A new synthesis of the GPIIb/IIIa receptor antagonist SB-214857-A

Article abstract of DOI:10.1016/S0040-4039(01)00843-7

A new synthesis of lotrafiban SB-214857-A is reported. The key steps are the preparation of racemic (4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-2-yl)-acetic acid methyl ester from 2-nitrobenzyl alcohol, a resolution using an immobilised li

Full text of DOI:10.1016/S0040-4039(01)00843-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4915–4917
A new synthesis of the GPIIb/IIIa receptor antagonist
SB-214857-A
Ian P. Andrews, Richard J. Atkins, Neil F. Badham, Richard K. Bellingham, Gary F. Breen,
John S. Carey,* Stephen K. Etridge, Jerome F. Hayes, Nigel Hussain, David O. Morgan,
Andrew C. Share, Stephen A. C. Smith, Timothy C. Walsgrove and Andrew S. Wells
Synthetic Chemistry, GlaxoSmithKline Pharmaceuticals, Old Powder Mills, Tonbridge, Kent TN11 9AN, UK
Received 1 May 2001; revised 4 May 2001; accepted 17 May 2001
Abstract—A new synthesis of lotrafiban SB-214857-A is reported. The key steps are the preparation of racemic (4-methyl-3-oxo-
2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-2-yl)-acetic acid methyl ester from 2-nitrobenzyl alcohol, a resolution using an
immobilised lipase enzyme and a palladium-catalysed aminocarbonylation reaction. © 2001 Elsevier Science Ltd. All rights
reserved.
SB-214857-A (lotrafiban) 1 is a potent non-peptidic
glycoprotein IIb/IIIa antagonist and consequently
inhibits platelet aggregation ex vivo.1,2 Previous synthe-
reduction, however, hydrogenation using Raney-Nickel
as catalyst led to clean and selective nitro reduction to
an intermediate aniline. This intermediate aniline was
not isolated and subsequent treatment with mild acid
caused cyclisation to the tetrahydroquinazoline 6. Con-
version of tetrahydroquinazoline 6 to benzodiazepine 7
could be achieved under a variety of different basic
conditions such as DBU in ethyl acetate, but the pre-
ferred conditions used sodium methoxide in methanol.
This particular reaction is thought to proceed via a
retro-Michael reaction and then lactam formation. Ben-
zodiazepine 7 was isolated as a single double bond
ses of SB-214857-A starting from
L
-aspartic acid3–5
have been reported. In this letter we report an alterna-
tive enantioselective synthesis of 1 in which the key
intermediate, racemic 1,4-benzodiazepine ester 2, is pre-
pared from 2-nitrobenzyl alcohol 3 using a novel tetra-
hydroquinazoline
to
diazepine
rearrangement.
Enzyme-catalysed resolution of 2 followed by function-
alisation at C-7 of the aromatic ring enabled a palla-
dium-catalysed
aminocarbonylation
process
to
complete the synthesis (Scheme 1).6
isomer as shown, with the geometry determined by H
1
NMR. Hydrogenation of 7 over palladium on carbon
gave the key intermediate 2. Overall 2 could be pre-
pared from 3 in 77% yield and if required without
isolation of any intermediates.
The preparation of the racemic 1,4-benzodiazepine ester
2 is outlined in Scheme 2. 2-Nitrobenzyl alcohol 3 was
converted to the sulfonate ester and then displacement
with aqueous methylamine gave 4. Reaction of 4 with
dimethyl acetylenedicarboxylate gave the intermediate
nitro-alkene 5. Attempted reduction of the nitro group
of 5 over palladium on carbon led to partial alkene
Resolution of the racemic 1,4-benzodiazepine ester 2
could be achieved using Candida antarctica lipase B
(supplied as Novozym 435 resin) which selectively
Scheme 1. Strategy for the synthesis of SB-214857-A 1.
Keywords: asymmetric synthesis; benzodiazepine; carbonylation; enzyme reaction; epimerisation; hydrogenation.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00843-7

