A solution oft-butyl penta ester (4.8g) in dioxane (1 0 rnL) taken in aRB
flask fitted with a condenser and thermometer pocket,olved in I ,4-dioxane (I 0 mL) was
cooled to 0-5°C. 4M dioxane-HCI (13.4 mL) solution was added dropwise in 30 min. The
reaction mixture slowly warmed to 25-30°C and stirred for 14h. Solvent was evaporated
off completely under vacuum at 40-45°C to obtain a solid residue which was suspended
in ethyl acetate (15 mL) and filtered to obtain crude BOPTA hydrochloride.
Weight: 2.lg
Yield: 67.63%
Process (I) B: To a solution of t-butyl penta ester (3.5g) in acetonitrile (35 mL) was
added Cone. HCI ( 4.6g) and stirred at 75-80°C for 3h. The reaction mass was
concentrated under vacuum at 50-60°C. The residue obtained was suspended in acetone
(20 mL) and stirred for lh. The solid was filtered and dried under vacuum at 25-30°C to
afford BOPT A hydrochloride.
Weight: 1.9g
Yield: 83.92%
STEP II: Purification of BOPTA hydrochloride:
To the suspension of crude BOPTA hydrochloride (5.0 g) in acetone (1 00 mL) was added
water (2.5 mL) at 55-60°C to get a clear solution. The resulting solution was stirred at 55-
600C for next 30 min and at 25-30°C for 3h. The precipitated solid was filtered and dried
under vacuum at 30-35°C for 12h to obtain pure BOPTA hydrochloride.
Weight: 3 .4g
Yield: 68%
STEP III: Neutralization ofBOPTA hydrochloride to BOPTA:
I.PO DELHI 20-01- 2JJ1.6 17 : Ot:9
------------ -------- ----------------------------------,
Process (Ill) A: A solution of BOPTA hydrochloride (2.0g) in purified water (20 mL)
was eluted from column packed with weakly basic anion exchange resin such as INDION
860. The fractions were monitored for the chloride content. The entire fraction was spray
dried to obtain BOPTA (1.3 g) as white solid with chloride content less than 100 ppm.
HPLC Purity: NLT 99.5%.
Yield: 74.29%
Process (III) B: A solution of BOPTA hydrochloride C2:0g) in purified water (20 mL)
was eluted from column packed with weakly basic anion exchange resin such as INDION
860. The fractions were monitored for the chloride content. The entire fraction was
azeotrope distilled with acetonitrile (I20.0 mL) to afford BOPTA (1.3g) as white solid
with chloride content less than I 00 ppm
HPLC Purity: NLT 99.5%
Yield: 74.29%
Process (III) C: A solution of BOPTA hydrochloride (6.0g) in purified water (60 mL)
was eluted from column packed with strongly basic anion exchange resin such as
Amberlyst A26 (OH). The fractions were monitored for the chloride content. The entire
fraction was azeotrope distilled with acetonitrile (120.0 mL) to afford BOPTA (4.6g) as
white solid with chloride content less than I 00 ppm.
HPLC Purity: NLT 99.5%
Yield: 87.62%
Process (Ill) D: : A solution of BOPTA hydr~chloride (6.0g) in purified water (60 mL)
was eluted from column packed with strongly basic anion exchange resin such as
Amberlyst A26 (OH). The fractions were monitored for the chloride content. The entire
fraction was azeotrope distilled with acetonitrile (120.0 mL) to afford BOPTA (4.6g) as
white solid with chloride content less than IOO ppm.
HPLC Purity: NLT 99.5%
Yield: 87.62%
I~O DELHI 20-01-2816 17:8~
Process {III) E: A solution of BOPTA hydrochloride salt {7.0 g) in water (7 ml) was
heated to 40-45 deg C for about 20 min and cooled the reaction mass to about 25-30 deg
C. The pH of reaction mass was adjusted to about 2-2.6 using 40% aqueous sodium
hydroxide solution and stirred the reaction mass for about 20 min. The pH of reaction
mass is again adjusted to 1.7-1.9 with 6N hydrochloric acid solution. To the resulting
solution, added acetone (1.2 ml) and raised the temperature of reaction mass to 45-50 OC
to obtain a clear solution and cooled it to 20-25 OC. The reaction mass is then seeded with
crystals ofBOPTA (50 mg) and stirred for about 12-14 hour. The solid so obtained was
filtered and dried under vacuum to obtain BOPTA.
