Improved synthesis of 10-(2-alkylamino-2-oxoethyl)-1,4,7,10- tetraazacyclododecane-1,4,7-triacetic acid derivatives bearing acid-sensitive linkers

Article abstract of DOI:10.1080/00397911.2013.813547

Alkylation of the hydrobromide salts of 1,4,7-tris(methoxycarbonylmethyl)- 1,4,7,10-tetraazacyclododecane and 1,4,7-tris(ethoxycarbonylmethyl)-1,4,7,10- tetraazacyclododecane with appropriate α-bromoacetamides, followed by hydrolysis, provides convenient

Full text of DOI:10.1080/00397911.2013.813547

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Improved Synthesis of 10-(2-
Alkylamino-2-oxoethyl)-1,4,7,10-
tetraazacyclododecane-1,4,7-triacetic
Acid Derivatives Bearing Acid-Sensitive
Linkers
Bhumasamudram Jagadish a , Tarik J. Ozumerzifon a , Sue A. Roberts
a , Gabriel B. Hall a , Eugene A. Mash a & Natarajan Raghunand b c
a Department of Chemistry and Biochemistry , University of
Arizona , Tucson , Arizona , USA
b Department of Medical Imaging , University of Arizona , Tucson ,
Arizona , USA
c Arizona Cancer Center , University of Arizona , Tucson , Arizona ,
USA
Published online: 20 Nov 2013.
To cite this article: Bhumasamudram Jagadish , Tarik J. Ozumerzifon , Sue A. Roberts , Gabriel B.
Hall , Eugene A. Mash & Natarajan Raghunand (2014) Improved Synthesis of 10-(2-Alkylamino-2-
oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic Acid Derivatives Bearing Acid-Sensitive
Linkers, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 44:3, 441-449, DOI: 10.1080/00397911.2013.813547
To link to this article: http://dx.doi.org/10.1080/00397911.2013.813547
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Synthetic Communications1, 44: 441–449, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.813547
IMPROVED SYNTHESIS OF 10-(2-ALKYLAMINO-
2-OXOETHYL)-1,4,7,10-TETRAAZACYCLODODECANE-
1,4,7-TRIACETIC ACID DERIVATIVES BEARING
ACID-SENSITIVE LINKERS
Bhumasamudram Jagadish,1 Tarik J. Ozumerzifon,1
Sue A. Roberts,1 Gabriel B. Hall,1 Eugene A. Mash,1 and
Natarajan Raghunand2,3
1Department of Chemistry and Biochemistry, University of Arizona,
Tucson, Arizona, USA
2Department of Medical Imaging, University of Arizona, Tucson,
Arizona, USA
3Arizona Cancer Center, University of Arizona, Tucson, Arizona, USA
GRAPHICAL ABSTRACT
Abstract Alkylation of the hydrobromide salts of 1,4,7-tris(methoxycarbonylmethyl)-
1,4,7,10-tetraazacyclododecane and 1,4,7-tris(ethoxycarbonylmethyl)-1,4,7,10-tetraaza
cyclododecane with appropriate a-bromoacetamides, followed by hydrolysis, provides
convenient access to 10-(2-alkylamino-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-
triacetic acid derivatives that contain acid-sensitive functional groups. The utility of the
method is demonstrated by improved syntheses of two known 1,4,7,10-tetraaza
cyclododecane-1,4,7,10-tetraacetic acid monoamides bearing acid-sensitive x-tritylthio
alkyl chains in much greater yields based on cyclen as the starting material.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords Cyclen; DO3A monoamide; DOTA monoamide; medical imaging; synthesis
Received May 3, 2013.
Address correspondence to Bhumasamudram Jagadish, Department of Chemistry and
Biochemistry, University of Arizona, P.O. Box 210041, Tucson, AZ 85721-0041, USA. E-mail:
bjagadis@email.arizona.edu
441

