Palladium-catalyzed arylation of diisopropyl malonate applied to the efficient synthesis of the selective MMP inhibitor 5-(4-phenoxyphenyl)-5-[4-(2-pyrimidinyl)-1-piperazinyl]barbituric acid

Article abstract of DOI:10.3987/COM-05-S(T)40

An efficient synthesis of the highly selective MMP inhibitor 5-(4-phenoxyphenyl)-5-[4-(2-pyrimidinyl)-1-piperazinyl]barbituric acid is reported. The title compound was prepared in three steps and 72% overall yield from 4-bromophenyl phenyl ether via an im

Full text of DOI:10.3987/COM-05-S(T)40

HETEROCYCLES, Vol. 67, No. 2, 2006
763
HETEROCYCLES, Vol. 67, No. 2, 2006, pp. 763 - 768. © The Japan Institute of Heterocyclic Chemistry
Received, 25th July, 2005, Accepted, 14th October, 2005, Published online, 14th October, 2005. COM-05-S(T)40
PALLADIUM-CATALYZED
ARYLATION
OF
DIISOPROPYL
MALONATE APPLIED TO THE EFFICIENT SYNTHESIS OF THE
SELECTIVE MMP INHIBITOR 5-(4-PHENOXYPHENYL)-
5-[4-(2-PYRIMIDINYL)-1-PIPERAZINYL]BARBITURIC
ACID
(MS
WORD STYLE “01 HET-TITLE”)
Stanley Hutchings, Wen Liu, and Roumen Radinov* (MS Word Style “02
Het-Author’s name”)
Chemical Synthesis – Process Research, Safety and Technical Sciences,
Pre-Clinical Research and Development, Hoffmann-La Roche Inc., Nutley, New
Jersey 07110, USA
roumen.radinov@roche.com
Dedicated to Professor Barry M. Trost on the occasion of his 65th birthday.(MS
Word Style “03 Het-Author’s address”)
Abstract – An efficient synthesis of the highly selective MMP inhibitor
5-(4-phenoxyphenyl)-5-[4-(2-pyrimidinyl)-1-piperazinyl]barbituric
acid
is
reported. The title compound was prepared in three steps and 72% overall yield
from 4-bromophenyl phenyl ether via an improved arylation of diisopropyl
malonate. (MS Word Style “04 Het-Abstract”)
5-(4-Phenoxyphenyl)-5-[4-(2-pyrimidinyl)-1-piperazinyl]barbituric acid (1) belongs to a barbiturate-type
of matrix metalloproteinase (MMP) inhibitors with increased selectivity for gelatinase B (MMP-9), which
has been associated with an enhanced antitumor and antimetastatic activity.1 In vitro, 1 is a more selective
inhibitor of MMP-9 over MMP-1, MMP-7 and MMP-13 than the leading candidate in this class, compound
(2),2 and ca. 2000-fold more selective than the broad-spectrum MMP inhibitor batimastat. Treatment with
1 was also more effective than 2 in reducing the number and size of macroscopic liver metastases in
T-cell lymphoma cells. Based on these results, 1 has been under consideration for the therapy of
aggressive lymphomas.

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HETEROCYCLES, Vol. 67, No. 2, 2006
O
O
NH
NH
HN
HN
O
N
O
O
O
N
N
N
N
O
N
1
2
NO2
In its original preparation, 4’-phenoxyacetophenone was converted to 1 via a Willgerodt-Kindler
rearrangement in seven steps and an overall yield of less than 30%. In the key step, condensation of methyl
4-phenoxyphenylacetate with dimethyl carbonate provided the requisite arylmalonate (4a) for the synthesis
of 5-arylbarbituric acid (5).3 Contemplating an efficient scalable synthesis of 1, we describe in this report
a more direct preparation based on the optimized coupling reaction of commercially available
4-bromophenyl phenyl ether (3) with a dialkyl malonate.
O
OR
OR
Br Pd(OAc)2 / t-Bu3P / CuF2
dialkyl malonate, t-BuONa
urea, t-BuOK
i-PrOH, reflux
O
O
O
THF, 67°C
3
4a (R = Me)
4b (R = Et)
4c (R = i-Pr)
4d (R = n-Bu)
4e (R = t-Bu)
H
O
N
O
i) NBS, DMF
NH
1
ii) N-(2-pyrimidyl)piperazine
dihydrochloride
K2CO3
O
O
5
Palladium / t-Bu3P complexes have recently been reported to catalyze the coupling of aryl bromide (3)
with diethyl malonate (2 mol% of Pd(dba)2, 4 mol% of t-Bu3P, sodium hydride as the base and THF as
the solvent at 70°C for 8 h).4 Arylmalonate (4b) was subsequently isolated by chromatography in 89%
yield on a 1 mmol scale. However, our initial evaluation indicated the reaction to be problematic upon
scale up. Incomplete conversion of 3 was generally obtained under a variety of reaction conditions,
producing a number of byproducts along with the desired arylation product (4b). The best conditions, in
our hands, required 5 mol% of palladium catalyst and an elevated temperature of ca. 100 °C in THF in a
sealed vessel in order to complete the reaction of 3 with diethyl malonate within 16 h on a 60-gram scale.
Lowering the amount of catalyst below 5 mol% led to increased amounts of byproducts.

