Direct synthesis of 1,1′-[1,4-phenylenebis(methylene)]-bis-1,4,8,11- tetraazacyclotetradecane octahydrochloride (AMD 3100) without the use of protecting groups

Article abstract of DOI:10.1021/jo030146r

A four-step synthesis of the title compound starting from methyl acrylate, ethylenediamine, and dimethyl malonate is reported. The synthesis can be run on a multigram scale and is operationally simple. The use of protecting groups is avoided by utilizing

Full text of DOI:10.1021/jo030146r

desired compound in reasonable overall yield. The req-
uisite dioxocyclam starting material was prepared in very
low (10%) yield, but from very inexpensive starting
materials (ethylenediamine and dimethyl malonate).
A final approach started with the inexpensive acyclic
tetraamine N,N′-bis(3-aminopropyl)ethylenediamine and
involved selective triprotection, coupling to R,R′-dibromo-
p-xylene, ring closure, and finally removal of the six tosyl
protecting groups.8 This could be run on a reasonable
scale, but, as was the case with the tritosylated cyclam
route above, over 60% of the mass is removed in the
deprotection step.
Desiring a more direct route that did not start from
the expensive cyclam and avoided protection/deprotection
sequences, the route shown in Scheme 1 was developed
in these laboratories. Trioxocyclam 3 was synthesized by
a minor variation of a literature procedure,9 from ethyl-
enediamine, methyl acrylate, and dimethyl malonate.
With only one free secondary amine, protection of 3 was
not required for the coupling step with R,R′-dibromo-p-
xylene, which proceeded in good yield on a 30 g scale.
Reduction of the six amides to amines followed by
precipitation with HCl in methanol produced AMD 3100
(1) in overall 16% yield from methyl acrylate and 47%
yield from trioxocyclam 3.
Dir ect Syn th esis of
1,1′-[1,4-P h en ylen ebis(m eth ylen e)]-bis-
1,4,8,11-tetr a a za cyclotetr a d eca n e
Octa h yd r och lor id e (AMD 3100) w ith ou t th e
Use of P r otectin g Gr ou p s
Michal Achmatowicz and Louis S. Hegedus*
Department of Chemistry, Colorado State University,
Fort Collins, Colorado 80523
hegedus@lamar.colostate.edu
Received April 28, 2003
Abstr a ct: A four-step synthesis of the title compound
starting from methyl acrylate, ethylenediamine, and dimeth-
yl malonate is reported. The synthesis can be run on a
multigram scale and is operationally simple. The use of
protecting groups is avoided by utilizing the trioxocyclam
as the key coupling intermediate.
Bis-cyclams (14-membered tetrazamacrocycles) con-
nected by hydrocarbon linkers at one of the secondary
amine nitrogens are of current interest because of their
potential anti-HIV activity.1,2 The p-xylyl-linked bis-
cyclam AMD 3100 (1) is currently in clinical trials against
AIDS. Because of this biological activity, several synthe-
ses of 1 have appeared. Most of these involve starting
with the preformed cyclam, 1,4,8,11-tetraazacyclotetra-
decane, selectively protecting three of the four secondary
amino groups, coupling by bis amination of R,R′-dibromo-
p-xylene, and deprotecting. Protected intermediates used
include the tris-tosylamide,3 the bis-tosylamide-Boc,4 the
bis-aminal,5 and metal carbonyl,6 phosphoryl,6 thiophos-
phoryl,6 boron,6 and trimethylsilyl derivatives.6 These
approaches afford varying degrees of efficiency and
scalability but suffer from the high cost of the starting
cyclam.
This synthesis is reasonably efficient and direct, and
is operationally simple. The first purification required
was for trioxocyclam 3. A first crop of crude product
precipitated from the reaction mixture, but the mother
liquors required filtration through silica gel to remove
oligomeric material before a second crop of product could
be isolated. Compounds 4 and 1 were purified by simple
recrystallization. The route presented in Scheme 1 offers
an attractive alternative to other routes extant.
Exp er im en ta l Section
Con d en sa tion /Mich a el Ad d ition of Eth ylen ed ia m in e
w ith Meth yl Acr yla te to P r od u ce Tr ia m in e Am id e 2.