442
B. JAGADISH ET AL.
INTRODUCTION
1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA, 1) forms
stable complexes with lanthanides and radio metals.[1,2] As a result, DOTA-derived
metal complexes are utilized as contrast agents in magnetic resonance imaging
(MRI),[3–5] in radiopharmaceuticals, and radionuclide imaging.[6–8] In recent years,
efforts to deliver bio molecules, such as proteins,[9,10] peptides,[11] and monoclonal
antibodies,[12,13] labeled with metal ions or radioactive metal ions to specific cellular
targets for imaging and therapy have gained importance. A common approach to
linking the metal ion to a biomolecule is by means of a modified DOTA chelate that
has been rendered bifunctional.[14] Many bifunctional derivatives of DOTA have
been obtained by conversion of one of the pendant acid groups into an N-substituted
acetamido derivative.1 The chelate strongly coordinates with the chosen metal ion,
while a functional group incorporated in the nitrogen substituent of the acetamido
group conjugates with the biomolecule. Several precursors to DOTA monoamides
have been described,[15–17] and some are commercially available. However, very little
has been published relating to the synthesis of DOTA monoamides bearing
acid-labile functional groups in the linker.
Previously we reported the synthesis of the gadolinium(III) DOTA monoamide
complex 2 bearing a hexyl side chain that terminated with a thiol group.[18] The
complex 2 was bound to human serum albumin (HSA) in a redox-sensitive manner.
More recently, we demonstrated the utility of 2 as a magnetic resonance imaging
biomarker of redox-active drugs in tumor-bearing mice.[19] We also synthesized
Gd-DOTA monoamide complex 3 bearing an x-thioheptyl side chain that showed
higher binding affinity for HSA as compared to 2.[21] DOTA monoamides 4 and
5, intermediates in the published syntheses[18,20] of complexes 2 and 3, respectively,
were prepared by monoactivation of 1 with isobutyl chloroformate, followed by
reaction with 6-tritylthiohexylamine and 7-tritylthioheptylamine, respectively,
in good yields based on the amine starting materials. However, based on DOTA,
the yields of 4 and 5 were 27% and 23%, respectively.[21] Assuming a yield of 82%
in the conversion of cyclen to DOTA,[22] the yields of 4 and 5 based on cyclen
were 22% and 19%, respectively. Existing procedures for the synthesis of DOTA
monoamides that employ an excess of DOTA to avoid mixtures of products are
not optimal, given the high cost of DOTA.[23] Other shortcomings of some
published methods are the use of high dilution conditions and long reaction times.
These issues limit large-scale preparations of DOTA monoamides. We describe
in this article an efficient and scalable synthesis that is amenable to preparations
of a series of DOTA monoamides, including compounds with acid-labile function-
ality in the linker, such as 4 and 5.
1
There is some ambiguity in the literature as to whether compounds such as 4 and 5 should be
termed ‘‘DOTA monoamides’’ or ‘‘DO3A monoamides.’’ CAS names such compounds as
10-(2-alkylamino-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid derivatives, which is
inconsistent with both of these common usages. We employ ‘‘DOTA monoamide’’ in this article
because this usage is consistent with use of the term ‘‘DOTA tetraamide’’ to indicate that all four
acetate arms of the DOTA are present as amides.

SYNTHESIS OF DOTA DERIVATIVES
443
RESULTS AND DISCUSSION
Of the methods reported for the preparation of DOTA monoamides,[24] two
are well suited for large-scale synthesis. The first involves monoalkylation of
1,4,7,10-tetraazacyclododecane (cyclen, 9) with an a-bromoacetamide, followed by
incorporation of three acetate ester arms (methyl, ethyl, or tert-butyl) and their
subsequent hydrolysis or cleavage to afford the DOTA monoamide. The second
method involves the preparation of a DO3A tris-ester, such as the hydrobromides
6–8, followed by neutralization, alkylation with an a-bromoacetamide, and sub-
sequent hydrolysis or cleavage to afford the DOTA monoamide. In either method,
one can choose methyl, ethyl, or tert-butyl ester groups, depending on the acid or
base sensitivity of moieties on the acetamide arm. In the first method, an excess of
cyclen is generally used to promote monoalkylation. This method can work well
for the synthesis of a single DOTA monoamide, but for the synthesis of a series
of DOTA monoamides, will involve the preparation and characterization of many
more intermediates than will the second method. Barge et al.,[25] prepared a set of
DOTA monoamide derivatives from 6 by the second method. For our work, the
necessary acidolysis of the t-butyl ester moieties undermines the application of this
synthetic method. However, the use of 7 or 8 in place of 6 would substitute base
hydrolysis for acidolysis and permit preparations of DOTA monoamides such as
4 and 5 possessing acid-labile functionality in the linker, possibly on large scales.
While commercially available 6 has been used in the synthesis of many bifunc-
tional chelates,[26,27] the related methyl and ethyl esters 7
[28–31]
and 8[32–37] have
found limited use. Few methods for the synthesis of 7 and 8 have been published.
Ester 7 was obtained as a free base in 54% yield by alkylation of 9 with 4 equivalents
of methyl bromoacetate in refluxing methanol in the presence of triethylamine,
followed by preparative thin-layer chromatography (TLC) purification.[28]
Alternatively, 7 was obtained as a triflate salt by alkylation of N-formylcyclen[36]

