A practical synthesis of cabergoline

Article abstract of DOI:10.1021/jo0203847

Cabergoline is an N-acylurea derived from 9,10-dihydrolysergic acid, which is a potent prolactin inhibitor. It is marketed by Pharmacia as Dostinex for the treatment of hyperprolactinemia and is currently under active development for the treatment of a variety of CNS disorders. In the existing process, the N-acylurea is formed by the reaction of an amide with a large excess of ethyl isocyanate at elevated temperatures. An improved process was developed that eliminates this hazardous reaction. The amide is reacted with phenyl chloroformate and then with ethylamine, which provides a mild and efficient means of forming the unsymmetrical N-acylurea.

Full text of DOI:10.1021/jo0203847

SCHEME 1
A P r a ctica l Syn th esis of Ca ber golin e
Scott W. Ashford, Kevin E. Henegar,*
Andrew M. Anderson, and Peter G. M. Wuts
Chemical Process Research and Development,
1500-91-201, Pharmacia Corporation, 7000 Portage Road,
Kalamazoo, Michigan 49001
kevin.e.henegar@pharmacia.com
Received J une 5, 2002
Abstr a ct: Cabergoline is an N-acylurea derived from 9,10-
dihydrolysergic acid, which is a potent prolactin inhibitor.
It is marketed by Pharmacia as Dostinex for the treatment
of hyperprolactinemia and is currently under active develop-
ment for the treatment of a variety of CNS disorders. In the
existing process, the N-acylurea is formed by the reaction
of an amide with a large excess of ethyl isocyanate at
elevated temperatures. An improved process was developed
that eliminates this hazardous reaction. The amide is
reacted with phenyl chloroformate and then with ethyl-
amine, which provides a mild and efficient means of forming
the unsymmetrical N-acylurea.
Previous work at Pharmacia showed that catalysis by
CuCl permitted the ethyl isocyanate reaction to be run
at rt with only 3 equiv of ethyl isocyanate.2 With
appropriate choice of phosphine or nitrogen ligands, the
ratio of 1/3/4 can be varied to produce the desired product
in abundance. Under optimum conditions (1:1 CuCl and
Ph3P), an 82:6:12 mixture of 1/3/4 was obtained. How-
ever, despite the moderation in reaction conditions with
CuCl catalysis, conversion to product is low (about 80%)
and the optimum product distribution and conversion are
not much different from the uncatalyzed thermal reac-
tion.
Methods for the preparation of N-acylureas are limited.
Acylation of ureas3 or carbodiimides4 provides access to
these types of compounds, but these approaches are
limited in utility to compounds symmetrically substituted
on the urea nitrogens since acylation of unsymmetrical
ureas or carbodiimides gives mixtures of both regioiso-
meric products. This approach was used in the original
synthesis of cabergoline and proceeds with poor selectiv-
ity.1 N-Acylureas have also been obtained from the
reactions of alkynyl-9-BBN derivatives with isocyanates,5
from acylium salts with isocyanates,6 and as byproducts
in the formation of amides from carbanions and isocy-
anates.7
Natural ergot alkaloids and various synthetic deriva-
tives exhibit a wide range of biological activity, and a
number of them have potent dopamine agonist properties
with applications as anti-Parkinson drugs and as pro-
lactin inhibitors. Cabergoline was prepared as part of a
program at Pharmacia to examine a series of amides
derived from 9,10-dihydrolysergic acid and was found to
be a potent long-lasting prolactin inhibitor.1 It is cur-
rently marketed by Pharmacia as Dostinex for the
treatment of hyperprolactinemia and is also being inves-
tigated for the management of Parkinson’s disease and
a number of other CNS disorders.