Methyl acrylate (71 mL, 0.79 mol) was slowly added to neat
ethylenediamine (0.85 L, 13 mol) with stirring. A slightly
exothermic reaction took place. The clear reaction mixture was
allowed to stand at room-temperature overnight and then was
stirred at 60 °C for 4 h. Excess ethylenediamine was removed
under reduced pressure and then under high vacuum overnight
(at room temperature) and for 1 h at 70 °C, affording pure
product 2 as clear, colorless oil (133 g, 97%): 1H NMR (CDCl3,
300 MHz) δ 7.80 (bs, 1H), 3.24 (q, J ) 5.7 Hz, 2H), 2.85 (t, J )
6.0 Hz, 2H), 2.76 (t, J ) 5.4 Hz, 4H), 2.65 (t, J ) 5.7 Hz, 2H),
2.33 (t, J ) 5.7 Hz, 2H), 1.30 (s, 5H); 13C NMR (CDCl3, 75 MHz)
δ 172.6, 52.0, 45.5, 41.9, 41.6, 41.5, 35.9; IR (film) 3275, 3068,
A related approach started with the 5,12-dioxocyclam
(1,4,8,11-tetraazacyclotetradecane-5,12-dione) in which
two of the cyclam ring nitrogens were masked as amides.7
Protection of one of the two amines as the tosyl or Boc
derivative, followed by alkylation, deprotection, and
finally reduction of the amides to amines, produced the
(1) De Clercq, E.; Yamamoto, N.; Pauwels, R.; Baba, M.; Schols, D.;
Nakashima, H.; Balzarini, J .; Debyser, Z.; Murrer, B. A.; Schwartz,
D.; Thornton, D.; Bridger, G.; Fricker, S.; Henson, G.; Abrams, M.;
Picker D.; Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 5286-5290.
(2) Bridger, G. J .; Skerlj, R. T.; Thornton, D.; Padmanabhan, S.;
Martellucci, S. A.; Henson, G. W.; Abrams, M. J .; Yamamoto, N.; De
Vreese, K.; Pauwels, R.; De Clercq, E. J . Med. Chem. 1995, 38, 366-
378.
2934, 2866, 1646, 1558, 1476, 1318 cm-1
.
Con d en sa tion of 2 w ith Dim eth yl Ma lon a te to P r od u ce
Tr ioxocycla m 3. To the triamine (66.5 g, 0.38 mol) solution in
methanol (3.8 L) was added a solution of dimethyl malonate (58
mL, 0.38 mol) in methanol (0.2 L) in one portion. A slightly
exothermic reaction took place. The resulting pinkish reaction
(3) Ciampolini, M.; Fabbrizzi, L.; Perotti, A.; Poggi, A.; Seghi, B.;
Zanobini, F. Inorg. Chem. 1987, 26, 3527-3533.
(4) Lachkar, M.; Guilard, R.; Atmani, A.; De Cian, A.; Fischer, J .;
Weiss, R. Inorg. Chem. 1998, 37, 1575-1584.
(5) Le Baccon, M.; Chuburu, F.; Toupet, L.; Handel, H.; Soibinet,
M.; De´champs-Olivier, I.; Barbier, J .-P.; Aplincourt, M. New J . Chem.
2001, 25, 1168-1174.
(8) Xu, D.; Mattner, P. G.; Prasad, K.; Repic, O.; Blacklock, T. J .;
Tetrahedron Lett. 1996, 37, 5301-5304.
(9) Kimura, E.; Koike, T.; Machida, R.; Nagai, R.; Kodama, M. Inorg.
Chem. 1984, 23, 4181-4188. This procedure differed only in the
sequence of steps and started with the reaction of ethylenediamine
with malonate, followed by reaction with methyl acrylate. Neither an
exact procedure nor a yield was reported.
(6) Gardinier, I.; Roignant, A.; Oget, N.; Bernard, H.; Yaouanc, J .
J .; Handel, H. Tetrahedron Lett. 1996, 37, 7711-7714 and references
therein.