444
B. JAGADISH ET AL.
with 3.3 equivalents of methyl bromoacetate, followed by removal of the formyl
group.[29] Ester 8 was reportedly isolated in 72% yield after reaction of cyclen with
2.24 equivalents of ethyl bromoacetate in dichloromethane without an additional
base.[37] More recently, Natrajan et al.,[38] prepared 8 in 63% yield as a hydrobromide
salt by reaction of cyclen with 3.3 equivalents of ethyl bromoacetate in acetonitrile in
the presence of sodium bicarbonate.
We described a synthesis of 6 as a hydrobromide salt in 79% yield by reaction
of 9 with 3.3 equivalents of t-butyl bromoacetate and sodium acetate in dimethyla-
cetamide at ꢀ20 ꢁC.[39] The workup procedure involved adding the reaction mixture
to water and isolating the hydrobromide salt by addition of potassium bicarbonate.
Following this procedure, 9 was allowed to react with 3 equivalents of methyl bro-
moacetate and sodium acetate in dimethylacetamide at ꢀ20 ꢁC. However, the hydro-
bromide salt 7 could not be isolated from the aqueous solution upon addition of
potassium bicarbonate, presumably because of its greater solubility in water. To
avoid a water workup, dimethylformamide (DMF) was used as solvent instead of
dimethylacetamide.
In a typical procedure, 3 equivalents of methyl bromoacetate in DMF were
added to a stirred suspension of one equivalent of 9 and 3.3 equivalents of sodium
acetate in DMF at ꢀ20 ꢁC (Scheme 1). After stirring for 6 h at room temperature,
the reaction mixture was diluted with dichloromethane (DCM) and the salts
removed by filtration. The filtrate was evaporated under reduced pressure and the
crude oil was purified on a flash silica-gel column eluted with DCM and DCM 5%
methanol. The hydrobromide salt 7 was obtained as a tan-colored oil, which solidi-
fied to a white solid upon scratching in the presence of ether at ꢀ20 ꢁC. The yield of 7
was 78%.
Recrystallization of 7 from toluene produced a shiny amorphous solid. How-
ever, slow evaporation of a toluene solution produced crystals that were suitable
for x-ray crystallographic analysis. The hydrobromide salt 7 crystallized in space
group P21=c with one molecule in the asymmetric unit and four molecules in the unit
cell (Fig. 1).
Following a similar protocol, the hydrobromide salt 8 was synthesized in 77%
yield by reaction of 9 with 3 equivalents of ethyl bromoacetate. With 7 and 8 in hand,
we set about preparing 4 and 5 by an alternate synthetic route as described below.
[18]
Treatment of 10
and 11[20] with bromoacetyl bromide in DCM in the pres-
ence of 1 N NaOH gave 12 and 13 in 92% and 94% yields, respectively (Scheme 2).[34]
While it was previously reported that alkylations of the hydrobromide salt of 6 gave
Scheme 1. Synthesis of 7 and 8.

SYNTHESIS OF DOTA DERIVATIVES
445
Figure 1. The structure of hydrobromide salt 7. A hydrogen bond interaction is present between N4-H and
˚
Br with a donor-acceptor distance of 3.277(4) A. Displacement ellipsoids are at the 50% probability level.
(Figure is provided in color online.)
Scheme 2. Synthesis of DOTA monoamides 4 and 5.