Cabergoline contains an unusual N-acylurea function-
ality appended to the C-8 carboxylic acid of N-allyldihy-
drolysergic acid (cabergolinic acid). In the current syn-
thetic process, this group is introduced by the reaction
of the amide 2 with ethyl isocyanate (Scheme 1). Al-
though this process provides a direct method for the
preparation of cabergoline, it has a number of drawbacks,
the most serious of which is the use of hazardous ethyl
isocyanate at elevated temperatures. Since this reaction
is an equilibrium, it requires the use of a large excess of
ethyl isocyanate (up to 40 equiv) for reasonable conver-
sion and must be conducted at 100 °C in toluene, 40 °C
above the boiling point of ethyl isocyanate. The use of
large quantities of toxic ethyl isocyanate under drastic
reaction conditions presents a serious safety hazard for
the large-scale preparation of cabergoline. In addition to
the safety-related issues, conversion to 1 is incomplete
and competitive acylation of the indole nitrogen to give
compounds 3 and 4 is a serious side reaction that reduces
yield and complicates product purification.
With increasing demand for cabergoline, safer and
more efficient alternatives to the current chemistry were
(2) Candiani, I.; Cabri, W.; Zarini, F.; Bedeschi, A.; Penco, S. Synlett
1995, 605-606.
(3) (a) Weisz, I. Hung. Patent 49848; Chem. Abstr. 1990, 113,
171518. (b) Dmitrichenko, M. Y.; Rozinov, V. G.; Donskikh, V. I.;
Ratovskii, G. V.; Sergienko, L. M.; Dolgushin, G. V.; Valeev, R. B. Zh.
Obshch. Khim. 1988, 58, 2252-2261. (c) Yamada, K.; Kishikawa, K.;
Kohmoto, S. Chem. Lett. 1988, 351-352. (d) Panzeri, A.; Ceriani, L.;
Griggi, P.; Nesi, M. Eur. Patent 523668; Chem. Abstr. 1993, 118,
234337. (e) Panzeri, A.; Nesi, M.; DiSalle, E. Wo. Patent 9220700;
Chem. Abstr. 1993, 118, 124875.
(4) (a) Corriu, R. J . P.; Gerard, F. L.; Perot-Petta, M. Synthesis 1991,
954-958. (b) Anglada, J . M.; Campos, T.; Camps, F.; Moreto, J . M.;
Pages, L. J . Heterocycl. Chem. 1996, 33, 1259-1270. (c) Zimmermann,
D. M.; Olofson, R. A. Tetrahedron. Lett. 1970, 3453-3456.
(5) Singaram, B.; Molander, G. A.; Brown, H. C. Heterocycles 1981,
15, 231-236.
(1) Brambilla, E.; Di Salle, E.; Briatico, G.; Mantegani, S.; A.
Temperilla, A. Eur. J . Med. Chem. 1989, 24, 421-426.
(6) Hamed, A.; Ismail, A.; Hitzler, M. G.; J ochims, J . C. J . Prakt.
Chem./ Chem.-Ztg. 1995, 337, 385-390.
10.1021/jo0203847 CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/12/2002
J . Org. Chem. 2002, 67, 7147-7150
7147

SCHEME 2
presence of DMAP gives the BOC-protected indole 9 in
essentially quantitative yield with high selectivity for
reaction at the indole nitrogen.9 Although amides are
reported to react with BOC2O under similar conditions,10
even after refluxing with several equivalents of BOC2O
for extended times, only trace amounts of the products
arising from acylation of the amide nitrogen are obtained.
Silyl protection of the indole nitrogen was also investi-
gated, but although both TMS and the more stable TIPS
groups could be installed, they proved to be too labile in
subsequent chemistry.
Extension of the amide side chain is done by deproto-
nation of 9 with NaHMDS followed by trapping the anion
with phenyl chloroformate to yield the phenyl carbamate
10. A survey of bases showed the highest conversion to
product with NaHMDS or KHMDS. Conversions were
significantly higher, and reactions were cleaner with
these bases than with the other bases examined, n-
butyllithium, LDA, or potassium tert-butoxide. Under the
optimized conditions, 1.3 equiv of NaHMDS and 1.3 equiv
of phenyl chloroformate are used for this conversion and
give the product 10 in >95% yield.
The penultimate step, formation of BOC-cabergoline
11, was the most problematic step in the synthesis.