4916
I. P. Andrews et al. / Tetrahedron Letters 42 (2001) 4915–4917
Scheme 2. Preparation of the racemic 1,4-benzodiazepine ester 2. (i) MsCl, NEt3, THF, rt; (ii) MeNH2, H2O, rt; (iii) dimethyl
acetylenedicarboxylate, PhMe, rt; (iv) H2, Raney-Ni, MeOH, 50 psi, 50°C; (v) AcOH, MeOH, 65°C; (vi) NaOMe, MeOH, 65°C;
(vii) H2, Pd/C, MeOH, 60 psi, 60°C.
hydrolysed the (S)-enantiomer to the corresponding
acid 9, addition of ammonia solution to maintain the
pH 7.0 enhanced the rate of reaction7 (Scheme 3). With
a chemical conversion of 48% the acid 9 was obtained
in 99.5% e.e., as determined by chiral HPLC. At the
end-point of the reaction the Novozym 435 was
removed by filtration and the unreacted (R)-ester 8 was
obtained in 42% yield by crystallisation from aqueous
sodium bicarbonate solution. Typically the acid 9 was
not isolated but the aqueous solution used directly in
the next reaction, which was the electrophilic iodination
at C-7. A range of iodinating reagents8 were studied for
the conversion of 9 to 10, from which pyridine iodine
monochloride complex9 was selected. Maintaining the
reaction at pH 7.0 using sodium hydroxide solution
catalytic sodium methoxide in methanol or DBU. The
key to success was the use of dimethyl carbonate as
either solvent or as co-solvent with toluene. Treatment
of 8 with catalytic sodium methoxide in dimethyl car-
bonate produced racemic ester 2 in 87% isolated yield
after 4 h at 50°C. The exact role of the dimethyl
carbonate is not clear, but its inclusion proved to be
essential. The efficient recovery and a single recycling of
the unreacted ester 8 effectively increased the yield of
iodo-acid 10 from racemic ester 2 to 60%.
The next key reaction was the palladium-catalysed
aminocarbonylation of aryl iodide 10 with 4,4%-bipipe-
ridine. This reaction was attempted under a wide vari-
ety of reaction conditions, although the required
product 1 was obtained, a considerable amount of
unwanted by-product arising from the addition of two
molecules of 10 to one of 4,4%-bipiperidine was always
obtained. To overcome this problem, a range of pro-
tected 4,4%-bipiperidines were studied. Although the
mono N-BOC 4,4%-bipiperidine3,4,10 and mono N-CBZ
4,4%-bipiperidine11 could be prepared and utilised, the
low yielding formation from 4,4%-bipiperidine precluded
their use here. The solution came in the form of 4,4%-
pyridylpiperidine 13,12 which could be selectively pre-
pared by the partial hydrogenation of 4,4%-bipyridine 12
gave
a
totally regioselective iodination and no
unwanted over oxidation by-products. Iodo-acid 10 was
isolated in 38% yield (over two steps) by crystallisation
from aqueous acid, this procedure increased the chiral
purity to 99.9% e.e., as determined by chiral capillary
electrophoresis. Recycling of the unreacted (R)-ester 8
to the racemic ester 2 was not straightforward. No
epimerisation at C-2 was observed when 8 was treated
under acidic conditions such as acetic acid or HCl in
methanol. Likewise no epimerisation was observed by
the treatment of 8 under typical basic conditions, e.g.
Scheme 3. Preparation of SB-214857-A 1. (i) Novozym 435, t-BuOH, H2O, NH3, pH 7.0, 50°C; (ii) pyridineiodine monochloride
complex, H2O, NaOH, pH 7.0, 10°C; (iii) NaOMe, MeOH, (MeO)2CO, 50°C; (iv) PdCl2(PPh3)2, CO, 13, anisole, dicyclohexyl-
amine, 15 psi, 100°C; (v) H2, Pd/C, iso-propanol, H2O, 60 psi, 75°C; (vi) C5H5N·HCl, EtOH, CH2Cl2, H2O, 40°C.

I. P. Andrews et al. / Tetrahedron Letters 42 (2001) 4915–4917
4917
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We are grateful to Richard Escott and Kaye Cat-
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.