446
B. JAGADISH ET AL.
poor yields, even in the presence of K2CO3,[25] we found that treatment of the
hydrobromide salt 7 with K2CO3 in acetonitrile for 1 h at 70 ꢁC prior to the addition
of bromoacetamide 12, followed by reaction at this temperature for 1 h produced
14 in 84% yield (Scheme 2). Reactions of 7 with 13, 8 with 12, and 8 with 13 under
similar conditions gave 15, 16, and 17 in excellent yields. Finally, hydrolysis of esters
14 and 16 in refluxing 1 N ethanolic KOH for 30 min gave DOTA monoamide
4 in 84% and 94% yields, respectively, while hydrolysis of esters 15 and 17 under
these conditions gave the DOTA monoamide 5 in 84% and 81% yields, respectively.
CONCLUSIONS
Efficient gram-scale syntheses of the hydrobromide salts 7 and 8 have been
developed, and the procedures seem amenable to further scale–up. The first x-ray
crystal structure of hydrobromide salt 7 has been obtained. Neutralization of the
hydrobromide salts 7 and 8 with K2CO3 prior to addition of a-bromoacetamides
12 and 13 produced alkylation products 14–17 in excellent yields. Saponification
of 14–17 gave 4 and 5 in good yields. Overall, the three-step reaction sequences
starting from cyclen (9) produced DOTA monoamides 4 and 5 in 57–69% yields
based on cyclen, about three-fold greater yields than the literature syntheses of these
same compounds.[18,20] Thus, hydrobromide salts 7 and 8 can be used as alternatives
to 6 in the preparation of sets of DOTA monoamides, avoiding the synthesis
and characterization of intermediates that would result from monoalkylation of
9 followed by incorporation of three acetate arms, or of single DOTA monoamide
targets on large scales, and will be especially useful in cases where the DOTA
monoamide derivatives contain acid-sensitive moieties.
EXPERIMENTAL
[1,4,7-Tris(methoxycarbonylmethyl)]-1,4,7,10-tetraaza
cyclododecane Hydrobromide (7)
To a suspension of cyclen (1.00 g, 5.81 mmol) and sodium acetate (1.57 g,
19.17 mmol) in DMF (8 mL) at ꢀ20 ꢁC was added a solution of methyl bromo-
acetate (2.66 g, 1.70 mL, 17.43 mmol) in DMF (4 mL) drop wise over 10 min.
The temperature was maintained at ꢀ20 ꢁC during the addition, after which the
reaction mixture was allowed to come to room temperature. After 6 h of vigorous
stirring, the reaction mixture was diluted with CH2Cl2 (50 mL) and the salts were
removed by filtration. The filtrate was evaporated under reduced pressure and the
resulting oil was loaded onto a flash silica-gel column (100 g). Elution with CH2Cl2
(200 mL), followed by CH2Cl2=MeOH (95:5), gave a tan oil. Scratching of the oil
under ether at ꢀ20 ꢁC gave 7 (2.12 g, 4.53 mmol, 78%) as a white solid, mp
113–114 ꢁC, Rf 0.42 (CH2Cl2=MeOH 5:1). 1H NMR (500 MHz, CDCl3) d 2.85
(4, m), 2.91 (8, m), 3.10 (4, m), 3.42 (2, s), 3.48 (4, s), 3.69 (9, s), 9.97 (1, br s);
13C NMR (125 MHz, CDCl3) d 47.3, 48.3, 49.3, 51.4, 51.6, 57.0, 170.6, 171.4. Anal.
calcd. for C17H33BrN4O6: C, 43.50; H, 7.09; N, 11.94. Found: C, 43.25; H, 7.05;
N, 12.01.