Reaction of 10 with ethylamine gives BOC-cabergoline
11 but also generates significant amounts of the ethyla-
mide 12. Little difference was seen between ethylamine
and ethylamine HCl; the HCl salt is preferred since it is
easier to control reaction stoichiometry. The amount of
12 formed is solvent dependent. Of the solvents examined
(DMF, THF, CH2Cl2, IPA, CH3CN, Et3N, and pyridine),
very little ethylamide formation occurred in IPA or CH3-
CN. IPA proved to be the superior solvent since these
reactions were homogeneous throughout and reactions
were cleaner than in acetonitrile. Five equivalents of
ethylamine HCl was the optimum amount, and larger
amounts did not cause a faster reaction. Control reactions
show that BOC-cabergoline does not react with ethyl-
amine. Purification of the product obtained in 2-propanol
proved to be unnecessary, and the crude product can be
used directly in the deprotection reaction.
The deprotection was initially done with TFA at rt, but
these conditions were not well tolerated by the substrate,
producing tars on scale-up. No significant conversion to
cabergoline was observed with weaker organic acids
(acetic, dichloroacetic, trichloroacetic, and formic acid) at
rt. Reactions run at 50 °C in methanol with anhydrous
HCl gave product, but the reaction was not clean. It was
found that the BOC group is readily removed by reaction
with 1 N aqueous hydrochloric acid at 80 °C. Because of
the basic nitrogen functionality, both 11 and cabergoline
are fully soluble under these conditions. The reaction
requires about 30-60 min for completion, and control
reactions showed that cabergoline is stable to these
conditions. No external nucleophile is needed to trap the
tert-butyl cation that presumably forms in the deprotec-
tion; the large excess of water evidently serves this
purpose. The product is then isolated by basification with
ammonium hydroxide and extraction into ethyl acetate.
investigated. A number of convergent methods for pre-
paring the ureide functionality from cabergolinic acid or
the methyl ester were examined, but these were univer-
sally unsuccessful. For example, a number of monopro-
tected unsymmetrical ureas (5, R ) trityl, BOC, trifluoro-
acetyl) were prepared, but these were unreactive toward
acylation with activated forms of cabergolinic acid (Scheme
2, X ) Cl, OCO(O-isobutyl)) or cabergolinic acid methyl
ester. Attempts at alkylating the ureide 6 (easily pre-
pared from ethylurea, cabergolinic acid methyl ester, and
potassium tert-butoxide) with various dimethylamino-
propylamine derivatives (7, X ) Cl, Br, OTs) proceeded
poorly due to low reactivity of the ureide and the
formation of multiple N- and O-alkylated products.
We now report a novel ethyl isocyanate-free method
for the preparation cabergoline. The starting point for
process development is cabergolinic acid methyl ester (8).1
Amidation of the ester is accomplished by reaction with
N,N-dimethylaminopropylamine in ethylene glycol at 100
°C with catalytic 2-hydroxypyridine8 (Scheme 3). The
amide 2 is obtained in 82% yield after extraction into
methylene chloride followed by crystallization. These
conditions are superior to the previous conditions used
for this transformation, heating the ester with 10 equiv
of dimethylaminopropylamine at 110 °C with acetic acid
as a catalyst. Reaction under these conditions required
>24 h for completion, and the product was isolated by
precipitation from water. Without a catalyst, the ami-
dation reaction is very slow and 2-hydroxypyridine was
found to be a more efficient catalyst than acetic acid,
allowing the reaction to be completed in <12 h. Crystal-
lization from toluene yields an easily handled crystalline
solid, rather than the slow-drying amorphous solid
obtained by water precipitation.
Many of the problems with the exiting ethyl isocyanate
process result from competing reaction with the indole
nitrogen. Protection of the indole nitrogen would elimi-
nate these competing pathways. A number of protecting
groups were examined, and it was found to be best
accomplished by protection as the tert-butyl carbamate.