(7) Rabiet, F.; Denat, F.; Guilard, R. Synth. Commun. 1997, 27, 979-
987.
10.1021/jo030146r CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/17/2003
J . Org. Chem. 2003, 68, 6435-6436
6435

SCHEME 1
mixture was allowed to stand at room temperature for 2 days
and was then stirred at reflux for 1 day. The reaction mixture
was concentrated under vacuum to a volume of 0.5 L, and the
resulting dark red viscous solution was allowed to stand at room
temperature for 2 days. The crude product that separated as
thick pink needles was collected by filtration (16 g). Concentrated
mother liquors were chromatographed on silica (0.40 kg; CH2Cl2/
MeOH ) 8:2) to give additional crop of crude trioxocyclam as a
pink powder (24 g). The combined crops of crude material were
recrystallized from methanol/diethyl ether to give trioxocyclam
3 as colorless crystals (32 g, 35%): mp 206-207 °C; 1H NMR
(DMSO-d6, 300 MHz) δ 8.06 (bs, 1H), 7.77 (bs, 1H), 7.65 (bs,
1H), 3.22-3.08 (m, 6H), 2.95 (s, 2H), 2.66 (t, J ) 5 Hz, 2H), 2.55
(t, J ) 4 Hz, 2H), 2.13 (t, J ) 5 Hz, 2H), 1.64 (bs, 1H); 13C NMR
(DMSO-d6, 75 MHz) δ 171.9, 166.7 (2C), 47.7, 45.4, 44.9, 38.3,
38.2, 37.3, 35.4; IR (KBr) 3314, 3078, 2940, 1677, 1633, 1436,
1358 cm-1. Anal. Calcd for C10H18N4O3: C, 49.59; H, 7.44; N,
23.14. Found: C, 49.82; H, 7.60; N, 23.33.
addition of MeOH (0.20 L). Volatiles were removed under
vacuum. The light-yellow powdery residue (21 g) was treated
with 0.6 M HCl in MeOH (0.50 L) and stirred at reflux until all
the material dissolved, giving a clear, colorless solution. Volatiles
were removed under vacuum, and the residue was redissolved
in MeOH (0.10 L) and stripped again in vacuo leaving a colorless
foam (19.3 g). This was taken up in distilled water (0.30 L),
gently warmed with stirring, and then passed through a Celite
pad to remove insoluble yellow material. The slightly cloudy
aqueous solution (0.5 L, pH 1) was washed with CH2Cl2 (2 ×
0.25 L) to remove sulfur byproducts, carefully basified using
NaOH pellets (pH > 11), and extracted once with CH2Cl2 (0.5
L). The aqueous layer was set aside. The organic solution was
dried over anhydrous Na2SO4, and the solvent was removed
under reduced pressure to afford pure bis-cyclam as a colorless
foam (6.4 g, 47%). The aqueous layer was stripped under
vacuum, and the resulting colorless material was extracted once
with CH2Cl2 (0.5 L). Subsequent drying (Na2SO4) and solvent
removal afforded an additional crop of bis-cyclam as an off-white
foam (5.4 g, 40%): 1H NMR (CDCl3, 300 MHz) δ 7.30 (s, 4H),
4.23 (bs, 6H), 3.53 (s, 4H), 2.95-2.50 (m, 32H), 1.87 (bs, 4H),
1.75 (bs, 4H); 13C NMR (CDCl3, 75 MHz) δ 137.4, 129.3, 57.8,
53.4 (2C), 50.7, 49.4, 48.9, 48.4, 47.1, 47.0, 27.0, 25.3; IR (film)
3280, 2927, 2883, 2807, 1458, 1265, 1117 cm-1. A methanolic
solution (1 L) of the free bis-cyclam (11.8 g, 23.5 mmol) was
treated with 1.3 M HCl in MeOH (0.28 L, 0.37 mol). Recrystal-
lization from hot MeOH afforded the bis-cyclam hydrochloride
salt H2O/MeOH solvate as a fine colorless powder (15.3 g, 64%):
Syn th esis of p-Xylen e-Lin k ed Bis-Tr ioxocycla m 4. To a
suspension of trioxocyclam 3 (35.5 g, 147 mmol) in MeCN (0.50
L) was added R,R′-dibromo-p-xylene (18.2 g, 68.9 mmol) followed
by diisopropylethylamine (0.13 L). The resulting suspension was
stirred at reflux (bath temperature ) 90 °C) for 42 h and then
was cooled to room temperature. The off-white precipitate was
collected on a paper filter, washed thoroughly with MeCN, and
dried in air (36.7 g). The solid was then treated with hot DMSO
(0.25 L) at which time most of the material went into solution.