Yield: 84%
HPLC purity: 99.9%
Process (III) F: A solution of BOPT A hydrochloride salt (2.0g) in purified water (14
mL) was heated to 50-55°C for 30 min: and clear solution was gradually cooled to 25- ,
30°C in 2-3h. The solution was further cooled to 1 0-15°C and stirred for 2-3h. The
precipitated solid was filtered and dried at 45-50°C. The solid was repeatedly crystallized
in purified water till chloride content is less than 100 ppm or satisfies the purity
specification required as BOPT A.
Yield: 56.8%
HPLC Purity: 99.5%
Process (Ill) G: To a suspension of BOPTA hydrochloride (5.0g) in purified water (5.0
mL) was added 40% aq. NaOH solution to adjust its pH to 10-11 at 20-25°C. The
resulting clear solution was stirred for 20-30 min at the same temperature and then
acidified to pH 1.7-1.9 with 6N HCI. The solution after diluting with acetone (2 mL) was
warmed to 50-55°C, then cooled to 25-30°C and stirred for 10-12h. The suspended
solution further diluting with 10% solution of acetone in water (20 mL) was reheated to
50-55°C, cooled to 20-25°C was stirred for 12-14h, the precipitated solid was filtered and
dried to obtain BOPT A.
HPLC Purity: 99.7%
Yield: 72.72%
IPO DELHL 20-01-2916 17:0~
Method C: Preparation of 4-carboxy-5,8,11-tris(carboxymethyl)-1-phenyl-2-oxa-
5,8,11-triazatridecan-13-oic acid (BOPTA) via preparation of BOPTA phosphate
salt:
STEP 1: Preparation of of 4-carboxy-5,8,11-tris(carboxyrnethyl)-1-phenyl-2-oxa-
5,8,11-triazatridecan-13-oic acid phosphate salt (BOPTA phosphate):
A suspension oft-butyl penta ester (1g) phosphoric acid (1.45g) in acetonitrile (10 mL)
was stirred at 75-80°C for 12h then cooled to 25-30°C and stirred for 2h. The separated
solid was filtered and dried under vacuum at room temperature for 12h to afford crude
BOPTA phosphate.
Weight: 0.30g
Yield: 46.37%
STEP II: Purification of BOPTA phosphate:
To the suspension of crude BOPTA phosphate (5.0 g) in acetone (100 mL) was added
water (2.5 mL) ·at 55-60°C to get a clear solution. The resulting solution was stirred at 55-
600C for next 30 min and at 25-30°C for 3h. The precipitated solid was filtered and dried
under vacuum at 30-35°C for 12h to obtain pure BOPT A phosphate.
Weight: 3.4g
Yield: 68%
STEP III: Neutralization ofBOPTA phosphate to BOPTA:
A solution of BOPTA phosphate salt (7 .0 g) in water (7 ml) was heated to 40-45 deg C
for about 20 min and cooled the reaction mass to about 25-30 deg C. The pH of reaction
mass was adjusted to about 2-2.6 using 40% aqueous sodium hydroxide solution and
stirred the reaction mass for about 20 min. The pH of reaction mass is again adjusted to
1.7-1.9 with 6N HCl solution. To the resulting solution, added acetone (1.2 ml) and
raised the temperature of reaction mass to 45-50 ·c to obtain a clear solution and cooled
it to 20-25 ·c. The reaction mass is then seeded with crystals of BOPTA (50 mg) and
stirred for about 12-14 hour. The solid so obtained was filtered and dried under vacuum
to obtain BOPT A.
Yield: 78%
HPLC purity: 99.5%

Claims:
1. A process for the preparation of 4-carboxy-5,8, 11-tri( carboxymethyl)-1-phenyl-2-
oxa-5,8, 11-triazatridecan-1-oic acid (BOPT A), comprising the steps of:
(a) brominating 0-benzyl serine of Formula II by diazotization to obtain 3-benyloxy-
2-bromo propanoic acid of formula III;
0
Bno__..-y~oH
NH2
Formula II Formula III
(b) reacting 3-benyloxy-2-bromo propanoic acid of formula III with an amme m
solvent to obtain amine salt of formula IliA;
0
BnOYOH .amine salt
Br
Formula IliA
(c) converting amine salt of formula IliA to 3-benyloxy-2-bromo propanoic acid of
formula III;
(d) esterifying 3-benzyloxy-2-bromo propanoic acid of formula III to t-butyl-3-
benzyloxy-2-bromo propanoate of formula IV
0
BnOYOBu1
Br
Formula IV
(e) reacting t-butyl-3-benzyloxy-2-bromo propanoate of formula IV with
diethylenetriamine in presence of a catalyst and solvent to obtain N-[2-[(2-
aminoethyl)amino ]ethyl-0-(phenylmethyl) serine 1, 1-dimethylethyl ester of
formula V;
.H 2N '-.../. ...... ' N .,~~ NH2
H
Diethylenetriamine
0
BnOYOBu'
HN-....../'-N~NH2
H
Formula V
I.PO DELHI.. 2.0-01-2:816 17" :Qi~
..