Reaction of amide 2 with di-tert-butyl dicarbonate in the
(7) (a) Peters, O.; Debaerdemaeker, T.; Friedrichsen, T. J . Chem.
Soc., Perkin Trans. 1 1999, 59-70. (b) Haut, S. A.; Comes, R. A. U.S.
Patent 4366317; Chem. Abstr. 1983, 98, 179686.
(9) Grehn, L.; Ragnarsson, U. Angew. Chem., Int. Ed. Engl. 1984,
23, 296-301.
(10) Grehn, L.; Gunnarsson, K.; Ragnarsson, U. J . Chem. Soc.,
Chem. Commun. 1985, 1317-1318.
(8) Openshaw, H. T.; Whittaker, N. J . Chem. Soc. C 1969, 89-91
7148 J . Org. Chem., Vol. 67, No. 20, 2002

SCHEME 3
pound 2 (30.17 g, 79.3 mmol), di-tert-butyl dicarbonate (20.78
g, 95.1 mmol), and 4-(dimethylamino)pyridine (1.45 g, 11.90
mmol) were dissolved in THF (120 mL). The reaction was stirred
at 40 °C for 2 h, EtOAc (240 mL) and H2O (100 mL) were added,
and the phases were separated. The organic layer was washed
with saturated aqueous NaCl solution (20 mL) and H2O (2 × 50
mL). The combined aqueous layers were extracted with EtOAc
(1 × 25 mL). The ethyl acetate solutions were combined, dried
over Na2SO4, filtered, and concentrated to a thick oil. Toluene
(3 × 150 mL) was added to the oil and distilled to remove
residual tert-butyl alcohol. The toluene was displaced with
successive heptane distillations to give 9 as a viscous oil (34.94
g, 92% yield): 1H NMR (400 MHz, CDCl3) δ 1.66 (s, 12H), 2.24
(s, 6H), 2.40-2.88 (m, 8H), 3.21 (m, 1H), 3.38 (m, 4H), 3,54 (m,
1H) 5.19 (d, J ) 10.2 Hz, 1H), 5.25 (d, J ) 16.8 Hz, 1H), 5.95
(m, 1H), 7.05 (d, J ) 7.6 Hz, 1H), 7.26 (m, 2H), 7.63 (s, 1H),
7.77 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 25.46, 26.31, 28.16,
30.89, 39.87, 40.13, 43.54, 45.42, 55.58, 56.34, 59.17, 63.05, 83.20,
113.02, 116.32, 116.83, 118.44, 119.19, 125.15, 128.33, 133.08,
133.43, 173.32; HRMS (FAB) m/e calcd for C28H40N4O3 481.3178
(M + H)+, found 481.3181 (M + H)+.
ter t-Bu t yl (5R,8R,10R)-6-Allyl-8-[[[3-(d im et h yla m in o)-
p r op yl](p h en oxyca r bon yl)a m in o]ca r bon yl]er golin e-1-ca r -
boxyla te (10). Compound 9 (34.94 g, 72.7 mmol) was dissolved
in THF (175 mL) and cooled to -40 °C. A solution of NaHMDS
in THF (1.0 M, 94.6 mL, 94.6 mmol) was added dropwise, and
the reaction was stirred for 15 min at -40 °C. Phenyl chloro-
formate (11.86 mL, 94.6 mmol) was added slowly, and the
reaction was stirred at -40 °C for 30 min and then warmed
slowly to rt. EtOAc (350 mL) and H2O (100 mL) were added,
and the layers were separated. The organic layer was dried over
Na2SO4, filtered, and concentrated to a thick dark red oil (57.1
g). The crude oil was used without purification in the ethylamine
reaction. A portion of the product was purified by chromatog-
raphy on silica eluting with acetone to give the product as a
slightly yellow gum: 1H NMR (400 MHz, CDCl3) δ 1.65 (s, 10H),
Chromatography on silica yields the purified product.
Isolated crude yields are essentially quantitative, and
yields after chromatography are about 78%.