SYNTHESIS OF DOTA DERIVATIVES
447
2-Bromo-N-(6-trityl-thiohexyl)acetamide (12)
Bromoacetyl bromide (5.75 g, 2.5 mL, 28 mmol) dropwise was added to a well
stirred, ice-cold mixture of amine 10 (5.34 g, 14 mmol) in CH2Cl2 (45 mL) and 1 N
NaOH (45 mL, 45 mmol). After 45 min, water (25 mL) was added, the layers were
separated, and the aqueous layer extracted with CH2Cl2 (3 ꢂ 25 mL). The combined
organic fractions were dried (MgSO4), filtered, and concentrated under reduced
pressure. The residue was purified by flash column chromatography on silica gel
eluted with hexanes=EtOAc (6:4) to afford 12 (6.36 g, 12.8 mmol, 92%) as a white
1
solid, mp 78–79 ꢁC, Rf 0.58 (EtOAc=hexanes 1:1). H NMR (500 MHz, CDCl3) d
1.16–1.22 (2, m), 1.23–1.29 (2, m), 1.38 (2, quintet, J ¼ 7.5 Hz), 1.48 (2, quintet,
J ¼ 7.5 Hz), 2.13 (2, t, J ¼ 7.5 Hz), 3.19–3.24 (2, m), 3.85 (2, s), 6.41 (1, s),
7.17–7.23 (3, m), 7.25–7.29 (6, m), 7.38–7.41 (6, m); 13C NMR (125 MHz, CDCl3)
d 26.3, 28.4, 28.5, 29.0, 29.3, 31.8, 40.1, 66.4, 126.5, 127.7, 129.5, 144.9, 165.0. Anal.
calcd. for C27H30BrNOS: C, 65.31; H, 6.09; N, 2.82; S, 6.46. Found: C, 64.93; H,
6.48; N, 2.52; S, 6.84.
[1,4,7-Tris(methoxycarbonylmethyl)-10-[N-(6-trityl-
thiohexyl)carbamoyl]-1,4,7,10-tetraazacyclo-dodecane (14)
Anhydrous K2CO3 (1.10 g, 8 mmol) was added to a stirred solution of 7 (0.94 g,
2 mmol) in dry CH3CN (20 mL) and the mixture was heated at 70 ꢁC. After 1 h,
heating was discontinued, bromoacetamide 12 (1.04 g, 2.1 mmol) was added, heating
was resumed, and the reaction mixture was stirred for an additional 1 h at 70 ꢁC. The
reaction mixture was cooled and filtered, and the filtrate evaporated to dryness under
reduced pressure. The residue was purified by flash column chromatography on silica
gel (100 g). Elution with MeOH=CH2Cl2 (98:2, 200 mL) followed by MeOH=CH2Cl2
(95:5) gave 14 (1.39 g, 1.74 mmol, 87%) as a white foam, Rf 0.52 (CH2Cl2=MeOH
5:1). 1H NMR (500 MHz, CDCl3) d 1.14–1.26 (4, m), 1.34–1.40 (2, quintet,
J ¼ 7.5 Hz), 1.46–1.52 (2, quintet, J ¼ 7.5 Hz), 2.15 (2, t, J ¼ 7.5 Hz), 2.20–3.30 (24,
m), 3.39 (2, s), 3.70 (6, s), 3.72 (3, m), 7.18–7.21 (3, m), 7.26–7.29 (6, m),
7.38–7.40 (6, m), 8.52 (1, m); 13C NMR (125 MHz, CDCl3) d 26.6, 28.5, 28.6,
29.2, 31.9, 39.1, 52.1, 53.3, 55.0, 56.5, 66.2, 126.3, 127.6, 129.4, 144.9, 171.6, 173.4.
HRMS (ESIþ, m=z) calculated for C44H62N5O7S 804.43645; found 804.43563.
[1,4,7-Tris(carboxymethyl)-10-[N-(6-trityl-thiohexyl)carbamoyl]-1,4,7,10-
tetraazacyclododecane (4)
The triester monoamide 14 (0.80 g, 1 mmol) was added to 1 N KOH solution
in EtOH=H2O (95:5, 20 mL) and the mixture was heated to reflux. After 0.5 h, the
solvent was removed under reduced pressure and the residue loaded onto a flash
silica-gel column. Elution with CH2Cl2 = MeOH = aqueous NH4OH (5:3:0.3) fol-
lowed by removal of solvents gave a viscous oil, which was dissolved in a minimal
amount of water and freeze-dried. By this procedure, 4 (0.64 g, 0.84 mmol, 84%)
was obtained as a white fluffy solid. The 1H NMR, 13C NMR, and mass spectra were
in agreement with results of the published procedure.[18]

448
B. JAGADISH ET AL.
Crystal Data for Hydrobromide Salt 7
C17H33N4O6Br, Mr ¼ 469.38 g molꢀ1; colorless block 0.46 ꢂ 0.17 ꢂ 0.14 mm3;
˚
T ¼ 100.31 K. MoKa, radiation (0.71073 A); space group P21=c, unit cell parameters
3
˚
˚
˚
˚
a ¼ 6.6414(12) A, b ¼ 6.6414(12) A, c ¼ 26.354(5) A, V ¼ 2445.6(7) A ; 24,826 mea-
sured reflections., 8025 unique reflections; final R1 ¼ 0.0383 (F2 > 2r), wR2 ¼
0.0822 (all data)
Supporting Information
1
Complete experimental details, H and 13C NMR spectra of compounds 7, 8,
and 12–17, and an x-ray crystallographic report for compound 7 can be found via
the Supplementary Content section of this article’s Web page.
ACKNOWLEDGMENTS
This work was supported by Grants R01-CA118359, P01-CA017094, and
P30-CA023074 from the National Institutes of Health.
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