HETEROCYCLES, Vol. 67, No. 2, 2006
765
The crude aryl malonate (4b) was submitted without purification to the condensation with urea as
previously described for the synthesis of 2.5 Then, the 5-arylbarbituric acid (5) was isolated by
crystallization in 65% yield over the two steps from 3, and the synthesis of 1 was accomplished in 49%
overall yield from 3. However, this product was found to contain ca. 300 ppm of palladium requiring
additional purification.
We, subsequently, found that the addition of a catalytic amount of copper(II) fluoride (ca. 1 equiv. to Pd)
and the use sodium tert-butoxide as the base promoted the reaction of 3 with diethyl malonate (ca. 1.2
equiv. each). This modification allowed us to reduce the P/Pd ratio to 1.3 and to lower the reaction
temperature. Thus, the bimetallic catalyst system of 4.4 mol% of palladium(II) acetate, 4.9 mol% of CuF2,
and 5.7 mol% t-Bu3P gave a clean and complete conversion of 3 to 4b at ca. 67°C in THF. The yield of
5-arylbarbituric acid (5) was consequently increased to 79%, which allowed the preparation of 1 in an
improved 64% overall yield on a 1-kg scale. However, our efforts to reduce the palladium loading further
to the 1 mol% level by changing the reaction conditions (i.e., ligand, palladium source, base, solvent,
temperature, additives etc.) once again proved unsuccessful.
Finally, a breakthrough occurred when a more sterically hindered malonate ester was employed for the
coupling with aryl bromide (3). The outcome of the reaction using malonate esters of increasing steric
bulk is presented in the Table. The lowest catalyst loading and the highest purity was achieved for
arylmalonate (4c) using diisopropyl malonate. Thus, a similar conversion was achieved with diisopropyl
malonate using only 0.56 mol% palladium loading, as compared to a 4.4 mol% palladium loading with
diethyl malonate. Dimethyl malonate was clearly inferior, and di-tert-butyl malonate did not offer any
advantage over diisopropyl malonate. Dibutyl malonate was better than diethyl but worse than
diisopropyl malonate. Based on these results, diisopropyl malonate was selected as the nucleophile of
choice for the arylation, and the synthesis of 1 was accomplished using a 1 mol% palladium loading as
described below.
A solution of 3, palladium(II) acetate (1 mol%), copper(II) fluoride (1 mol%), t-Bu3P (1.3 mol%), sodium
tert-butoxide (1.21 equiv.) and diisopropyl malonate (1.26 equiv.) was heated in THF (2 vol) to 67°C for
15 h. The reaction mixture was diluted with heptane, quenched by the addition of 3M HCl, filtered and
concentrated, and then diluted with methyl tert-butyl ether (MTBE).