An improved synthesis of cabergoline has been dem-
onstrated. The current inefficient and hazardous ethyl
isocyanate reaction has been replaced by a process
involving formation of a phenyl carbamate followed by
reaction with ethylamine to generate the N-acylurea. An
efficient protection-deprotection sequence gives the prod-
uct with high regioselectivity, and the entire process can
be run without purification of the intermediates.
Exp er im en ta l Section
(5R,8R,10R)-6-Allyl-N-[3-(dim eth ylam in o)pr opyl]er golin e-
8-ca r boxa m id e (2). Compound 8 (30.0 g, 96.6 mmol), 2-hy-
droxypyridine (2.76 g, 28.9 mmol), and N,N-dimethylaminopro-
pylamine (49.37 g, 60.80 mL, 483.2 mmol) were combined and
stirred at rt. Ethylene glycol (26.90 mL) was added, and the
reaction was heated at 100 °C for 18 h. The mixture was cooled
to 50 °C, and H2O (100 mL) was added. CH2Cl2 (200 mL) was
added to dissolve the product. The organic phase was separated
and dried over Na2SO4. The CH2Cl2 was replaced with toluene
by distillation. On cooling the product crystallized. After cooling
to 0 °C, the product was filtered and dried on a nitrogen press
(31.3 g, 85% yield): 1H NMR (400 MHz, CDCl3) δ 1.66 (m, 3H),
2.25 (s, 3H), 2.4-2.8 (m, 7H), 3.29 (m, 1H), 3.25 (d, J ) 11.2 Hz,
1H), 3.41 (m, 3H), 3.45 (m, 4H), 3.6 (m, 1H), 5.19 (d, J ) 10.2
Hz, 1H), 5.25 (d, J ) 16.3 Hz, 1H), 5.98 (m, 1H), 6.90 (m, 2H),
7.16 (m, 2H), 7.59 (s, 1H), 8.18 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 25.46, 26.67, 30.99, 39.97, 40.53, 43.68, 45.45, 55.67,
56.48, 59.28, 63.57, 108.66, 111.66, 113.05, 117.86, 118.38,
123.00, 126.08, 132.91, 133.32, 133.65, 173.59.
ter t-Bu t yl (5R,8R,10R)-6-Allyl-8-[[[3-(d im et h yla m in o)-
p r op yl]a m in o]ca r bon yl]er golin e-1-ca r boxyla te (9). Com-
J . Org. Chem, Vol. 67, No. 20, 2002 7149

1.89 (m, 2H), 2.24 (s, 6H), 2.37 (t, J ) 7.1 Hz, 2H), 2.57 (m, 3H),
2.93 (m, 2H), 3.33 (m, 3H), 3.52 (m, 1H), 3.96 (m, 3H), 5.17 (d,
J ) 10.2 Hz, 1H), 5.24 (d, J ) 17.3 Hz, 1H), 5.94 (m, 1H), 7.04
(d, J ) 7.6 Hz, 1H), 7.23 (m, 5H), 7.42 (t, J ) 7.6 Hz, 2H), 7.76
(s, 1H); 13C NMR (100 MHz, CDCl3) δ 26.33, 26.98, 28.10, 28.18,
31.43, 39.82, 43.46, 43.62, 45.41, 55.48, 56.01, 57.08, 63.38, 83.15,
113.00, 116.51, 116.97, 118.08, 119.13, 121.40, 125.11, 126.31,
128.37, 129.51, 129.58, 129.62, 129.65, 133.14, 133.99, 150.10,
150.27, 153.05, 177.18; HRMS (FAB) m/e calcd for C35H44N4O5
601.3390 (M + H)+, found 601.3394 (M + H)+. Anal. Calcd for
C35H44N4O5: C, 69.97; H, 7.38; N, 9.33. Found: C, 70.07; H, 7.38;
N, 9.37.