After the mixture was cooled to room temperature, an orange
resinous precipitate was removed by filtration through a Celite
pad leaving a clear yellow-orange solution. This was concen-
trated to ca. 0.18 L, diluted with CH2Cl2 (0.8 L), and left at -20
°C overnight to produce colorless sand-like crystals of bis-
trioxocyclam solvate (29.6 g, 65%): mp 285 °C (dec). Anal. Calcd
for C28H42N8O6‚H2O‚0.7CH2Cl2: C, 52.02; H, 6.64; N, 16.92; Cl,
7.51. Found: C, 52.16; H, 6.70; N, 16.91; Cl, 7.75. Further crops
of pure bis-trioxocyclam 4 were obtained by recrystallization
from DMSO/MeOH (3.2 g, 8%): 1H NMR (DMSO-d6, 300 MHz)
δ 7.96 (bs, 2H), 7.83 (bs, 2H), 7.26 (bs, 2H), 7.18 (s, 4H), 3.48 (s,
4H), 3.33 (s, 4H), 3.30-3.07 (br m, 12H), 2.99 (s, 4H), 2.37 (br
m, 4H), 2.15 (br m, 4H); 13C NMR (DMSO-d6, 75 MHz) δ 171.9,
167.0, 165.6, 136.5, 128.9, 57.0, 51.6, 48.8, 45.6, 37.7, 35.6, 33.3;
IR (KBr) 3296, 3084, 2937, 2820, 1666, 1550, 1435, 1360, 1319,
1
mp 232 °C (dec); H NMR (D2O, 300 MHz) δ 7.55 (s, 4H), 4.66
(bs, 16H), 4.40 (s, 4H), 3.65-3.40 (br m, 16H), 3.40-3.20 (br m,
16H), 2.06 (br m, 8H); 13C NMR (D2O, 75 MHz) δ 132.0, 130.9,
58.6, 47.7, 44.6, 41.7, 41.1 (2C), 37.6, 37.2 (2C), 18.8, 18.3. Anal.
Calcd for C28H54N8‚9HCl‚H2O‚CH3OH: C, 39.52; H, 7.84; N,
12.72; Cl, 36.29. Found: C, 39.49; H, 7.62; N, 12.85; Cl, 36.64.
A sample of this material was dissolved in a minimal amount
of water and treated with excess methanol followed by cooling
in a freezer. This resulted in the precipitation of fine colorless
crystals of the bis-cyclam octahydrochloride trihydrate (1). Anal.
Calcd for C28H54N8‚8HCl‚3H2O: C, 39.62; H, 8.02; N, 13.21; Cl,
33.49. Found: C, 39.56; H, 7.89; N, 12.94; Cl, 33.61.
Ack n ow led gm en t. Support for this research under
Grant No. CHE-9908661 from the National Science
Foundation is gratefully acknowledged.
1258, 1152 cm-1
.
Syn th esis of AMD 3100. To a suspension of bis-trioxocyclam
solvate (18.0 g, 27.2 mmol) in dry THF (0.63 L) was slowly added
borane dimethyl sulfide complex (ca. 10 M, 0.16 L, 1.6 mol) under
argon. Once the vigorous bubbling ceased, the suspension was
stirred at reflux (bath temperature ) 80 °C) for 43 h. The
yellowish slurry was cooled to room temperature and placed in
an ice-bath, and the excess borane was destroyed by careful
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for 1-4. This material is available free of charge via
the Internet at http://pubs.acs.org.
J O030146R
6436 J . Org. Chem., Vol. 68, No. 16, 2003