--- ----------
(f) alkylating N-[2-[(2-aminoethyl)amino ]ethyl-0-(phenylmethyl) serine I, 1-
dimethylethyl ester of formula V with halo-t-butylacetate in solvent in presence of
base to obtain 6,9, 12-tris[2-(1, 1-dimethylethoxy)-2-oxoethyl]-2,2-dimethyl-5-
[(phenylmethoxy)methyl]-4-oxo-3-oxa-6,9, 12-triazatetradecan-14-oic acid 1,1-
dimethylethyl ester of formula VI;
Formula VI
(g) hydrolysis of 6,9, 12-tris[2-(l, 1-dimethylethoxy)-2-oxoethyl]-2,2-dimethyl-5-
[(phenylmethoxy)methyl]-4-oxo-3-oxa-6,9, 12-triazatetradecan-14-oic acid 1,1-
dimethylethyl ester of formula VI using a hydrolyzing agent in solvent to obtain
4-carboxy-5,8, 11-tris( carboxymethyl)-1-phenyl-2-oxa-5,8, 11-triazatridecan-13- .
oic acid (BOPTA) salt of formula VII, optionally, treating BOPTA salt with a
solvent
.X
Formula VII
wherein X is hydrochloride, hydroiodide, hydrobromide, sulphate, trifluroacetate
or phosphate and
(h) isolating pure BOPTA from BOPTA salt.
2. The process according to claim 1, wherein the amine used in step (b) is selected
from the group comprising of cyclohexylamine, benzylamine, phenethyl amine,
dicyclohexyl amine, glucosamine, diethanolamine and methoxyethylamine.
3. The process according to claim 1, wherein the solvent used in step (b) is selected
from the group compnsmg of alcohols selected from methanol, ethanol,
I:P:o DEL.H·T 2.0- Ocl.- 2:016 1 7 : 02.3
..
--------------------
·isopropanol; esters selected from ethyl acetate, propyl acetate; nitrites selected
from acetonitrile, propionitrile; water and mixtures thereof.
4. The process according to claim 1, wherein the catalyst used in step (e) is selected
from the group comprising of potassium iodide and sodium iodide.
5. The process according to claim 1, wherein the base used in step (f) is selected
from the group comprising of organic selected from triethylamine, diisopropyl
ethyl amine and inorgani~,; selected from alkali or alkaline earth metal carbonates,
bicarbonates, hydroxides and ammonia.
6. The process according to claim 1, wherein the halo group oft-butyl haloacetate
used in step (f) is selected from the group comprising of chloro, bromo and iodo.
7. The process according to claim 1, wherein the solvent used in step (f) is selected
from the group comprising of ketones selected from acetone, ethyl methyl ketone;
nitrites selected from acetonitrile, propionitrile; water and mixtures thereof.
8. The process according to claim 1, wherein the hydrolyzing agent used in step (g)
is selected from the group comprising of hydrochloric acid, hydrobromic acid,
hydroiodic acid, phosphoric acid, silica and the like.
9. The process according to claim I, wherein the solvent used in steps (c) and (g) is
selected from the group comprising of esters selected from ethyl acetate, propyl
acetate; ethers . selected from tetrahydrofuran, dioxane, t-butyl methyl ether;
halogenated hydrocarbons selected from methylene chloride, ethylene dichloride;
aromatic hydrocarbons selected from toluene, xylene; water and mixtures thereof.
10. BOPTA substantially free from any one or more of 2,2'-((2-(3-
((benzyloxy)methyl)-4-( carboxymethyl)-2-oxopiperazin-1-
yl)ethyl)azanediyl)diacetic acid impurity, dimer impurity, trimer impurity or
quaternary salt of BOPT A impurity having the formulae:
I.FQ DELHI 20-01-201& 1.7:o~5
2,2'-((2-(3-((benzyloxy)methyl)-4-(carboxymethyl)-2-oxopiperazin-1-
yl)ethyl)azanediyl)diacetic acid
0~ 0~
BnO~N~N~N~OBn
_l__ L /.0 /.~
o'l' 'oH ~ o~ 'oH
OH
Dimer Impurity ofBOPTA
0 0-•-B, 1 /"-_ /'----- t-Bu-0....- ~ "o 1'h
Ph'-./0 N~N~NrO
y~-B' On ~·-B'
0 0-t-Bu 0'-......._/ Ph
Trimer Impurity ofBOPTA
,o~c G
O OH . ~
HO
0 .
0
Quaternary Salt ofBOPTA