ter t-Bu t yl (5R,8R,10R)-6-Allyl-8-[[[3-(d im et h yla m in o)-
p r op yl][(eth yla m in o)ca r bon yl]a m in o]ca r bon yl)er golin e-
1-ca r boxyla te (11). Compound 10 (43.70 g, 72.7 mmol) was
dissolved in 2-propanol (220 mL). Ethylamine HCl (29.7 g, 36.4
mmol) was added, and the reaction was heated to 50 °C. After
18 h, the excess ethylamine HCl was precipitated with EtOAc
(440 mL) and collected by filtration. The organic layer was
extracted with a 1:1 solution of H2O and saturated NaCl (3 ×
200 mL) and dried over Na2SO4. The yellow solution was
concentrated to a thick oil (43.6 g) and used without purification
in the next step. A portion of the product was purified by
chromatography on silica eluting with acetone and then with
99:1 (v/v) acetone/TEA to give the product as a slightly yellow
gum: 1H NMR (400 MHz, CDCl3) δ 1.19 (t, J ) 7.1 Hz, 3H),
1.73 (s, 9H), 1.85 (m, 2H), 2.24 (s, 6H), 2.34 (m, 2H), 2.60 (m,
3H), 2.80 (m, 1H), 2.94 (m, 1H), 3.16 (d, J ) 11.2 Hz, 1H), 3.3-
3.5 (m, 7H), 3.83 (m, 2H), 5.2 (d, J ) 10.2 Hz, 1H), 5.25 (d, J )
16.8 Hz, 1H), 5.95 (m, 1H), 7.05 (d, J ) 7.1 Hz, 1H), 7.27 (m,
2H), 7.77 (s, 1H), 9.45 (s, 1H); 13C NMR (100 MHz, CDCl3) δ
14.68, 26.32, 28.16, 29.23, 31.23, 35.39, 39.72, 42.18, 43.24, 44.84,
55.59, 56.01, 63.25, 83.18, 113.05, 116.32, 116.91, 118.36, 119.18,
125.15, 128.30, 132.94, 133.67, 150.05, 177.54; HRMS (FAB)
m/e calcd for C31H45N5O4 552.3549 (M + H)+, found 552.3546
(M + H)+.
N-[[(5R,8R,10R)-6-Allyler golin -8-yl]ca r b on yl]-N-[3-(d i-
m eth yla m in o)p r op yl]-N′-eth ylu r ea (1). Compound 11 (40.13
g, 72.7 mmol), H2O (200 mL), and 1 M aqueous hydrochloric acid
(182 mL, 182 mmol) were combined and heated to 80 °C for 1 h.
EtOAc (300 mL) was added to the light yellow solution. The pH
was adjusted to 10 with concentrated NH4OH (30 mL). The
organic phase was separated and extracted with H2O (2 × 100
mL). The aqueous layer was extracted with EtOAc (1 × 100 mL),
and the combined organic layer was dried over Na2SO4, filtered,
and concentrated to an amorphous solid. Cabergoline was
isolated in 94% yield (55% chemical yield overall from 8 in high
purity (99 area % by HPLC): 1H NMR (CDCl3) δ 1.18 (t, J )
7.1 Hz, 3H), 1.76 (m, 2H), 1.85 (m, 2H), 2.23 (s, 6H), 2.34 (m,
2H), 2.53-2.84 (m, 4H), 2.98 (m, 1H), 3.17 (m, 1H), 3.29-3.44
(m, 4H), 3.55 (m, 1H), 3.83 (m, 2H), 5.19 (d, J ) 10.2 Hz, 1H),
5.25 (d, J ) 16.8 Hz, 1H), 5.95 (m, 1H), 6.87 (m, 2H), 7.14 (m,
2H), 8.88 (s, 1H), 9.45 (s, 1H); 13C NMR (100 MHz, CDCl3) δ
14.7, 26.61, 31.31, 35.41, 40.04, 42.23, 43.21, 44.93, 55.61, 56.10,
63.74, 108.7, 111.58, 113.10, 117.88, 118.36, 122.98, 126.02,
132.67, 133.31, 133.83, 177.89.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 1, 2, 9, 10, and 11. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O0203847
7150 J . Org. Chem., Vol. 67, No. 20, 2002