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HETEROCYCLES, Vol. 67, No. 2, 2006
Table. Palladium Catalyzed Coupling Reaction with Dialkyl Matonatesa)
Product (%) in the reaction mixture as estimated by HPLC
Pd mol%
4a
-
4b
94
86
82
-
4c
4d
4e
-
4.44
2.23
1.11
0.56
0.20
-
-
23
-
97
97
95
55
94
88
82
9
-
-
-
-
-
-
52
a) Pd(OAc)2 / t-Bu3P / CuF2 (1:1.3:1), dialkyl malonate (1.26 equiv.), t-BuONa (1.21 equiv.), THF, 67°C, 16 h.
The MTBE solution was washed consecutively with 3M HCl, 1M KHCO3 and brine and concentrated.
The crude aryl malonate (4c) thus obtained, was treated with urea and potassium tert-butoxide in
isopropanol, and the crystalline barbituric acid (5) was isolated in 84% yield from 3. One-pot bromination
and amination of 5 provided 1, which was isolated by crystallization from aqueous ethanol in an
improved 72% overall yield from 3. As a result of the lower catalyst loading used in the preparation of 4c,
the heavy metal content was reduced to ca. 150 ppm in 4c, ca. 20 ppm in 5, and less than 1 ppm in 1
without additional purification.
In summary, an efficient three-step synthesis of the barbituric acid derivative (1) was achieved from
commercially available 4-bromophenyl phenyl ether (3) using an improved arylation with diisopropyl
malonate. (MS Word Style “05 Het-Text”)
EXPERIMENTAL
5-(4-Phenoxyphenyl)barbituric Acid (5). To a mixture of Pd(OAc)2 (135 mg, 0.6 mmol), CuF2 (60 mg,
0.6 mmol), t-Bu3P (90% grade, 220 µL, 0.8 mmol), t-BuONa (6.98 g, 73 mmol) and THF (30 mL) were
added consecutively 4-bromophenyl phenyl ether (3, 10.5 mL, 60 mmol) and diisopropyl malonate (14.4
mL, 76 mmol). The clear solution was heated to 67 °C for 15 h. The suspension was allowed to cool to
ambient temperature and diluted with hexane (30 mL), and then the reaction mixture was quenched by the
addition of 3M HCl (7.5 mL, 22.5 mmol). The mixture was filtered through Celite and the filter pad was
rinsed with hexane-THF 1:1 (100 mL). The combined filtrates were concentrated under reduced pressure
and the residue was dissolved in MTBE. The resulting solution was washed with 3M HCl (2x25 mL), 1M
KHCO3 (2x25 mL) and brine, dried over Na2SO4 and concentrated under reduced pressure to give 24.0 g of
crude 4c as a yellow oil. To this crude product were added urea (6.41 g, 107 mmol) and isopropanol (127
mL). The mixture was heated to 80 °C and a 1M solution of t-BuOK in THF (152 mL, 152 mmol) was
added slowly over 3 h while distilling off ca. 60 mL of solvent to maintain a reflux temperature between

HETEROCYCLES, Vol. 67, No. 2, 2006
767
78-86 °C. After the addition was complete, the mixture was heated to reflux (ca. 78-79 °C) for an
additional 14 h. The mixture was allowed to cool to ambient temperature and a mixture of conc. HCl
(14.9 mL, 178 mmol) and water (35 mL) was slowly added. The mixture was stirred for an additional 10
min, then concentrated under reduced pressure to remove the organic solvents. The resulting aqueous
mixture was diluted with water (100 mL) and the precipitate was collected by filtration and washed with
water (70 mL). The wet solid was suspended in ethyl acetate (70 mL) and the mixture was heated to
reflux for 10 min to remove residual water by azeotropic distillation, and then diluted with hexane (35
mL). After cooling to 25 °C, the solid was collected by filtration, washed with ethyl acetate – hexane 1:1
(2x40 mL) and dried by suction to give 15.0 g (84.4% yield) of 5 as a white solid.
5-(4-Phenoxyphenyl)-5-[4-(2-pyrimidinyl)-1-piperazinyl]barbituric Acid (1). A solution of 5 (10.0 g,
34 mmol) in DMF (30 mL) was cooled to 10 °C , and a solution of NBS (6.20 g, 34 mmol) in DMF (15
mL) was added over 16 min, while maintaining the temperature of the reaction mixture between 5 and
10 °C. The addition funnel was rinsed with DMF (5 mL) and the rinse was added to the reaction mixture.
After stirring at 5-10 °C for 20 min, 1-(2-pyrimidyl)piperazine dihydrochloride (8.08 g, 34 mmol) was
added in one protion, followed by potassium carbonate (9.34 g, 68 mmol). After stirring for 1 h at
5-10 °C, the mixture was allowed to warm to 25 °C and then stirred for an additional 20 h. The mixture
was diluted with ethyl acetate (25 mL) and a solution of citric acid (6.49 g, 34 mmol) in water (75 mL)
was added slowly, while maintaining the temperature at 24-28 °C. After completion of the addition, the
organic phase was separated, and the aqueous phase was extracted with ethyl acetate (2x35 mL). The
combined organic extracts were washed with water (50 mL), and the solvent was exchanged with ethanol
by distillation (bp 77 °C). The solution was concentrated to ca. 40 mL and water (10 mL) was added. The
mixture was heated to reflux for 5 min, and then allowed to cool to 20 °C over 40 min. The solid was
collected by filtration, washed with 70% aq ethanol (2x25 mL) and dried by suction. The resulting solid
was further dried at 56 °C/70 mmHg to give 13.2 g (85.3% yield) of 1 as an off-white solid.
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(MS Word Style “07 Het-Reference”)
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